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Muscular dystrophy has deficient stem cell dystrophin

Posted in Biological Networks, Ca2+ triggered activation, Ca2+ triggered activation, Cell Biology, Signaling & Cell Circuits, Clinical Genomics, Curation, Developmental biology, Disease Biology, Gene Regulation, Genetics & Innovations in Treatment, Genetics & Pharmaceutical, Genome Biology, Inflammasome, Interviews with Scientific Leaders, Investment in Technological Breakthrough, MS, Neurodegenerative Diseases, Neurohumoral Transmission, Neurological Diseases, Neuroscience, Pharmaceutical Analytics, Pharmaceutical Discovery, Population genetics, Proteins, Proteomics, Regenerative Biology and Medicine, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Skeletal muscle regeneration, Stem Cells for Regenerative Medicine, tagged blocking cell differentiation, Ca2+-regulation, Clinical trial, dystrophin, genomic expression, Muscular dystrophy, skeletal and cardiomyocyte, Stem cell on November 21, 2015| Leave a Comment »

Muscular dystrophy has deficient stem cell dystrophin

Larry H. Bernstein, MD, FCAP, Curator

LPBI

Article ID #198: Muscular dystrophy has deficient stem cell dystrophin. Published on 11/21/2015

WordCloud Image Produced by Adam Tubman

Dystrophin Deficient Stem Cell Pathology

Muscular Dystrophy is a Stem Cell-Based Disease

November 19, 2015 by mburatov

https://beyondthedish.wordpress.com/2015/11/19/muscular-dystrophy-is-a-stem-cell-based-disease/

Michael Rudnicki, who has done pioneering work in muscle stem cell biology and muscle regeneration, and whose work has been featured several times on this blog, has struck again. Rudnicki, who serves as director of the Regenerative Medicine Program at The Ottawa Hospital and a professor at the University of Ottawa and holds the prestigious Canada Research Chair in Molecular Genetics, teamed up with workers from the Sprott Centre for Stem Cell Research and the Sinclair Centre for Regenerative Medicine to investigate the role of muscle-specific stem cells in patients who suffer from Duchenne muscular dystrophy. This new earth-shaking study, which was published in the journal Nature Medicine (November 16, 2015), has changed the way we think about muscular dystrophy and will almost certainly force people to rethink the treatments and cures for this dreadful disease.

According to this new study, Duchenne muscular dystrophy directly affects muscle stem cells, and is, largely a disease of muscle stem cells.

Rudicki said: “For nearly 20 years, we’ve thought that the muscle weakness observed in patients with Duchenne muscular dystrophy is primarily due to problems in their muscle fibers, but our research shows that it is also due to intrinsic defects in the function of their muscle stem cells. This completely changes our understanding of Duchenne muscular dystrophy and could eventually lead to far more effective treatments.”

Muscular dystrophy comes in several different forms, but the predominant sign of muscular dystrophy is progressive muscle weakness. Altogether, muscular dystrophy refers to a group of more than 30 genetic diseases, all of which cause progressive weakness and degeneration of skeletal muscles used during voluntary movement. Approximately half of all who suffer from muscular dystrophy have Duchenne muscular dystrophy (DMD). Because muscular dystrophy results from mutations in the dystrophin gene, which is on the X chromosome, the vast majority of muscular dystrophy patients are male. Girls can be carriers of muscular dystrophy and can be mildly affected.

Interestingly, somewhere around one-third of boys who suffer from DMD have no family history of the disease. Because the dystrophin gene is so large, spontaneous mutations in it are probably relatively common.

The signs and symptoms typically appear between the ages of 2 and 3, and may include frequent falls, difficulty getting up from a lying or sitting position, trouble running and jumping, a strange, shuffling way of walking or having a tendency to walk on their toes, calf muscles that are abnormally large, muscle pain and stiffness, and some learning disabilities.

Muscular dystrophy affects all ethnic groups and occurs globally. It affects around 1 in every 3,500 to 6,000 male births each year in the United States. DMD affects approximately one in 3,600 boys.

Because DMD results from mutations in the dystrophin gene, the vast majority of muscular dystrophy research was based on a simple model in which the Dystrophin protein played a structural role in the structural integrity of muscle fibers. Abnormal versions of the Dystrophin protein caused the muscle fibers to become damaged and die as a result of contraction. Dystrophin anchors the cytoskeleton of the muscle fibers, which are essential for muscle contraction, to the muscle cell membrane, and then to the extracellular matrix outside the cell that serves as a foundation upon which the muscle cells are built.

However in this current study, Rudnicki and his team discovered that muscle stem cells also express the dystrophin protein. This is a revelation because Dystrophin was thought to be protein that ONLY appeared in mature muscle. However, in this study, it became exceedingly clear that in the absence of Dystrophin, muscle stem cells generated ten-fold fewer muscle precursor cells, and, consequently, far fewer functional muscle fibers. Dystrophin is also a component of a signal transduction pathway that allows muscle stem cells to properly ascertain if they need to replace dead or dying muscle. Muscle stem cells repair the muscle in response to injury or exercise by dividing to generate precursor cells that differentiate into muscle fibers.

Even though Rudnicki used mice as a model system in these experiments, the Dystrophin protein is highly conserved in most vertebrate animals. Therefore, it is highly likely that these results will also apply to human muscle stem cells.

Gene therapy experiments and trials are in progress and even show some promise, but Rudnicki’s work tells us that gene therapy approaches must target muscle stem cells as well as muscle fibers if they are to work properly.

“We’re already looking at approaches to correct this problem in muscle stem cells,” said Dr. Rudnicki.

This paper has received high praise from the likes of Ronald Worton, who was one of the co-discovers of the dystrophin gene with Louis Kunkel in 1987.

Early pathogenesis of Duchenne muscular dystrophy modelled in patient-derived human induced pluripotent stem cells

Emi Shoji, Hidetoshi Sakurai, Tokiko Nishino, Tatsutoshi Nakahata, Toshio Heike, Tomonari Awaya, Nobuharu Fujii, Yasuko Manabe, Masafumi Matsuo & Atsuko Sehara-Fujisawa

Scientific Reports 5, Article number: 12831 (2015) http://dx.doi.org:/10.1038/srep12831

Duchenne muscular dystrophy (DMD) is a progressive and fatal muscle degenerating disease caused by a dystrophin deficiency. Effective suppression of the primary pathology observed in DMD is critical for treatment. Patient-derived human induced pluripotent stem cells (hiPSCs) are a promising tool for drug discovery. Here, we report an in vitro evaluation system for a DMD therapy using hiPSCs that recapitulate the primary pathology and can be used for DMD drug screening. Skeletal myotubes generated from hiPSCs are intact, which allows them to be used to model the initial pathology of DMD in vitro. Induced control and DMD myotubes were morphologically and physiologically comparable. However, electric stimulation of these myotubes for in vitro contraction caused pronounced calcium ion (Ca²⁺) influx only in DMD myocytes. Restoration of dystrophin by the exon-skipping technique suppressed this Ca²⁺ overflow and reduced the secretion of creatine kinase (CK) in DMD myotubes. These results suggest that the early pathogenesis of DMD can be effectively modelled in skeletal myotubes induced from patient-derived iPSCs, thereby enabling the development and evaluation of novel drugs.

Duchenne muscular dystrophy (DMD) is characterised by progressive muscle atrophy and weakness that eventually leads to ambulatory and respiratory deficiency from early childhood¹. It is an X-linked recessive inherited disease with a relatively high frequency of 1 in 3500 males^1,2.DMD, which is responsible for DMD, encodes 79 exons and produces dystrophin, which is one of the largest known cytoskeletal structural proteins³. Most DMD patients have various types of deletions or mutations in DMD that create premature terminations, resulting in a loss of protein expression⁴. Several promising approaches could be used to treat this devastating disease, such as mutation-specific drug exon-skipping^5,6, cell therapy⁷, and gene therapy^1,2.

Myoblasts from patients are the most common cell sources for assessing the disease phenotypes of DMD^11,12. …Previous reports have shown that muscle cell differentiation from DMD patient myoblasts is delayed and that these cells have poor proliferation capacity compared to those of healthy individuals^11,12. Our study revealed that control and DMD myoblasts obtained by activating tetracycline-dependent MyoD transfected into iPS cells (iPS^tet-MyoD cells) have comparable growth and differentiation potential and can produce a large number of intact and homogeneous myotubes repeatedly.

The pathogenesis of DMD is initiated and progresses with muscle contraction. The degree of muscle cell damage at the early stage of DMD can be evaluated by measuring the leakage of creatine kinase (CK) into the extracellular space¹⁵. Excess calcium ion (Ca²⁺) influx into skeletal muscle cells, together with increased susceptibility to plasma membrane injury, is regarded as the initial trigger of muscle damage in DMD^{19,20,21,22,23,24}. Targeting these early pathogenic events is considered essential for developing therapeutics for DMD.

In this study, we established a novel evaluation system to analyse the cellular basis of early DMD pathogenesis by comparing DMD myotubes with the same clone but with truncated dystrophin-expressing DMD myotubes, using the exon-skipping technique. We demonstrated through in vitro contraction that excessive Ca²⁺ influx is one of the earliest events to occur in intact dystrophin-deficient muscle leading to extracellular leakage of CK in DMD myotubes.

Generation of tetracycline-inducible MyoD-transfected DMD patient-derived iPSCs (iPS^tet-MyoD cells)

Figure 1: Generation and characterization of control and DMD patient-derived Tet-MyoD-transfected hiPS cells. Full size image

Morphologically and physiologically comparable intact myotubes differentiated from control and DMD-derived hiPSCs

Figure 2: Morphologically and physiologically comparable skeletal muscle cells differentiated from Control-iPS^tet-MyoD and DMD-iPS^tet-MyoD. Full size image

Exon-skipping with AO88 restored expression of Dystrophin in DMD myotubes differentiated from DMD-iPS^tet-MyoD cells

Figure 3: Restoration of dystrophin protein expression by AO88. Full size image

Restored dystrophin expression attenuates Ca²⁺ overflow in DMD-Myocytes

Figure 4: Restored expression of dystrophin diminishes Ca²⁺ influx in DMD muscle in response to electric stimulation. Full size image

Ca²⁺ influx provokes skeletal muscle cellular damage in DMD muscle

Figure 5: Ca²⁺ influx induces prominent skeletal muscle cellular damage in DMD-Myocytes. Full size image

Skeletal muscle differentiation in myoblasts from DMD patients is generally delayed compared to that in healthy individuals^11,36,37. Our differentiation system successfully induced the formation of myotubes from DMD patients, and the myotubes displayed analogous morphology and maturity compared with control myotubes (Fig. 2a–c). Comparing myotubes generated from patient-derived iPS cells with those derived from the same DMD clones but expressing dystrophin by application of the exon-skipping technique enabled us to demonstrate the primary cellular phenotypes in skeletal muscle solely resulting from the loss of the dystrophin protein (Fig. 4b). Our results demonstrate that truncated but functional dystrophin protein expression improved the cellular phenotype of DMD myotubes.

In DMD, the lack of dystrophin induces an excess influx of Ca²⁺ , leading to pathological dystrophic changes²². We consistently observed excess Ca²⁺ influx in DMD-Myocytes compared to Control-Myocytes (Supplementary Figure S3a and S3b) in response to electric stimulation. TRP channels, which are mechanical stimuli-activated Ca²⁺ channels⁴⁰that are expressed in skeletal muscle cells⁴¹, can account for this pathogenic Ca²⁺ influx…

In conclusion, our study revealed that the absence of dystrophin protein induces skeletal muscle damage by allowing excess Ca²⁺ influx in DMD myotubes. Our experimental system recapitulated the early phase of DMD pathology as demonstrated by visualisation and quantification of Ca²⁺ influx using intact myotubes differentiated from hiPS cells. This evaluation system significantly expands prospective applications with regard to assessing the effectiveness of exon-skipping drugs and also enables the discovery of drugs that regulate the initial events in DMD.

Duchenne muscular dystrophy affects stem cells, University of Ottawa study finds

New treatments could one day be available for the most common form of muscular dystrophy after a study suggests the debilitating genetic disease affects the stem cells that produce healthy muscle fibres.

The findings are based on research from the University of Ottawa and The Ottawa Hospital, published Monday in the journal Nature Medicine.

For nearly two decades, doctors had thought the muscular weakness that is the hallmark of the disease was due to problems with human muscle fibers, said Dr. Michael Rudnicki, the study’s senior author.

The new research shows the specific protein characterized by its absence in Duchenne muscular dystrophy normally exists in stem cells.

Dystrophin protein found in stem cells

“The prevailing notion was that the protein that’s missing in Duchenne muscular dystrophy — a protein called dystrophin — was not involved at all in the function of the stem cells.”

http://soundcloud.com/cbcottawa1

When the genetic mutations caused by Duchenne muscular dystrophy inhibit the production of dystrophin in stem cells, those stem cells produce significantly fewer precursor cells — and thus fewer properly functioning muscle fibres. Further, stem cells need dystrophin to sense their environment to figure out if they need to divide to produce more stem cells or perform muscle repair work.

Genetic repair might treat Duchenne muscular dystrophy

July 25, 2011|By Thomas H. Maugh II, Los Angeles Times

A genetic technique that allows the body to work around a crucial mutation that causes Duchenne muscular dystrophy increased the mass and function of muscles in a small group of patients with the devastating disease, paving the way for larger clinical trials of the drug. The study in a handful of boys age 5 to 15 showed that patients receiving the highest level of the drug, called AVI-4658 or eteplirsen, had a significant increase in production of a missing protein and increases in muscle fibers. The study demonstrated that the drug is safe in the short term. Results were reported Sunday in the journal Lancet.

Duchenne muscular dystrophy affects about one in every 3,500 males worldwide. It is caused by any one of several different mutations that affect production of a protein called dystrophin, which is important for the production and maintenance of muscle fibers. Affected patients become unable to walk and must use a wheelchair by age 8 to 12. Deterioration continues through their teens and 20s, and the condition typically proves fatal as muscle failure impairs their ability to breathe.

This study is designed to assess the efficacy, safety, tolerability, and pharmacokinetics (PK) of AVI-4658 (eteplirsen) in both 50.0 mg/kg and 30.0 mg/kg doses administered over 24 weeks in subjects diagnosed with Duchenne muscular dystrophy (DMD).

Condition	Intervention	Phase
Duchenne Muscular Dystrophy	Drug: AVI-4658 (Eteplirsen) Other: Placebo	Phase 2

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Treatment
Official Title:	A Randomized, Double-Blind, Placebo-Controlled, Multiple Dose Efficacy, Safety, Tolerability and Pharmacokinetics Study of AVI-4658(Eteplirsen),in the Treatment of Ambulant Subjects With Duchenne Muscular Dystrophy

Resource links provided by NLM:

Genetics Home Reference related topics: Duchenne and Becker muscular dystrophy

MedlinePlus related topics: Muscular Dystrophy

Genetic and Rare Diseases Information Center resources: Becker Muscular Dystrophy Duchenne Muscular Dystrophy Muscular Dystrophy

U.S. FDA Resources

Dystrophin expression in muscle stem cells regulates their polarity and asymmetric division

Nicolas A Dumont, Yu Xin Wang, Julia von Maltzahn, Alessandra Pasut, C Florian Bentzinger, Caroline E Brun & Michael A Rudnicki

Nature Medicine(2015) http://dx.doi.org:/10.1038/nm.3990

Dystrophin is expressed in differentiated myofibers, in which it is required for sarcolemmal integrity, and loss-of-function mutations in the gene that encodes it result in Duchenne muscular dystrophy (DMD), a disease characterized by progressive and severe skeletal muscle degeneration. Here we found that dystrophin is also highly expressed in activated muscle stem cells (also known as satellite cells), in which it associates with the serine-threonine kinase Mark2 (also known as Par1b), an important regulator of cell polarity. In the absence of dystrophin, expression of Mark2 protein is downregulated, resulting in the inability to localize the cell polarity regulator Pard3 to the opposite side of the cell. Consequently, the number of asymmetric divisions is strikingly reduced in dystrophin-deficient satellite cells, which also display a loss of polarity, abnormal division patterns (including centrosome amplification), impaired mitotic spindle orientation and prolonged cell divisions. Altogether, these intrinsic defects strongly reduce the generation of myogenic progenitors that are needed for proper muscle regeneration. Therefore, we conclude that dystrophin has an essential role in the regulation of satellite cell polarity and asymmetric division. Our findings indicate that muscle wasting in DMD not only is caused by myofiber fragility, but also is exacerbated by impaired regeneration owing to intrinsic satellite cell dysfunction.

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Rheumatoid arthritis update

Posted in Biological Networks, Gene Regulation and Evolution, Biomedical Measurement Science, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Clinical & Translational, Conference Coverage with Social Media, Curation, Cytokines, Disease Biology, Small Molecules in Development of Therapeutic Drugs, FDA Regulatory Affairs, Gene Regulation, Immunology, Innovations, Metabolism, Pharmaceutical Analytics, Pharmaceutical Drug Discovery, Pharmaceutical Industry Competitive Intelligence, Pharmaceutical R&D Investment, Population Health Management, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Signaling & Cell Circuits, Systemic Inflammatory Response Related Disorders, Translational Science on November 19, 2015| Leave a Comment »

Rheumatoid arthritis update

Larry H. Bernstein, MD, FCAP, Curator

LPBI

Innovation update: Advancing the standard of care in rheumatoid arthritis

By Nicole Gray | November 19, 2015

http://www.biopharmadive.com/news/innovation-update-advancing-the-standard-of-care-in-rheumatoid-arthritis/409496/

This year’s American College of Rheumatology (ACR) meeting, which took place in San Francisco from November 6 to 11, reflected an unprecedented level of innovation, including numerous advances in the area of rheumatoid arthritis (RA).

BioPharma Dive spoke with executives from Pfizer and Eli Lilly to discuss the new treatment landscape and ongoing innovation in this therapeutic space.

Old innovation makes way for new innovation

Twenty years ago, the standard of care for RA was some combination of basic NSAIDS, along with methotrexate. Caregivers focused on symptom relief, and it was widely understood that many patients would fail to achieve remission. As the disease developed, patients would eventually develop severely life-limiting disabilities as their disease progressed.

During this period, researchers presenting at conferences grew excited about data on a new class of drugs known as anti-tumor necrosis factor (TNF) antibodies. In an article published in Acta Orthopaedica Scandinavica in 1995, two physician-researchers wrote the following:

“Primary results have recently been published on the use of anti-TNF monoclonal antibodies. In a controlled trial these antibodies were able to significantly influence a number of disease-activity variables in RA. An important observation was that the clinical effect lasted from weeks to, in some cases, months. Although the potential of these agents for clinical use is still uncertain, these observations suggest that interfering with certain targets of the immune-inflammatory process is possible, effective and so far without side effects.”

About four years after Drs. Van de Putte and Van Riel extolled the virtues of disease-modifying biologics in clinical trials, the first anti-TNF antibody, Remicade (infliximab) was approved in 1999. At that point, the standard of care for RA improved significantly, forever changing the treatment paradigm for patients with RA.

The expanding class of JAK inhibitors

At this year’s ACR meeting, researchers focused on anti-inflammatory antibodies and a relatively new class of oral drugs known as janus kinase (JAK) inhibitors. Interest in JAK inhibitors has spiked since the approval of Pfizer’s oral medication Xeljanz (tofacitinib) —the first, and currently the only, JAK inhibitor approved for the treatment of moderate-to-severe RA.JAK inhibitors have garnered interest because of the role they can play in expanding a treatment area dominated by synthetic and biologic disease-modifying anti-rheumatic drugs (DMARDs). Could JAK inhibitors provide the breakthrough in RA that the anti-TNF antibodies provided almost 20 years ago?

Currently, Eli Lilly and Incyte are in late-stage development of baricitinib, a JAK1/JAK2 inhibitor for treatment of RA. Until last December, Johnson & Johnson (J&J) and Astellas were working jointly on another JAK inhibitor, known as ASPO15K, but J&J exercised its opt-out option and left the partnership. Astellas vowed to go it alone or look for a new partner, but there have not been many updates on ASPO15K within the last year.

Innovation means understanding and responding to unmet needs

Like many other therapeutic areas, RA treatments are often used in combination. For some patients, the combination of methotrexate and a powerful biologic, such as Remicade (infliximab), will help a patient achieve remission Yet others will either not respond to methotrexate and Remicade, or will have a negative reaction. Understanding how to help nonresponders achieve relief has become a key area of research in RA.

According to Terence Rooney, MD, Medical Director at Lilly Bio-Medicines, “A substantial proportion of patients treated with methotrexate – commonly used across the disease continuum for 25 years – do not achieve satisfactory disease control, signaling a need for more effective RA treatment options. In addition, studies have shown that some patients who initially respond to biologics lose response over time, and approximately 40 percent of patients with high disease activity never respond adequately to TNF antagonist biologics.”

Innovative clinical trial design

As Lilly and Incyte approach the end of the development process for baricitinib, they have been collecting results from clinical trials designed to both establish basic efficacy and safety in placebo-controlled and comparator trials, and to obtain data on targeted patient populations.

According to Rooney, “The baricitinib phase three program investigated the benefit of baricitinib across the spectrum of patients with rheumatoid arthritis, including newly diagnosed patients, patients who had failed to respond to conventional DMARDs, and patients who had failed multiple injectable biologic DMARD therapies.”

“In addition, the phase 3 program included two 52-week studies that incorporated either methotrexate or adalimumab as active comparators to provide useful information for therapeutic positioning of baricitinib. In these studies, baricitinib was statistically superior to methotrexate and to adalimumab in improving signs and symptoms, physical function, and important patient-reported outcomes including pain, fatigue and stiffness.”

Rooney also pointed out that there is additional data establishing baricitinib as a DMARD that significantly inhibits progressive radiographic joint damage.

Experience plus evidence equals more innovation

As has become the norm, companies at ACR often highlight new data confirming the efficacy and safety of already approved drugs in larger patient populations and in real-world settings..

Lilly currently has data on more than 40,000 patients worldwide, reflecting its global ambitions. Assuming that baricitinib is approved next year (the goal is to file at the end of the year), Lilly will continue to present data at ACR in the coming years highlighting the results of its long-term extension study, RA-BEYOND.

Pfizer’s up-to-date Xeljanz data presentation at ACR

Although Xeljanz has been on the market for three years in more than 40 countries, Pfizer continues to focus on collecting new data and using it to expand use of Xeljanz. In fact, Pfizer had 20 abstracts focused solely on Xeljanz at ACR 2015.

According to Rory O’Connor, MD, Senior Vice President and Head of Global Medical Affairs, Global Innovative Pharmaceuticals Business, Pfizer, “Ongoing clinical trials and long-term extension studies provide important information about the safety and efficacy of Xeljanz in RA. We are focused on continuing to build on our knowledge of the clinical application of Xeljanz in real-world settings.”

Pfizer was also able to highlight new data that supports their recent NDA for Xeljanz XR, a once-daily formulation of Xeljanz, which is currently approved as a twice-daily dosing formulation.

JAK inhibition beyond RA

One of the most exciting things about the progress with JAK inhibitors is the possibility to innovate treatments beyond RA. Lilly has been exploring the role of JAK-dependent cytokines in the pathogenesis of numerous inflammatory and autoimmune diseases. The company also plans to meet with regulatory authorities to develop a pediatric program for juvenile RA and idiopathic arthritis.

Meanwhile, Pfizer has developed a broad portfolio of various JAK inhibitors and therapies with new modes of action. Already, Pfizer researchers have completed two phase three studies in ulcerative colitis and the top-line results have been positive.

Medical meetings are exciting, because they provide a forum for discussing breakthroughs and portending a future in which the standard of care improves. For companies like Lilly, Incyte, and Pfizer, continual development of more novel approaches to serious diseasesis like a call-response echo chamber in which innovation drives more innovation, resulting in better long-term outcomes for patients.

The JAK/STAT signaling pathway

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Journal of Cell Science 2004 117: 1281-1283; http://dx.doi.org:/10.1242/jcs.00963

The Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway is one of a handful of pleiotropic cascades used to transduce a multitude of signals for development and homeostasis in animals, from humans to flies. In mammals, the JAK/STAT pathway is the principal signaling mechanism for a wide array of cytokines and growth factors. JAK activation stimulates cell proliferation, differentiation, cell migration and apoptosis. These cellular events are critical to hematopoiesis, immune development, mammary gland development and lactation, adipogenesis, sexually dimorphic growth and other processes. Predictably, mutations that reduce JAK/STAT pathway activity affect these processes (reviewed by Igaz et al., 2001; O’Shea et al., 2002). Conversely, mutations that constitutively activate or fail to regulate JAK signaling properly cause inflammatory disease, erythrocytosis, gigantism and an array of leukemias. Here we present a general overview of the JAK/STAT pathway and illustrate the primary mechanisms of activation and regulation of this essential signaling cascade.

Mechanistically, JAK/STAT signaling is relatively simple, with only a few principal components (for reviews, see Aaronson and Horvath, 2002; Heinrich et al., 2003; Kisseleva et al., 2002; O’Shea et al., 2002). As described above, a variety of ligands and their receptors stimulate the JAK/STAT pathway. Intracellular activation occurs when ligand binding induces the multimerization of receptor subunits. For some ligands, such as erythropoietin and growth hormone, the receptor subunits are bound as homodimers while, for others, such as interferons and interleukins, the receptor subunits are heteromultimers. For signal propagation through either homodimers or heteromultimers, the cytoplasmic domains of two receptor subunits must be associated with JAK tyrosine kinases. JAKs are distinctive in that they have tandem kinase-homologous domains at the C-terminus. The first is a non-catalytic regulatory domain, whereas the second has tyrosine kinase activity. In mammals, the JAK family comprises four members: JAK1, JAK2, JAK 3 and Tyk2. JAK activation occurs upon ligand-mediated receptor multimerization because two JAKs are brought into close proximity, allowing trans-phosphorylation. The activated JAKs subsequently phosphorylate additional targets, including both the receptors and the major substrates, STATs. STATs are latent transcription factors that reside in the cytoplasm until activated. The seven mammalian STATs bear a conserved tyrosine residue near the C-terminus that is phosphorylated by JAKs. This phosphotyrosine permits the dimerization of STATs through interaction with a conserved SH2 domain. Phosphorylated STATs enter the nucleus by a mechanism that is dependent on importin α-5 (also called nucleoprotein interactor 1) and the Ran nuclear import pathway. Once in the nucleus, dimerized STATs bind specific regulatory sequences to activate or repress transcription of target genes. Thus the JAK/STAT cascade provides a direct mechanism to translate an extracellular signal into a transcriptional response.

http://d1dvw62tmnyoft.cloudfront.net/content/joces/117/8/1281/F1.large.jpg

In addition to the principal components of the pathway, other effector proteins have been identified that contribute to at least a subset of JAK/STAT signaling events. STAMs (signal-transducing adapter molecules) are adapter molecules with conserved VHS and SH3 domains (Lohi and Lehto, 2001). STAM1 and STAM2A can be phosphorylated by JAK1-JAK3 in a manner that is dependent on a third domain present in some STAMs, the ITAM (inducible tyrosine-based activation motif). Through a poorly understood mechanism, the STAMs facilitate the transcriptional activation of specific target genes, including MYC. A second adapter that facilitates JAK/STAT pathway activation is StIP (stat-interacting protein), a WD40 protein. StIPs can associate with both JAKs and unphosphorylated STATs, perhaps serving as a scaffold to facilitate the phosphorylation of STATs by JAKs. A third class of adapter with function in JAK/STAT signaling is the SH2B/Lnk/APS family. These proteins contain both pleckstrin homology and SH2 domains and are also substrates for JAK phosphorylation. Both SH2-Bβ and APS associate with JAKs, but the former facilitates JAK/STAT signaling while the latter inhibits it. The degree to which each of these adapter families contributes to JAK/STAT signaling is not yet well understood, but it is clear that various proteins outside the basic pathway machinery influence JAK/STAT signaling.

In addition to JAK/STAT pathway effectors, there are three major classes of negative regulator: SOCS (suppressors of cytokine signaling), PIAS (protein inhibitors of activated stats) and PTPs (protein tyrosine phosphatases) (reviewed by Greenhalgh and Hilton, 2001). Perhaps the simplest are the tyrosine phosphatases, which reverse the activity of the JAKs. The best characterized of these is SHP-1, the product of the mouse motheaten gene. SHP-1 contains two SH2 domains and can bind to either phosphorylated JAKs or phosphorylated receptors to facilitate dephosphorylation of these activated signaling molecules. Other tyrosine phosphatases, such as CD45, appear to have a role in regulating JAK/STAT signaling through a subset of receptors.

SOCS proteins are a family of at least eight members containing an SH2 domain and a SOCS box at the C-terminus (reviewed by Alexander, 2002). In addition, a small kinase inhibitory region located N-terminal to the SH2 domain has been identified for SOCS1 and SOCS3. The SOCS complete a simple negative feedback loop in the JAK/STAT circuitry: activated STATs stimulate transcription of the SOCS genes and the resulting SOCS proteins bind phosphorylated JAKs and their receptors to turn off the pathway. The SOCS can affect their negative regulation by three means. First, by binding phosphotyrosines on the receptors, SOCS physically block the recruitment of signal transducers, such as STATs, to the receptor. Second, SOCS proteins can bind directly to JAKs or to the receptors to specifically inhibit JAK kinase activity. Third, SOCS interact with the elongin BC complex and cullin 2, facilitating the ubiquitination of JAKs and, presumably, the receptors. Ubiquitination of these targets decreases their stability by targeting them for proteasomal degradation.

The third class of negative regulator is the PIAS proteins: PIAS1, PIAS3, PIASx and PIASy. These proteins have a Zn-binding RING-finger domain in the central portion, a well-conserved SAP (SAF-A/Acinus/PIAS) domain at the N-terminus, and a less-well-conserved carboxyl domain. The latter domains are involved in target protein binding. The PIAS proteins bind to activated STAT dimers and prevent them from binding DNA. The mechanism by which PIAS proteins act remains unclear. However, PIAS proteins have recently been demonstrated to associate with the E2 conjugase Ubc9 and to have E3 conjugase activity for sumoylation that is mediated by the RING finger domain (reviewed by Jackson, 2001). Although there is evidence that STATs can be modified by sumoylation (Rogers et al., 2003), the function of that modification in negative regulation is not yet known.

Although the mechanism of JAK/STAT signaling is relatively simple in theory, the biological consequences of pathway activation are complicated by interactions with other signaling pathways (reviewed by Heinrich et al., 2003; Rane and Reddy, 2000; Shuai, 2000). An understanding of this cross-talk is only beginning to emerge, but the best characterized interactions of the JAK/STAT pathway are with the receptor tyrosine kinase (RTK)/Ras/MAPK (mitogen-activated protein kinase) pathway. The relationship between these cascades is complex and their paths cross at multiple levels, each enhancing activation of the other. First, activated JAKs can phosphorylate tyrosines on their associated receptors that can serve as docking sites for SH2-containing adapter proteins from other signaling pathways. These include SHP-2 and Shc, which recruit the GRB2 adapter and stimulate the Ras cascade. The same mechanism stimulates other cascades, such as the recruitment and JAK phosphorylation of insulin receptor substrate (IRS) and p85, which results in the activation of the phosphoinositide 3-kinase (PI3K) pathway [for more on PI3K signaling, see Foster et al. (Foster et al., 2003)]. JAK/STAT signaling also indirectly promotes Ras signaling through the transcriptional activation of SOCS3. SOCS3 binds RasGAP, a negative regulator of Ras signaling, and reduces its activity, thereby promoting activation of the Ras pathway. Reciprocally, RTK pathway activity promotes JAK/STAT signaling by at least two mechanisms. First, the activation of some RTKs, including EGFR and PDGFR, results in the JAK-independent tyrosine phosphorylation of STATs, probably by the Src kinase. Second, RTK/Ras pathway stimulation causes the downstream activation of MAPK. MAPK specifically phosphorylates a serine near the C-terminus of most STATs. While not absolutely necessary for STAT activity, this serine phosphorylation dramatically enhances transcriptional activation by STAT. In addition to RTK and PI3K interactions with JAK/STAT signaling, multiple levels of cross-talk with the TGF-β signaling pathway have been recently reported [for a review of TGF-β, see (Moustakas, 2002)]. Furthermore, the functions of activated STATs can be altered through association with other transcription factors and cofactors that are regulated by other signaling pathways. Thus the integration of input from many signaling pathways must be considered if we are to understand the biological consequences of cytokine stimulation.

References

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Aaronson, D. S. and Horvath, C. M. (2002). A road map for those who know JAK-STAT. Science 296, 1653-1655.

Abstract/FREE Full Text
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Agaisse, H., Petersen, U. M., Boutros, M., Mathey-Prevot, B. and Perrimon, N. (2003). Signaling role of hemocytes in Drosophila JAK/STAT-dependent response to septic injury. Dev. Cell 5, 441-450.

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Alexander, W. S. (2002). Suppressors of cytokine signalling (SOCS) in the immune system. Nat. Rev. Immunol. 2,410-416.

Medline Web of Science
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Dearolf, C. R. (1999). JAKs and STATs in invertebrate model organisms. Cell. Mol. Life Sci. 55, 1578-1584.

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Foster, F. M., Traer, C. J., Abraham, S. M. and Fry, M. J. (2003). The phosphoinositide (PI) 3-kinase family. J. Cell Sci.116, 3037-3040.

FREE Full Text

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https://youtu.be/9JHBHSHaBeI

Published on 27 Feb 2014

The JAK/STAT secondary messenger signaliing pathway..
Presented by: Joseph Farahany, M.D

Jak/Stat Signaling Pathway

Jaks and Stats are critical components of many cytokine receptor systems; regulating growth, survival, differentiation, and pathogen resistance. An example of these pathways is shown for the IL-6 (or gp130) family of receptors, which coregulate B cell differentiation, plasmacytogenesis, and the acute phase reaction. Cytokine binding induces receptor dimerization, activating the associated Jaks, which phosphorylate themselves and the receptor. The phosphorylated sites on the receptor and Jaks serve as docking sites for the SH2-containing Stats, such as Stat3, and for SH2-containing proteins and adaptors that link the receptor to MAP kinase, PI3K/Akt, and other cellular pathways.

Phosphorylated Stats dimerize and translocate into the nucleus to regulate target gene transcription. Members of the suppressor of cytokine signaling (SOCS) family dampen receptor signaling via homologous or heterologous feedback regulation. Jaks or Stats can also participate in signaling through other receptor classes, as outlined in the Jak/Stat Utilization Table. Researchers have found Stat3 and Stat5 to be constitutively activated by tyrosine kinases other than Jaks in several solid tumors

The Jak/Stat pathway mediates the effects of cytokines, like erythropoietin, thrombopoietin, and G-CSF, which are protein drugs for the treatment of anemia, thrombocytopenia, and neutropenia, respectively. The pathway also mediates signaling by interferons, which are used as antiviral and antiproliferative agents. Researchers have found that dysregulated cytokine signaling contributes to cancer. Aberrant IL-6 signaling contributes to the pathogenesis of autoimmune diseases, inflammation, and cancers such as prostate cancer and multiple myeloma. Jak inhibitors currently are being tested in models of multiple myeloma. Stat3 can act as an oncogene and is constitutively active in many tumors. Crosstalk between cytokine signaling and EGFR family members is seen in some cancer cells. Research has shown that in glioblastoma cells overexpressing EGFR, resistance to EGFR kinase inhibitors is induced by Jak2 binding to EGFR via the FERM domain of the former [Sci. Signal. (2013) 6, ra55].

Activating Jak mutations are major molecular events in human hematological malignancies. Researchers have found a unique somatic mutation in the Jak2 pseudokinase domain (V617F) that commonly occurs in polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis. This mutation results in the pathologic activation Jak2, associated with receptors for erythropoietin, thrombopoietin, and G-CSF, which control erythroid, megakaryocytic, and granulocytic proliferation and differentiation. Researchers have also shown that somatic acquired gain-of-function mutations of Jak1 are found in adult T cell acute lymphoblastic leukemia. Somatic activating mutations in Jak1, Jak2, and Jak3 have also been identified in pediatric acute lymphoblastic leukemia (ALL). Furthermore, Jak2 mutations have been detected around pseudokinase domain R683 (R683G or DIREED) in Down syndrome childhood B-ALL and pediatric B-ALL.

Selected Reviews:

Beekman R, Touw IP (2010) G-CSF and its receptor in myeloid malignancy. Blood 115(25), 5131–6.
Neurath MF, Finotto S (2011) IL-6 signaling in autoimmunity, chronic inflammation and inflammation-associated cancer. Cytokine Growth Factor Rev. 22(2), 83–9.
Sansone P, Bromberg J (2012) Targeting the interleukin-6/Jak/stat pathway in human malignancies. J. Clin. Oncol. 30(9), 1005–14.
Vainchenker W, Constantinescu SN (2013) JAK/STAT signaling in hematological malignancies. Oncogene 32(21), 2601–13.
Yu H, Pardoll D, Jove R (2009) STATs in cancer inflammation and immunity: a leading role for STAT3. Nat. Rev. Cancer 9(11), 798–809.

– See more at: http://www.cellsignal.com/contents/science-pathway-research-immunology-and-inflammation/jak-stat-signaling-pathway/pathways-il6#sthash.8SVwSWXw.dpuf

The JAK-STAT Signaling Pathway: Input and Output Integration¹

Peter J. Murray

The Journal of Immunology Mar 1, 2007; 178(5): 2623-2629 http://dx.doi.org:/10.4049/jimmunol.178.5.2623

Universal and essential to cytokine receptor signaling, the JAK-STAT pathway is one of the best understood signal transduction cascades. Almost 40 cytokine receptors signal through combinations of four JAK and seven STAT family members, suggesting commonality across the JAK-STAT signaling system. Despite intense study, there remain substantial gaps in understanding how the cascades are activated and regulated. Using the examples of the IL-6 and IL-10 receptors, I will discuss how diverse outcomes in gene expression result from regulatory events that effect the JAK1-STAT3 pathway, common to both receptors. I also consider receptor preferences by different STATs and interpretive problems in the use of STAT-deficient cells and mice. Finally, I consider how the suppressor of cytokine signaling (SOCS) proteins regulate the quality and quantity of STAT signals from cytokine receptors. New data suggests that SOCS proteins introduce additional diversity into the JAK-STAT pathway by adjusting the output of activated STATs that alters downstream gene activation.

The mammalian JAK and STAT family members have been extensively, and seemingly exhaustively, analyzed in the mouse and human systems. All four JAK and seven STAT family members have been deleted in the mouse, in addition to the creation of conditional alleles for genes whose loss of function leads to embryonic or perinatal lethality (Stat3, combined deficiency of Stat5a and Stat5b, and Jak2). In humans, detailed genetic studies have been performed in people bearing mutant Jak or Stat genes. Specific Abs to phospho-forms of each protein are used to study how the JAK-STAT cascade is activated by cytokine receptors. Crystallographic studies have illuminated structural information for multiple STAT family members in different forms. Pharmacological inhibitors have been developed for clinical use where JAK-STAT signaling is implicated in disease pathology and progression. Finally, in most cases, a specific JAK-STAT combination has been paired with each cytokine receptor, and this information translated into cell-type specific patterns of cytokine responsiveness and gene expression.

Major questions remain concerning how the JAK-STAT cascade functions to control specific gene expression patterns, and how the cascades are regulated. I will describe three elements of JAK-STAT signaling that require experimental investigation. First, I will address an unexpected experimental complication that arises from the analysis of mice and cells that lack one or more STAT family member. Second, I will use JAK1-STAT3 signaling from the IL-10R and IL-6R systems to illustrate that we lack detailed understanding of how specificity in gene expression is generated by receptors that use identical JAK-STAT members. Third, we have yet to explain how STAT activation is negatively regulated. Although the suppressor of cytokine signaling (SOCS)³ proteins are the best understood negative regulators of the JAK-STAT pathway, the biochemical mechanism of SOCS-mediated inhibition is unexplained. Moreover, additional inhibitory pathways have also been proposed to block the production of activated STATs. Collectively, I will argue that our understanding of the pathway from cytokine receptor to gene expression profile is in its infancy, but remains one of the best opportunities to dissect signal transduction.

Overview of the proximal JAK-STAT activation mechanism

The current model of JAK-STAT signaling holds that cytokine receptor engagement activates the associated JAK combination, which in turn phosphorylates the receptor cytoplasmic domain to allow recruitment of a STAT, which in turn is phosphorylated, dimerizes and moves to the nucleus to bind specific sequences in the genome and activate gene expression. Cytoplasmic domains of cytokine receptors associate with JAKs via JAK binding sites located close to the membrane (1). The postulated role of JAKs in trafficking or chaperoning the receptors to the cell surface is debated (2, 3, 4, 5, 6). Regardless of the when and where cytokine receptors and JAKs associate, their close apposition at the membrane is required to stimulate the kinase activity of the JAK following cytokine binding. At this stage in the activation of the pathway, we understand next to nothing about the structural basis of the JAK-receptor interaction, how receptor intracellular domains reorient upon cytokine binding and physically contact the JAK to receive the phosphorylation modification.

JAK-mediated phosphorylation of the receptor creates binding sites for the Src homology 2 (SH2) domains of the STATs. STAT recruitment is followed by tyrosine, and in some cases, serine phosphorylation on key residues (by the JAKs and other closely associated kinases) that leads to transit into the nucleus. This brief summary of the activation of the JAK-STAT pathway omits numerous unresolved details: the STAT monomer to dimer transition has been questioned, as has the role of phosphorylation in dimerization and nuclear transit (7). Furthermore, it is unclear how many configurations of STAT homo- and heterocomplexes are present in cells before, during, and after cytokine stimulation (8, 9,10). We do not understand the detailed structural basis for the preference of one SH2 domain for a given receptor, and we have little knowledge of how other non-JAK kinases are recruited to the receptors and phosphorylate the STATs.

Many receptors signal through a small number of JAKs

Cytokine receptors signal through two types of pathways: the JAK-STAT pathway and other pathways that usually involve the activation of the MAP kinase cascade. Although the latter will not be discussed here, it is worth noting that elegant genetic studies have demonstrated the importance of these pathways in various pathological systems (11, 12,13, 14). There are now ∼36 cytokine receptor combinations that respond to ∼38 cytokines (counting the type I IFNs as one because they all signal through the IFN-αβR). Different cells and tissues express distinct receptor combinations that respond to cytokine combinations unique to the microenvironment or systemic response of the organism. Hence, at any given time, a single cell may integrate signals from multiple cytokine receptors. Genetic studies have established that the cytokine receptor system is restrictive in that different classes of receptors preferentially use one JAK or JAK combination (7): receptors required for hemopoietic cell development and proliferation use JAK2, common γ-chain receptors use JAK1 and JAK3 whereas other receptors use only JAK1 (Fig. 1⇓). Unexplained is the selective use of these combinations: why the IFN-γR rigidly uses the JAK1, JAK2 combination is unknown as is the restricted use of TYK2. Compared with JAK1–3, TYK2 is unusual in that loss of function mutations in the mouse have shown obligate, but not absolute, requirements in IFN-αβR and IL-12R signaling (15, 16). In contrast, human TYK2 seems to be essential for signaling through a broader range of cytokine receptors (17).

FIGURE 1.

The majority of cytokine receptors use three JAK combinations. Shown are well-studied cases where JAK usage by each cytokine receptor has been established by genetic and biochemical studies. Exceptions shown are the G-CSFR (∗) where it is currently unclear whether both JAK1 and JAK2 are required together. Additionally, the IL-12R (†) and IL-23R (†) require TYK2 but the requirement for JAK2 has not been definitively determined. Receptors that use JAK2 and JAK3, JAK3 alone, TYK2 alone, or JAK3 and TYK2 have not been described.

The preferential association of JAKs to certain receptor classes raises several issues. First, how did the JAK-receptor combinations evolve? Because the number of receptors is relatively large, why has the number of JAKs remained small? Why have the combinations of JAK pairs also remained small given that there are 10 possible combinations that can be used (Fig. 1⇑)? Second, how flexible is the cytokine receptor-JAK pair? That is, can receptors be engineered for interchangeable JAK use, or is a given JAK combination fixed for a specific receptor class? For example, can JAK1, JAK3, or TYK2 activate erythropoietin receptor (EpoR) signaling (if so engineered) or is JAK2 obligatory for signaling? These questions allude to a fundamental issue that concerns the function of the JAK in cytokine receptor activation: if the only function of the JAKs is to phosphorylate tyrosine resides on the cytoplasmic domain of the receptors, then it should be possible to trade JAK-receptor pairs. If these receptors retain identical downstream gene expression profiles, then the signal generated by the JAK is generic and functions primarily to activate the receptor (6). Conversely, it is also possible that each receptor-JAK combination retains crucial specificity functions and swapping, for example, JAK1 for JAK2 on the EpoR will modify or destroy a specific function in erythrogenesis. These questions can be addressed experimentally by replacing one preferred JAK binding site for another in genes encoding different receptors. The EpoR is a good test example because the activity of the receptor and its signaling pathway is essential for life and erythropoiesis is readily assayed.

Core versus cell-type specific STAT signaling

Microarray experiments designed to monitor changes in gene expression induced by JAK-STAT signaling have revealed that both cell-type specific transcription and core, or stereotypic, mRNA profiles are induced by activated cytokine receptors in different cell types (Fig. 2⇓). For example, IFN-γ, via STAT1, induces the expression of a similar cohort of genes regardless of the cell type tested (18). These genes are often termed the “IFN signature” and overlap with the gene expression pattern induced by IFN-αβ signaling that also involves STAT1, in cooperation with STAT2 and IRF9. The IFN signature is readily observed in microarray experiments and is indicative of STAT1 activity. The STAT6 pathway activated by IL-4 or IL-13 provides an example of a cell-type specific response. IL-4-regulated genes in T cells have a distinct signature compared with IL-4/IL-13 signaling in macrophages or other non-lymphocytes (19, 20, 21, 22). In the latter, genes such as Arg1(encoding arginase 1) are often induced >100-fold but are silent in T cells (23, 24, 25, 26,27). Collectively these data argue that STATs activate defined gene sets, depending on their genomic accessibility, and possibly on cofactors that further refine gene expression profiles. STAT3 signaling illustrates a more complex system and will be discussed below to illustrate the distinctions between IL-6 and IL-10 signaling.

FIGURE 2.

Core signaling by STATs. Representative examples of gene expression induced by STAT signaling in different tissues. The examples were extracted and edited from numerous microarray and empirical studies.

Interpreting experiments using STAT loss-of-function systems

Experiments with the different STAT knockout mice, and cells derived from these animals, have been critical for understanding specific requirements of individual STATs in gene expression following cytokine receptor signaling. The interpretation of these experiments is generally straightforward. For example, STAT5a and STAT5b are essential for the expression of genes that promote hemopoietic survival (28, 29, 30) whereas STAT1 is required for the expression of IFN-regulated genes that are involved in the protection against pathogens (18). However, by EMSA and immunoblotting experiments, most cytokines have been shown to activate multiple STATs, prompting experiments to determine transcriptional responses that can be activated in the absence of a given STAT. An initial example of this type of approach was performed by Schreiber and colleagues who interrogated gene expression profiles induced by IFN-γ signaling in the absence of STAT1 (31, 32). In these experiments, IFN-γ was used to stimulate STAT1-deficient bone marrow-derived macrophages and fibroblasts. Numerous genes were induced by IFN-γ in the absence of STAT1, leading to the conclusion that the IFN-γR activates a STAT1-independent gene expression program. However, inspection of the genes induced by IFN-γ signaling in STAT1-deficient cells shows many to be STAT3-regulated genes such asSocs3, Gadd45, and Cebpb. STAT3 phosphorylation is normally induced by IFN-γ in wild-type cells but in the absence of STAT1, STAT3 signaling is dominant. What is the mechanism of this effect? We now know from experiments using STAT-deficient cells that receptor occupancy, or lack of occupancy by the dominant STAT that binds the receptor, causes a switch from one activated STAT to another (33). A converse example is the conversion of IL-6R signaling to a dominant STAT1 activation in STAT3-deficient cells (34). This switch causes the downstream induction of the IFN gene expression pathway just as IFN-γ would cause in wild-type cells.

A related example is observed when IL-6 signaling is tested in the absence of SOCS3. SOCS3 is induced by STAT signaling from different cytokine receptors and functions as a feedback inhibitor of the IL-6R (and the G-CSFR, LIFR, and leptinR) by binding to phosphorylated Y757 on the gp130 cytoplasmic domain (see below). However in the absence of SOCS3, STAT3 phosphorylation is greatly increased (35, 36, 37). At the same time however, STAT1 phosphorylation is also induced, leading to a dominant IFN-like gene expression signature (35, 36). Thus SOCS3 regulates both the quantity and type of STAT signal generated from the IL-6R. Although the mechanism of the SOCS3 effect is unclear, the promiscuity of different receptors for different STATs argues that loss-of-function experiments must be carefully examined for the activation of other STAT molecules that fill the “hole” created by the loss of one STAT. These data also suggest that different cytokine receptors have evolved selectivity for different classes of STATs. Although STAT1 and STAT3 can apparently interchangeably bind the IL-6R or IFN-γR when either molecule is missing, signaling in wild-type cells shows a strong preference for one STAT over the other. Likewise, other receptors may have evolved to bind only one STAT, and in the absence of the key STAT, the other STATs cannot bind and/or be activated by the receptor.

The above examples primarily describe experiments using STAT1–STAT3-activating receptors but these are not isolated cases. In T cells stimulated by IL-12, STAT4 is activated and drives IFN-γ production. This pathway is a central regulatory event in the development of the Th1 type T cell responses. IFN-αβ, via the IFN-αβR, also activates STAT4 (in addition to STAT1 and STAT2 that forms a complex with IRF-9 to mediate anti-viral gene expression) but cannot activate strong IFN-γ production and therefore cannot drive Th1 development (38). However, in the absence of STAT1, IFN-αβ causes a large increase in IFN-γ production, especially in vivo during viral infection (39, 40). These data were originally interpreted to mean that STAT1 normally suppressed IFN-γ production. However, the data can just as easily be resolved when we consider that STAT4 activation from the IFN-αβR is increased in the absence of STAT1. Recent data confirm this interpretation but also show that STAT4 activation by the IFN-αβR, although increased, cannot sustain IFN-γ production from T cells when compared with IL-12 (38). This is probably because of the stronger differential activity of SOCS1 on the IFN-αβR versus the IL-12R (discussed below). I would predict that an IFN-αβR that is refractory to SOCS1 (or active in a Socs1^−/− background) would behave identically to the IL-12R in the absence of STAT1.

Although loss of gene expression may be observed in a given STAT knockout, a corresponding increase in the ectopic activation of another STAT pathway may confound the interpretation of results in both in vitro and in vivo systems. Because specific Abs are available for each tyrosine-phosphorylated STAT molecule, a simple solution is to first measure which other STATs are activated by a given receptor in the absence of the STAT of interest. Experiments using STAT knockout systems should also be supported by additional data that uses complimentary mutations in the receptor that ablate STAT recruitment, or complete loss of the receptor. Finally, it is worth noting that the loss of a STAT pathway from a receptor signaling system can cause additional loss of key negative regulatory systems including feedback loops such as SOCS induction as presently debated for G-CSFR signaling and receptor systems discussed below (41, 42, 43, 44, 45).

FIGURE 3.

Proposed differential STAT activation by IL-10 or IL-6. Shown are three classes of genes activated by STAT3 where Socs3 is a representative “common” gene induced by both receptors. In the absence of SOCS3, the IL-6R can activate the anti-inflammatory genes in the same way as the IL-10R. The mechanism of this effect remains to be established.

JAK/STAT Activation Inhibitors

The JAK/STAT pathway plays an important role in cytokine receptor-mediated signal transduction via activation of downstream signal transducers and activators of transcription (STAT), phosphatidylinositol 3-kinase (PI3K), and mitogen-activated protein kinase (MAPK) pathways.
These inhibitors are useful tools for exploring the contribution of JAK/STAT-mediated signaling.

JAK/STAT Activation Inhibitors

AG490	JAK2 inhibitor	10 mg
AZD1480 NEW!	JAK1 & JAK2 inhibitor	5 mg
CP-690550	JAK3 Inhibitor	5 mg
CYT387 NEW!	JAK1/JAK2 & TBK1/IKK-ε inhibitor	10 mg
Ruxolitinib	JAK1 & JAK2 Inhibitor	5 mg

Methotrexate Is a JAK/STAT Pathway Inhibitor

Sally Thomas, Katherine H. Fisher, John A. Snowden, Sarah J. Danson, Stephen Brown, Martin P. Zeidler

Published: July 1, 2015
DOI: http://dx.doi.org:/10.1371/journal.pone.0130078

Background

The JAK/STAT pathway transduces signals from multiple cytokines and controls haematopoiesis, immunity and inflammation. In addition, pathological activation is seen in multiple malignancies including the myeloproliferative neoplasms (MPNs). Given this, drug development efforts have targeted the pathway with JAK inhibitors such as ruxolitinib. Although effective, high costs and side effects have limited its adoption. Thus, a need for effective low cost treatments remains.

Methods & Findings

We used the low-complexity Drosophila melanogaster pathway to screen for small molecules that modulate JAK/STAT signalling. This screen identified methotrexate and the closely related aminopterin as potent suppressors of STAT activation. We show that methotrexate suppresses human JAK/STAT signalling without affecting other phosphorylation-dependent pathways. Furthermore, methotrexate significantly reduces STAT5 phosphorylation in cells expressing JAK2 V617F, a mutation associated with most human MPNs. Methotrexate acts independently of dihydrofolate reductase (DHFR) and is comparable to the JAK1/2 inhibitor ruxolitinib. However, cells treated with methotrexate still retain their ability to respond to physiological levels of the ligand erythropoietin.

Conclusions

Aminopterin and methotrexate represent the first chemotherapy agents developed and act as competitive inhibitors of DHFR. Methotrexate is also widely used at low doses to treat inflammatory and immune-mediated conditions including rheumatoid arthritis. In this low-dose regime, folate supplements are given to mitigate side effects by bypassing the biochemical requirement for DHFR. Although independent of DHFR, the mechanism-of-action underlying the low-dose effects of methotrexate is unknown. Given that multiple pro-inflammatory cytokines signal through the pathway, we suggest that suppression of the JAK/STAT pathway is likely to be the principal anti-inflammatory and immunosuppressive mechanism-of-action of low-dose methotrexate. In addition, we suggest that patients with JAK/STAT-associated haematological malignancies may benefit from low-dose methotrexate treatments. While the JAK1/2 inhibitor ruxolitinib is effective, a £43,200 annual cost precludes widespread adoption. With an annual methotrexate cost of around £32, our findings represent an important development with significant future potential.

Citation: Thomas S, Fisher KH, Snowden JA, Danson SJ, Brown S, Zeidler MP (2015) Methotrexate Is a JAK/STAT Pathway Inhibitor. PLoS ONE 10(7): e0130078. http://dx.doi.org:/10.1371/journal.pone.0130078

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Targeting Neuropathologies with GSK33 Inhibitor

Posted in Behavior, Biochemical pathways, Cancer and Current Therapeutics, Cell Biology, Signaling & Cell Circuits, Clinical & Translational, Curation, Disease Biology, Disease Biology, Small Molecules in Development of Therapeutic Drugs, FDA Regulatory Affairs, Innovations, Innovations in Neurophysiology & Neuropsychology, Metabolism, Neurodegenerative Diseases, Neuroscience, Patents, Pharmaceutical Analytics, Pharmaceutical Drug Discovery, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, tagged glycogen synthase kinase (GSK), GSK33, mood disorders on November 17, 2015| Leave a Comment »

Targeting Neuropathologies with GSK33 Inhibitor

Larry H. Bernstein, MD, FCAP, Curator

LPBI

New 5-Substituted-N-(piperidin-4-ylmethyl)-1H-indazole-3-carboxamides: Potent Glycogen Synthase Kinase-3 (GSK-3) Inhibitors in Model of Mood Disorders

by DR ANTHONY MELVIN CRASTO Ph.D

CAS 1452582-16-9, 428.47, C₂₃ H₂₆ F₂ N₄ O₂

1H-Indazole-3-carboxamide, 5-(2,3-difluorophenyl)-N-[[1-(2-methoxyethyl)-4-piperidinyl]methyl]-

Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A.

1 H-indazole-3-carboxamide compounds acting as glycogen synthase kinase 3 beta (GSK-33) inhibitors and to their use in the treatment of GSK-33-related disorders such as (i) insulin-resistance disorders; (ii) neurodegenerative diseases; (iii) mood disorders; (iv) schizophrenic disorders; (v) cancerous disorders; (vi) inflammation, (vii) substance abuse disorders; (viii) epilepsies; and (ix) neuropathic pain.

Protein kinases constitute a large family of structurally related enzymes, which transfer phosphate groups from high-energy donor molecules (such as adenosine triphosphate, ATP) to specific substrates, usually proteins. After phosphorylation, the substrate undergoes to a functional change, by which kinases can modulate various biological functions.

In general, protein kinases can be divided in several groups, according to the substrate that is phosphorylated. For example, serine/threonine kinase phosphorylates the hydroxyl group on the side chain of serine or threonine aminoacid.

Glycogen synthase kinases 3 (GSK-3) are constitutively active multifunctional enzymes, quite recently discovered, belonging to the serine/threonine kinases group.

Human GSK-3 are encoded by two different and independent genes, which leads to GSK-3a and GSK-33 proteins, with molecular weights of about 51 and 47 kDa, respectively. The two isoforms share nearly identical sequences in their kinase domains, while outside of the kinase domain, their sequences differ substantially (Benedetti et al., Neuroscience Letters, 2004, 368, 123-126). GSK-3a is a multifunctional protein serine kinase and GSK-33 is a serine-threonine kinase.

It has been found that GSK-33 is widely expressed in all tissues, with widespread expression in the adult brain, suggesting a fundamental role in neuronal signaling pathways (Grimes and Jope, Progress in Neurobiology, 2001, 65, 391-426). Interest in glycogen synthase kinases 3 arises from its role in various physiological pathways, such as, for example, metabolism, cell cycle, gene expression, embryonic development oncogenesis and neuroprotection (Geetha et al., British Journal Pharmacology, 2009, 156, 885-898).

GSK-33 was originally identified for its role in the regulation of glycogen synthase for the conversion of glucose to glycogen (Embi et al., Eur J Biochem, 1980, 107, 519-527). GSK-33 showed a high degree of specificity for glycogen synthase.

Type 2 diabetes was the first disease condition implicated with GSK- 3β, due to its negative regulation of several aspects of insulin signaling pathway. In this pathway 3-phosphoinositide-dependent protein kinase 1 (PDK-1 ) activates PKB, which in turn inactivates GSK-33. This inactivation of GSK-33 leads to the dephosphorylation and activation of glycogen synthase, which helps glycogen synthesis (Cohen et al., FEBS Lett, 1997, 410, 3-10). Moreover, selective inhibitors of GSK-33 are expected to enhances insulin signaling in prediabetic insulin- resistant rat skeletal muscle, thus making GSK-33 an attractive target for the treatment of skeletal muscle insulin resistance in the pre-diabetic state (Dokken et al., Am J. Physiol. Endocrinol. Metab., 2005, 288, E1 188-E1 194).

GSK-33 was also found to be a potential drug target in others pathological conditions due to insulin-resistance disorders, such as syndrome X, obesity and polycystic ovary syndrome (Ring DB et al., Diabetes, 2003, 52: 588-595).

It has been found that GSK-33 is involved in the abnormal phosphorylation of pathological tau in Alzheimer’s disease (Hanger et al., Neurosci. Lett, 1992, 147, 58-62; Mazanetz and Fischer, Nat Rev Drug Discov., 2007, 6, 464-479; Hong and Lee, J. Biol. Chem., 1997, 272, 19547- 19553). Moreover, it was proved that early activation of GSK-33, induced by apolipoprotein ApoE4 and β-amyloid, could lead to apoptosis and tau hyperphosphorylation (Cedazo-Minguez et al., Journal of Neurochemistry, 2003, 87, 1 152- 1 164). Among other aspect of Alzheimer’s disease, it was also reported the relevance of activation of GSK-33 at molecular level (Hernandez and Avila, FEBS Letters, 2008, 582, 3848-3854).

Moreover, it was demonstrated that GSK-33 is involved in the genesis and maintenance of neurodegenerative changes associated with Parkinson’s disease (Duka T. et al., The FASEB Journal, 2009; 23, 2820- 2830).

Accordingly to these experimental observations, inhibitors of GSK-33 may find applications in the treatment of the neuropathological consequences and the cognitive and attention deficits associated with tauopathies; Alzheimer’s disease; Parkinson’s disease; Huntington’s disease (the involvement of GSK-33 in such deficits and diseases is disclosed in Meijer L. et al., TRENDS Pharm Sci, 2004; 25, 471 -480); dementia, such as, but not limited to, vascular dementia, post-traumatic dementia, dementia caused by meningitis and the like; acute stroke; traumatic injuries; cerebrovascular accidents; brain and spinal cord trauma; peripheral neuropathies; retinopathies and glaucoma (the involvement of GSK-33 in such conditions is disclosed in WO 2010/109005).

The treatment of spinal neurodegenerative disorders, like amyotrophic lateral sclerosis, multiple sclerosis, spinal muscular atrophy and neurodegeneration due to spinal cord injury has been also suggested in several studies related to GSK-33 inhibition, such as, for example in Caldero J. et al., “Lithium prevents excitotoxic cell death of motoneurons in organotypic slice cultures of spinal cord”, Neuroscience. 2010 Feb 17;165(4):1353-69, Leger B. et al., “Atrogin-1 , MuRF1 , and FoXO, as well as phosphorylated GSK-3beta and 4E-BP1 are reduced in skeletal muscle of chronic spinal cord-injured patients”, Muscle Nerve, 2009 Jul; 40(1 ):69-78, and Galimberti D. et al., “GSK33 genetic variability in patients with Multiple Sclerosis”, Neurosci Lett. 201 1 Jun 1 5;497(1 ):46- 8. Furthermore, GSK-33 has been linked to the mood disorders, such as bipolar disorders, depression, and schizophrenia.

Inhibition of GSK-33 may be an important therapeutic target of mood stabilizers, and regulation of GSK-33 may be involved in the therapeutic effects of other drugs used in psychiatry. Dysregulated GSK-33 in mood disorder, bipolar disorder, depression and schizophrenia could have multiple effects that could impair neural plasticity, such as modulation of neuronal architecture, neurogenesis, gene expression and the ability of neurons to respond to stressful, potentially lethal conditions (Jope and Ron, Curr. Drug Targets, 2006, 7, 1421- 1434).

The role of GSK-33 in mood disorder was highlighted by the study of lithium and valproate (Chen et al., J. Neurochem., 1999, 72, 1327- 1330; Klein and Melton, Proc. Natl. Acad. Sci. USA, 1996, 93, 8455-8459), both of which are GSK-33 inhibitors and are used to treat mood disorders. There are also existing reports from the genetic perspective supporting the role of GSK-33 in the disease physiology of bipolar disorder (Gould, Expert. Opin. Ther. Targets, 2006, 10, 377-392).

It was reported a decrease in AKT1 protein levels and its phosphorylation of GSK-33 at Serine-9 in the peripheral lymphocytes and brains of individuals with schizophrenia. Accordingly, this finding supports the proposal that alterations in AKT1 -GSK-33 signaling contribute to schizophrenia pathogenesis (Emamian et al., Nat Genet, 2004, 36, 131- 137).

Additionally, the role of GSK-33 in cancer is a well-accepted phenomenon.

The potential of small molecules that inhibit GSK-33 has been evidenced for some specific cancer treatments (Jia Luo, Cancer Letters, 2009, 273, 194-200). GSK-33 expression and activation are associated with prostate cancer progression (Rinnab et al., Neoplasia, 2008, 10, 624-633) and the inhibition of GSK3b was also proposed as specific target for pancreatic cancer (Garcea et al., Current Cancer Drug Targets, 2007, 7, 209-215) and ovarian cancer (Qi Cao et al., Cell Research, 2006, 16 671 -677). Acute inhibition of GSK-33 in colon-rectal cancer cells activates p53-dependent apoptosis and antagonizes tumor growth (Ghosh et al., Clin Cancer Res 2005, 1 1 , 4580-4588).

The identification of a functional role for GSK-33 in MLL-associated leukaemia suggests that GSK-33 inhibition may be a promising therapy that is selective for transformed cells that are dependent on HOX overexpression (Birch et al., Cancer Cell, 2010, 1 7, 529-531 ).

GSK-33 is involved in numerous inflammatory signalling pathways, for example, among others GSK-33 inhibition has been shown to induce secretion of the anti-inflammatory cytokine IL-1 0. According to this finding, GSK-33 inhibitors could be useful to regulate suppression of inflammation (G. Klamer et al., Current Medicinal Chemistry, 2010, 17(26), 2873-2281, Wang et al., Cytokine, 2010, 53, 130-140).

GSK-33 inhibition has been also shown to attenuate cocaine-induced behaviors in mice. The administration of cocaine in mice pretreated with a GSK-33 inhibitor demonstrated that pharmacological inhibition of GSK3 reduced both the acute behavioral responses to cocaine and the long- term neuroadaptations produced by repeated cocaine (Cocaine-induced hyperactivity and sensitization are dependent on GSK3, Miller JS et al. Neuropharmacology. 2009 Jun; 56(8):1 1 16-23, Epub 2009 Mar 27).

The role of GSK-33 in the development of several forms of epilepsies has been demonstrated in several studies, which suggest that inhibition of GSK-33 could be a pathway for the treatment of epilepsy (Novel glycogen synthase kinase 3 and ubiquitination pathways in progressive myoclonus epilepsy, Lohi H et al., Hum Mol Genet. 2005 Sep 15;14(18):2727-36 and Hyperphosphorylation and aggregation of Tau in laforin-deficient mice, an animal model for Lafora disease, Purl R et al., J Biol Chem. 2009 Aug 21 ;284(34) 22657-63). The relationship between GSK-33 inhibition and treatment of neuropathic pain has been demonstrated in Mazzardo-Martins L. et al., “Glycogen synthase kinase 3-specific inhibitor AR-A014418 decreases neuropathic pain in mice: evidence for the mechanisms of action”, Neuroscience. 2012 Dec 13;226, and Xiaoping Gu et al., “The Role of Akt/GSK33 Signaling Pathway in Neuropathic Pain in Mice”, Poster A525, Anesthesiology 2012 October 13-17, 2012 Washington.

A review on GSK-33, its function, its therapeutic potential and its possible inhibitors is given in “GSK-33: role in therapeutic landscape and development of modulators” (S. Phukan et al., British Journal of Pharmacology (2010), 160, 1- 19).

WO 2004/014864 discloses 1 H-indazole-3-carboxamide compounds as selective cyclin-dependant kinases (CDK) inhibitors. Such compounds are assumed to be useful in the treatment of cancer, through a mechanism mediated by CDK₂, and neurodegenerative diseases, in particular Alzheimer’s disease, through a mechanism mediated by CDK₅, and as anti-viral and anti-fungine, through a mechanism mediated by CDK₇, CDK₈ and CDK₉.

Cyclin-dependant kinases (CDKs) are serine/threonine kinases, first discovered for their role in regulating the cell cycle. CDKs are also involved in regulating transcription, mRNA processing, and the differentiation of nerve cells. Such kinases activate only after their interaction and binding with regulatory subunits, namely cyclins.

Moreover, 1 H-indazole-3-carboxamide compounds were also described as analgesics in the treatment of chronic and neuropathic pain (see, for example, WO 2004/074275 and WO 2004/101 548) and as 5-HT₄ receptor antagonists, useful in the treatment of gastrointestinal disorders, central nervous system disorders and cardiovascular disorders (see, for example, WO 1994/101 74).

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pathway and network analysis of complex ‘omics data

Posted in Clinical Diagnostics, Clinical Genomics, Commercialization, Computational Biology/Systems and Bioinformatics, Curation, Genetics & Pharmaceutical, Genome Biology, Health Economics and Outcomes Research, Health Law & Patient Safety, Innovations, Intellectual Property, Innovations, Commercialization, Investment in technological breakthrough, Law and Medicine Conflicts, Metabolomics, Molecular Genetics & Pharmaceutical, Patents, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Analytics, Population Health Management, Genetics & Pharmaceutical, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, RNA Biology, Cancer and Therapeutics, tagged discrepancy between the FDA and the manufacturer, Identify causal variants from human sequencing data, pathway and network analysis, Pathway Genomics on October 23, 2015| Leave a Comment »

pathway and network analysis of complex ‘omics data

Larry H. Bernstein, MD, FCAP, Curator

LPBI

While blood tests can be used to detect some cancers, the FDA said a San Diego company has no proof its blood test works in patients who have not already been diagnosed with some form of the disease.

WASHINGTON, Sept. 25 (UPI) — A San Diego company selling an early cancer detection test was notified by the U.S. Food and Drug Administration it can find no evidence the test actually works, and is concerned it could prove to be harmful for some people.

Pathway Genomics debuted its CancerIntercept test in early September with claims it can detect cancer cell DNA in the blood, picking up mutations linked to as many as 10 different cancers. The goal is to catch cancer early in people who are “otherwise healthy” and not showing symptoms of the disease.

“Based on our review of your promotional materials and the research publication cited above, we believe you are offering a high risk test that has not received adequate clinical validation and may harm the public health,” said FDA Deputy Director James L. Woods in a letter to the company.

CancerIntercept is billed by the company as a blood test looking for DNA fragments in the bloodstream and testing them for 96 genomic markers it says are found in several specific tumor types.

The direct-to-consumer test can be purchased through the Pathway Genomics website, with programs ranging from a one-time test to a quarterly “subscription” for people who want regular testing.

The company states, in several sections of its website, “the presence of one or more of these genomic markers in a patient’s bloodstream may indicate that the patient has a previously undetected cancer. However, the test is not diagnostic, and thus, follow-up screening and clinical testing would be required to confirm the presence or absence of a specific cancer in the patient.”

The FDA is concerned that people may seek treatment for tumors that do not require medical attention, or spend money and possibly seek out treatment they do not need at all — in either case, unnecessary treatment for cancer is potentially harmful to people, the agency said.

CancerIntercept has not been approved by the FDA for use as a medical device, nor has it been subjected to peer review as most tests of its type would be. The company published a white paper on its website which outlines how the test works, supporting its efficacy with references to several clinical trials on detection of mutated DNA in the bloodstream.

Glenn Braunstein, Chief Medical Officer at Pathway Genomics, told The VergePathway had validated its tests with “hundreds” of patients, though those patients had well-defined, often advanced cancers.

In the letter from the FDA, Woods requests the company provide a timeline for meeting with the agency to review plans for future longitudinal studies on the product and specific details on studies that have been conducted before it was made available to consumers.

http://www.upi.com/Health_News/2015/09/25/FDA-Start-ups-cancer-blood-test-may-be-harmful/4191443181676/

The clinical laboratory is an essential player in the treatment of cancer providing a diagnostic, potentially a prognostic, and follow-up treatment armamentarium. The laboratory diagnostics industry has grown over the last half century into a highly accurate, well regulated industry with highly automated and point of care technologies. Prior to introduction, the tests that are put on the market have to be validated prior to introduction.

How are they validated?

The most common approach is for the test to be used concomitantly with treatment in a clinical trial. Measurements may be made prior to surgical biopsy and treatment, and at a month or 6 months to a year later. The pharmaceutical and diagnostics industries are independent, even though a large company may have both pharmaceutical and diagnostic divisions. Consequently, the integration of diagnostics and therapeutics occurs on the front lines of patient care.

How this discrepancy between the FDA and the manufacturer could occur is not clear because prior to introduction, the test would have to be rigorously reviewed by the American Association for Clinical Chemistry, the largest and most competent organization to cover the scientific work, having industry-based committees. The only problem is that the companies may have products that are patented and have competing claims or interests. This is perhaps most likely to be problematic in the competitive environment of genomics testing.

The company here reported on is Pathway Genomics, that offers Ingenuity for pathway and variant analysis. There is no concern about the analysis methods, that are well studied. The concern is the validation of such method for screening of patients without prior diagnosis.

Model, analyze, and understand the complex biological and chemical systems at the core of life science research with IPA

QIAGEN’S Ingenuity Pathway Analysis (IPA) has been broadly adopted by the life science research community and is cited in thousands of peer-reviewed journal articles.

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https://youtu.be/_HDkjuxYRcY?t=25

For the analysis and interpretation of ’omics data

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Get a better understanding of the isoform-specific biology resulting from RNA-Seq experiments.

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Rapidly Identify and Prioritize Variants

Ingenuity Variant Analysis combines analytical tools and integrated content to help you rapidly identify and prioritize variants by drilling down to a small, targeted subset of compelling variants based both upon published biological evidence and your own knowledge of disease biology. With Variant Analysis, you can interrogate your variants from multiple biological perspectives, explore different biological hypotheses, and identify the most promising variants for follow-up.

Variant Analysis used in NCI-60 Interpretation of Genomic Variants

The NCI-60 Data Set offers tremendous promise in the development and prescription of cancer drugs

97% of surveyed researchers are satisfied with the ease of use of Ingenuity Variant Analysis and we are honored that they chose to share the data through our Publish tool.

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“Being a bioinformatician, I appreciated the speed and the complexity of analysis. Without Variant Analysis, I couldn’t have completed the analysis of 700 exomes in such a short time …. I found Variant Analysis very intuitive and easy to use.”

Francesco Lescai, Senior Research Associate in Genome Analysis, University College of London.

This appears to be the new rocky road to verification for validity in diagnostic and treatment application.

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Atul Butte Talks on Big Data, Open Data and Clinical Trials

Posted in BioIT: BioInformatics, BioIT: BioInformatics, NGS, Clinical & Translational, Pharmaceutical R&D Informatics, Clinical Genomics, Cancer Informatics, Biomedical Measurement Science, Components and IRB related issues, Computational Biology/Systems and Bioinformatics, Regulated Clinical Trials: Design, Methods, Components and IRB related issues on October 17, 2015| Leave a Comment »

Atul Butte TALK on YouTube on Big Data, Open Data and Clinical Trials

Reporter: Aviva Lev-Ari, PhD

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Proteins that control neurotransmitter release

Posted in Academic Publishing, Biological Networks, Cell Biology, Cerebrovascular and Neurodegenerative Diseases, Clinical & Translational, Clinical Genomics, Disease Biology, Gene Regulation, Genetics & Pharmaceutical, Genome Biology, Innovations in Neurophysiology & Neuropsychology, Intellectual Property, International Global Work in Pharmaceutical, Investment in Technological Breakthrough, Molecular Genetics & Pharmaceutical, Neurological Diseases, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Analytics, Pharmaceutical Drug Discovery, Pharmaceutical Industry Competitive Intelligence, Pharmacogenomics, Population Health Management, Proteins, Proteomics, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Schizophrenia, Signaling & Cell Circuits, Small Molecules in Development of Therapeutic Drugs, tagged Genentech, Neuroscience, Richard H. Scheller, Roche Holding, Stanford University School of Medicine on September 6, 2015| Leave a Comment »

Proteins that control neurotransmitter release

Author & Curator: Larry H. Bernstein, MD, FCAP

Richard H. Scheller, PhD

The sec6/8 Complex Is Located at Neurite Outgrowth and Axonal Synapse-Assembly Domains

Christopher D. Hazuka, Davide L. Foletti, Shu-Chan Hsu, Yun Kee, F. Woodward Hopf, and Richard H. Scheller
Department of Molecular and Cellular Physiology, Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California 94305-5428

The Journal of Neuroscience, February 15, 1999, 19(4):1324–1334 http://www.jneurosci.org/content/19/4/1324.full.pdf

The molecules that specify domains on the neuronal plasma membrane for the delivery and accumulation of vesicles during neurite outgrowth and synapse formation are unknown. We investigated the role of the sec6/8 complex, a set of proteins that specifies vesicle targeting sites in yeast and epithelial cells, in neuronal membrane trafficking. This complex was found in layers of developing rat brain undergoing synaptogenesis. In cultured hippocampal neurons, the sec6/8 complex was present in regions of ongoing membrane addition: the tips of growing neurites, filopodia, and growth cones. In young axons, the sec6/8 complex was also confined to periodic domains of the plasma membrane. The distribution of synaptotagmin, synapsin1, sec6, and FM1–43 labeling in cultured neurons suggested that the plasma membrane localization of the sec6/8 complex preceded the arrival of synaptic markers and was downregulated in mature synapses. We propose that the sec6/8 complex specifies sites for targeting vesicles at domains of neurite outgrowth and potential active zones during synaptogenesis. Key words: synaptogenesis; neurotransmission; secretion; exocytosis; synaptic vesicle; vesicle targeting

Targeting of vesicles to synaptic sites during development may use similar mechanisms as those involved in vesicle fusion underlying membrane outgrowth. Before contact with a postsynaptic target, axons possess mobile vesicle clusters bearing synaptotagmin, which fuse with the plasma membrane after stimulation (Matteoli et al., 1992; Kraszewski et al., 1995; Dai and Peng, 1996). Thus, growing axons must contain the molecular machinery required for constitutive exocytosis, endocytosis, and activitydependent vesicle release. However, it is unclear how vesicles become clustered at synapses. Although vesicle fusion in axons might occur anywhere along the plasma membrane, there must be membrane targets that signal the clustering of vesicles for synapse formation. Furthermore, it is unclear how sites of vesicle exocytosis are modified as the neuron forms stable contacts with postsynaptic partners.

Identification of a Novel Rab11/25 Binding Domain Present in Eferin and Rip Proteins

Rytis Prekeris*, Jason M. Davies*, and Richard H. Scheller#
JBC Papers in Press. Published on July 31, 2001 as Manuscript M106133200
http://www.jbc.org/content/early/2001/07/31/jbc.M106133200.full.pdf

Rab11, a low molecular weight GTP binding protein, has been shown to play a key role in a variety of cellular processes, including endosomal recycling, phagocytosis, and transport of secretory proteins from the TGN. In this study we describe a novel Rab11 effector, EF hands containing Rab11 interacting protein (eferin). In addition, we identify a 20 amino acid domain that is present at the C-terminus of eferin and other Rab11/25 interacting proteins, such as Rip11 and nRip11. Using biochemical techniques we demonstrate that this domain is necessary and sufficient for Rab11 binding in vitro and that it is required for localization of Rab11 effector proteins in vivo. The data suggest that various Rab effectors compete with each other for the binding to Rab11/25 possibly accounting for the diversity of Rab11 functions.

Members of the Rab/Ypt GTPase family have emerged as important regulators of vesicular trafficking (1). Rab proteins have been proposed to mediate a variety of functions, including vesicle translocation and docking at a specific fusion sites. Like all small GTPases, Rabs cycle between active (GTP bound) and inactive (GDP bound) conformations (2). In the GTP bound state, Rab proteins can bind a variety of downstream effector proteins, while GTP hydrolysis leads to a conformational change in the “switch” region that renders the Rab GTPase unrecognizable to its effector proteins (3,4). A key question in understanding the interactions between Rabs and their effectors concerns the mechanisms by which Rab GTPases specifically bind a diverse spectrum of effectors and how this is regulated by the common structural motif used as a GTP switch. Biochemical and genetic studies have identified several hypervariable regions that might be involved in determining Rab specificity, including N- and C-termini, as well as α3/β5 by guest on September 6, 2015 http://www.jbc.org/ Downloaded from loop (5,6). Indeed, the recently reported structure of Rab3a bound to a putative effector, rabphillin-3a, revealed that Rab3a/rabphillin-3a complex interacts through two main regions (7). The first consists of conformationally sensitive “switch” regions of Rab3a bound to the a1 helix and the C-terminal part of rabphillin-3a. The second involves the SGAWFF domain of rabphillin-3a which fits into a pocket formed by the three hypervariable complementary determining regions (CDRs) of Rab3a, corresponding to the N- and C-termini and α3/β5 loop. Thus, it appears that the hypervariable RabCDR are involved in determining the specificity of effector binding, while the conserved “switch” regions impart GTP dependency and binding. It remains to be determined, however, whether this paradigm also applies to other Rab/effector complexes. Rab11a, -11b, and -25 are closely related members of Rab GTPase family that have been implicated in regulating a variety of different post-Golgi trafficking pathways, such as protein recycling (8), phagocytosis (9), insulin-stimulated Glut4 insertion in the plasma membrane (10), and membrane trafficking from early endosomes to the transGolgi network (11). During the last few years several Rab11/25 interacting proteins have been identified, including Rab11BP/Rabphilin-11, Rip11, nRip11, and myosin Vb (12- 15). However, the mechanisms of their function, as well as molecular aspects of their interactions with Rab11, remain to be fully understood. In the present study, we report the identification of EF-hands containing Rab11/25 interacting protein (eferin). Furthermore, we characterized a Rab binding domain (RBD11) which is present at the Cterminus of eferin as well as other Rab11/25 binding proteins, such as Rip11 and nRip11. Using biochemical techniques we demonstrated that RBD11 is the region which encodes the specificity for Rab11/25, but is distinct from the region interacting with Rab “switch” domain, since its interactions with the Rab11/25 are not GTP-dependent.

The functional significance of the differences in Rip and eferin interactions with Rab11/25 remains to be determined. One possibility is that additional cellular factors can regulate the affinity of Rab11/25 binding to its effectors. Indeed, the recombinant full length Rip11 binds poorly to Rab11a in pull down and yeast-two hybrid assays as compared to full length endogenous Rip11 from cellular TX-100 extracts (data not shown). Furthermore, it has been previously shown that Rip11 can also interact with γSNAP and cytoskeleton (13,24). Thus, the interactions of Rips and eferin with different factors could be used as a means of differentially regulating Rab11/25 binding. Alternatively, the Rab11/25 binding motif in eferin and Rip11 might be conformationlly hidden and require activation before binding to Rab11/25. We have previously demonstrated that phosphorylation of Rip11 plays an important role in its trafficking (13). Thus, differential phosphorylation on Rab11/25 binding motifs could also play a role in regulating the binding of Rip11 and eferin to Rab GTPases. Despite to recent progress in understanding the roles of Rabs and their effectors in regulating membrane trafficking, we are only beginning to unravel the structural determinants of their function. Identification and characterization of the Rab11/25 binding regions in Rip and Eferin proteins will be of a crucial importance in understanding the molecular mechanisms involved in differential regulation of the variety of Rab11-dependent trafficking pathways.

Rapid identification of reactive cysteine residues for site-specific labeling of antibody-Fabs.

J. Immunol. Methods

J Immunol Methods 2008 Mar 14;332(1-2):41-52. Epub 2008 Jan 14.

Jagath R Junutula, Sunil Bhakta, Helga Raab, Karen E Ervin, Charles Eigenbrot, Richard Vandlen, Richard H Scheller,Henry B Lowman

Genentech Inc., 1DNA Way, South San Francisco, California, 94080, United States. jagath@gene.com

Cysteines with reactive thiol groups are attractive tools for site-specific labeling of proteins. Engineering a reactive cysteine residue into proteins with multiple disulfide bonds is often a challenging task as it may interfere with structural and functional properties of the protein. Here we developed a phage display-based biochemical assay, PHESELECTOR (Phage ELISA for Selection of Reactive Thiols) to rapidly screen reactive thiol groups on antibody fragments without interfering with their antigen binding, using trastuzumab-Fab (hu4D5Fab) as a model system

Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index.

Nat. Biotechnol.

Nat Biotechnol 2008 Aug 20;26(8):925-32. Epub 2008 Jul 20.

Genentech Inc, South San Francisco, California 94080, USA.

Antibody-drug conjugates enhance the antitumor effects of antibodies and reduce adverse systemic effects of potent cytotoxic drugs. However, conventional drug conjugation strategies yield heterogenous conjugates with relatively narrow therapeutic index (maximum tolerated dose/curative dose). Using leads from our previously described phage display-based method to predict suitable conjugation sites, we engineered cysteine substitutions at positions on light and heavy chains that provide reactive thiol groups and do not perturb immunoglobulin folding and assembly, or alter antigen binding.

Isolation and characterization of a Drosophila neuropeptide gene.

Neuron

Neuron 2008 Nov;60(3):400-1

Richard H Scheller, John R Nambu

Engineered thio-trastuzumab-DM1 conjugate with an improved therapeutic index to target human epidermal growth factor receptor 2-positive breast cancer.

Clin. Cancer Res.

Clin Cancer Res 2010 Oct 30;16(19):4769-78. Epub 2010 Aug 30.

Genentech, Inc., South San Francisco, California 94080, USA. jagath@gene.com

Antibody drug conjugates (ADCs) combine the ideal properties of both antibodies and cytotoxic drugs by targeting potent drugs to the antigen-expressing tumor cells, thereby enhancing their antitumor activity. Successful ADC development for a given target antigen depends on optimization of antibody selection, linker stability, cytotoxic drug potency, and mode of linker-drug conjugation to the antibody. Here, we systematically examined the in vitro potency as well as in vivo preclinical efficacy and safety profiles of a heterogeneous preparation of conventional trastuzumab-mcc-DM1 (TMAb-mcc-DM1) ADC with that of a homogeneous engineered thio-trastuzumab-mpeo-DM1 (thioTMAb-mpeo-DM1) conjugate.

Primary cilia membrane assembly is initiated by Rab11 and transport protein particle II (TRAPPII) complex-dependent trafficking of Rabin8 to the centrosome.

Proc. Natl. Acad. Sci. U.S.A.

Proc Natl Acad Sci U S A 2011 Feb 27;108(7):2759-64. Epub 2011 Jan 27.

Christopher J Westlake, Lisa M Baye, Maxence V Nachury, Kevin J Wright, Karen E Ervin, Lilian Phu, Cecile Chalouni,John S Beck, Donald S Kirkpatrick, Diane C Slusarski, Val C Sheffield, Richard H Scheller, Peter K Jackson

Genentech, South San Francisco, CA 94080, USA.

Sensory and signaling pathways are exquisitely organized in primary cilia. Bardet-Biedl syndrome (BBS) patients have compromised cilia and signaling. BBS proteins form the BBSome, which binds Rabin8, a guanine nucleotide exchange factor (GEF) activating the Rab8 GTPase, required for ciliary assembly.

Conjugation site modulates the in vivo stability and therapeutic activity of antibody-drug conjugates.

Nat. Biotechnol.

Nat Biotechnol 2012 Feb 22;30(2):184-9. Epub 2012 Jan 22.

Genentech Inc., 1 DNA Way, S. San Francisco, California, USA.

The reactive thiol in cysteine is used for coupling maleimide linkers in the generation of antibody conjugates. To assess the impact of the conjugation site, we engineered cysteines into a therapeutic HER2/neu antibody at three sites differing in solvent accessibility and local charge. The highly solvent-accessible site rapidly lost conjugated thiol-reactive linkers in plasma owing to maleimide exchange with reactive thiols in albumin, free cysteine or glutathione.

Rac and Rab GTPases dual effector Nischarin regulates vesicle maturation to facilitate survival of intracellular bacteria.

EMBO J.

EMBO J 2013 Mar 5;32(5):713-27. Epub 2013 Feb 5.

Coenraad Kuijl, Manohar Pilli, Suresh K Alahari, Hans Janssen, Poh-Sim Khoo, Karen E Ervin, Monica Calero,Sobhanaditya Jonnalagadda, Richard H Scheller, Jacques Neefjes, Jagath R Junutula

Genentech Inc., South San Francisco, CA 94080, USA. kuijlc@gene.com

The intracellular pathogenic bacterium Salmonella enterica serovar typhimurium (Salmonella) relies on acidification of the Salmonella-containing vacuole (SCV) for survival inside host cells. The transport and fusion of membrane-bound compartments in a cell is regulated by small GTPases, including Rac and members of the Rab GTPase family, and their effector proteins. However, the role of these components in survival of intracellular pathogens is not completely understood.

In search of the molecular mechanism of intracellular membrane fusion and neurotransmitter release.

Nat. Med.

Nat Med 2013 Oct;19(10):1232-5

Richard H Scheller

Genentech Research and Early Development, 1 DNA Way, San Francisco, California, USA.

An improved and robust DNA immunization method to develop antibodies against extracellular loops of multi-transmembrane proteins.

MAbs

MAbs 2014 Jan-Feb;6(1):95-107

Meredith Hazen, Sunil Bhakta, Rajesh Vij, Steven Randle, Dara Kallop, Vicki Chiang, Isidro Hötzel, Bijay S Jaiswal, Karen E Ervin, Bing Li, Robby M Weimer, Paul Polakis, Richard H Scheller, Jagath R Junutula, Jo-Anne S Hongo

Multi-transmembrane proteins are especially difficult targets for antibody generation largely due to the challenge of producing a protein that maintains its native conformation in the absence of a stabilizing membrane. Here, we describe an immunization strategy that successfully resulted in the identification of monoclonal antibodies that bind specifically to extracellular epitopes of a 12 transmembrane protein, multi-drug resistant protein 4 (MRP4). These monoclonal antibodies were developed following hydrodynamic tail vein immunization with a cytomegalovirus (CMV) promoter-based plasmid expressing MRP4 cDNA and were characterized by flow cytometry.

Site-specific trastuzumab maytansinoid antibody-drug conjugates with improved therapeutic activity through linker and antibody engineering.

J. Med. Chem.

J Med Chem 2014 Oct 18;57(19):7890-9. Epub 2014 Sep 18.

Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.

Antibody-drug conjugates (ADCs) have a significant impact toward the treatment of cancer, as evidenced by the clinical activity of the recently approved ADCs, brentuximab vedotin for Hodgkin lymphoma and ado-trastuzumab emtansine (trastuzumab-MCC-DM1) for metastatic HER2+ breast cancer. DM1 is an analog of the natural product maytansine, a microtubule inhibitor that by itself has limited clinical activity and high systemic toxicity. However, by conjugation of DM1 to trastuzumab, the safety was improved and clinical activity was demonstrated.

Richard H Scheller, PhD

Published on 16 Sep 2014

The Keck School of Medicine of USC is the first medical school in the nation to host the Lasker Lectures, featuring recipients of the prestigious 2013 Albert Lasker Basic Medical Research Award. In this installment, Richard H. Scheller, PhD, executive vice president of Genentech research and early development, discusses breakthoughs in drug development that are turning the tide in the war against cancer.

https://www.youtube.com/watch?v=Fx54EVJMcxM

Kavli Prize 2015

Xenon Pharmaceuticals Appoints Dr. Richard H. Scheller to Its Board of Directors http://fb.me/78z2HoJKa

Biopharmaceutical company Xenon Pharmaceuticals (NasdaqGM:XENE) reported on Monday the addition of Richard H. Scheller, PhD to its board of directors.

Most recently, Dr Scheller has served as chief science officer and head of Therapeutics at 23andMe.

Previously Dr Scheller was the executive vice president at Genentech Research and Early Development & a member of the Roche Corporate Executive Committee; chief scientific officer, executive vice president of Research and senior vice president of Research at Genentech; as well as a professor of Molecular and Cellular Physiology and of Biological Sciences at Stanford University Medical Center and an investigator of the Howard Hughes Medical Institute.

Dr Scheller is currently an adjunct professor in the Department of Biochemistry and Biophysics, School of Medicine at the University of California, San Francisco.

He has been a Director at Xenon Pharmaceuticals Inc. since March 16, 2015 and Medrio, Inc. since November 2012. He serves as a Member of the Medical and Scientific Review Board of Evotec (US), Inc. (Renovis Inc.). In 2014, he was named a trustee of Caltech. He served as a Member of Scientific Advisory Board of Intra-Cellular Therapies, Inc. and Rinat Neuroscience Corporation.

He served on numerous advisory boards including the National Advisory Mental Health Council of the National Institutes of Health. Dr. Scheller served as chairman of the Genentech Foundation’s board of directors. He is a globally recognized leader in biomedical research.

He has published over 200 papers in scientific journals, and worked in cell biology. He has received several additional awards for his work elucidating the molecular mechanisms governing neurotransmitter release, including the 2013 Albert Lasker Basic Medical Research Award, the 2014 California Institute of Technology’s Caltech Distinguished Alumni Award, the 2010 Kavli Prize in Neuroscience, and the 1997 U.S. National Academy of Sciences Award in Molecular Biology. He is a Fellow of the American Academy of Arts and Sciences. Dr. Scheller holds a Doctorate in Chemistry from the California Institute of Technology in 1980, where he was also a Postdoctoral Fellow, Division of Biology. He was also a Postdoctoral Fellow at Columbia University, College of Physicians & Surgeons. He has Bachelor’s Degree in Biochemistry in 1975 at the University of Wisconsin, Madison.

Education: 1971-1975 University of Wisconsin-Madison B.S. – Biochemistry with Honors 1975-1980 California Institute of Technology Ph.D. – Chemistry – Advisor: Eric H. Davidson 1980-1981 California Institute of Technology Postdoctoral Fellow-Division of Biology Advisor: Eric H. Davidson 1981-1982 Columbia University-College of Physicians & Surgeons Postdoctoral Fellow-Molecular Neurobiology Advisors: Richard Axel and Eric R. Kandel Industry Positions: 2001-2003 Senior Vice President – Research Genentech, Inc. 2003-2009 Executive Vice President – Research Genentech, Inc. 2008-2009 Chief Scientific Officer and Executive Vice President – Research Genentech, Inc. 2009- Executive Vice President – Genentech Research and Early Development (gRED) and Member of the Enlarged Roche Corporate Executive Committee Academic Appointments: 1982-1987 Assistant Professor, Department of Biological Sciences, Stanford University 1987-1990 Associate Professor, Department of Biological Sciences, Stanford University 1990-1993 Associate Professor, Department of Molecular and Cellular Physiology, Stanford University Associate Professor (by courtesy), Department of Biological Sciences, Stanford University

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Sexual Desire Disorder in Pre-menopausal Women: Addyi (flibanserin) is intended to increase libido – ‘Female Viagra’ approved by FDA

Posted in Endocrine Diseases, FDA, FDA Regulatory Affairs, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Reproductive Andrology, Embryology, Genomic Endocrinology, Preimplantation Genetic Diagnosis and Reproductive Genomics, Reproductive Biology & Bio Instrumentation on August 18, 2015| Leave a Comment »

Sexual Desire Disorder in Pre-menopausal Women: Addyi (flibanserin) is intended to increase libido – ‘Female Viagra’ approved by FDA

Reporter: Aviva Lev-Ari, PhD

FDA News Release

FDA approves first treatment for sexual desire disorder

For Immediate Release

August 18, 2015

Release

Español

The U.S. Food and Drug Administration today approved Addyi (flibanserin) to treat acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women. Prior to Addyi’s approval, there were no FDA-approved treatments for sexual desire disorders in men or women.

“Today’s approval provides women distressed by their low sexual desire with an approved treatment option,” said Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research (CDER). “The FDA strives to protect and advance the health of women, and we are committed to supporting the development of safe and effective treatments for female sexual dysfunction.”

HSDD is characterized by low sexual desire that causes marked distress or interpersonal difficulty and is not due to a co-existing medical or psychiatric condition, problems within the relationship, or the effects of a medication or other drug substance. HSDD is acquired when it develops in a patient who previously had no problems with sexual desire. HSDD is generalized when it occurs regardless of the type of sexual activity, the situation or the sexual partner.

“Because of a potentially serious interaction with alcohol, treatment with Addyi will only be available through certified health care professionals and certified pharmacies,” continued Dr. Woodcock. “Patients and prescribers should fully understand the risks associated with the use of Addyi before considering treatment.”

Addyi can cause severely low blood pressure (hypotension) and loss of consciousness (syncope). These risks are increased and more severe when patients drink alcohol or take Addyi with certain medicines (known as moderate or strong CYP3A4 inhibitors) that interfere with the breakdown of Addyi in the body. Because of the alcohol interaction, the use of alcohol is contraindicated while taking Addyi. Health care professionals must assess the likelihood of the patient reliably abstaining from alcohol before prescribing Addyi.

Addyi is being approved with a risk evaluation and mitigation strategy (REMS), which includes elements to assure safe use (ETASU). The FDA is requiring this REMS because of the increased risk of severe hypotension and syncope due to the interaction between Addyi and alcohol. The REMS requires that prescribers be certified with the REMS program by enrolling and completing training. Certified prescribers must counsel patients using a Patient-Provider Agreement Form about the increased risk of severe hypotension and syncope and about the importance of not drinking alcohol during treatment with Addyi. Additionally, pharmacies must be certified with the REMS program by enrolling and completing training. Certified pharmacies must only dispense Addyi to patients with a prescription from a certified prescriber. Additionally, pharmacists must counsel patients prior to dispensing not to drink alcohol during treatment with Addyi.

Addyi is also being approved with a Boxed Warning to highlight the risks of severe hypotension and syncope in patients who drink alcohol during treatment with Addyi, in those who also use moderate or strong CYP3A4 inhibitors, and in those who have liver impairment. Addyi is contraindicated in these patients. In addition, the FDA is requiring the company that owns Addyi to conduct three well-designed studies in women to better understand the known serious risks of the interaction between Addyi and alcohol.

Addyi is a serotonin 1A receptor agonist and a serotonin 2A receptor antagonist, but the mechanism by which the drug improves sexual desire and related distress is not known. Addyi is taken once daily. It is dosed at bedtime to help decrease the risk of adverse events occurring due to possible hypotension, syncope and central nervous system depression (such as sleepiness and sedation). Patients should discontinue treatment after eight weeks if they do not report an improvement in sexual desire and associated distress.

The effectiveness of the 100 mg bedtime dose of Addyi was evaluated in three 24-week randomized, double-blind, placebo-controlled trials in about 2,400 premenopausal women with acquired, generalized HSDD. The average age of the trial participants was 36 years, with an average duration of HSDD of approximately five years. In these trials, women counted the number of satisfying sexual events, reported sexual desire over the preceding four weeks (scored on a range of 1.2 to 6.0) and reported distress related to low sexual desire (on a range of 0 to 4). On average, treatment with Addyi increased the number of satisfying sexual events by 0.5 to one additional event per month over placebo increased the sexual desire score by 0.3 to 0.4 over placebo, and decreased the distress score related to sexual desire by 0.3 to 0.4 over placebo. Additional analyses explored whether the improvements with Addyi were meaningful to patients, taking into account the effects of treatment seen among those patients who reported feeling much improved or very much improved overall. Across the three trials, about 10 percent more Addyi-treated patients than placebo-treated patients reported meaningful improvements in satisfying sexual events, sexual desire or distress. Addyi has not been shown to enhance sexual performance.

The 100 mg bedtime dose of Addyi has been administered to about 3,000 generally healthy premenopausal women with acquired, generalized HSDD in clinical trials, of whom about 1,700 received treatment for at least six months and 850 received treatment for at least one year.

The most common adverse reactions associated with the use of Addyi are dizziness, somnolence (sleepiness), nausea, fatigue, insomnia and dry mouth.

The FDA has recognized for some time the challenges involved in developing treatments for female sexual dysfunction. The FDA held a public Patient-Focused Drug Development meeting and scientific workshop on female sexual dysfunction on October 27 and October 28, 2014, to solicit perspectives directly from patients about their condition and its impact on daily life, and to discuss the scientific challenges related to developing drugs to treat these disorders. The FDA continues to encourage drug development in this area.

Consumers and health care professionals are encouraged to report adverse reactions from the use of Addyi to the FDA’s MedWatch Adverse Event Reporting program at www.fda.gov/MedWatch or by calling 1-800-FDA-1088.

Addyi is marketed by Sprout Pharmaceuticals, based in Raleigh, North Carolina.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

SOURCE

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm458734.htm

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Treatment for Chronic Leukemias [2.4.4B]

Posted in Academic Publishing, Automated Cell Processing, BioIT: BioInformatics, Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Informatics, Cancer Screening, Clinical & Translational, Clinical Genomics, Curation, Diagnostics and Lab Tests, Discovery process, Disease Biology, Experimental validation, Explanatory, Gene Regulation, Genetics & Innovations in Treatment, Genetics & Pharmaceutical, Genomic Expression, Hematopoiesis, Historical relevance, Human Immune System in Health and in Disease, Molecular Genetics & Pharmaceutical, Mutant Gene Expression, Myelodysplasia, Myelofibrosis, Neutrophilia, Pharmaceutical Analytics, Pharmaceutical Drug Discovery, Platelet count disorder, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Technology Advance Assessment of, tagged Chemotherapy, chronic lymphocytic leukemia, Chronic myelogenous leukemia, myelodyspalstic syndromes on August 11, 2015| Leave a Comment »

Treatment for Chronic Leukemias [2.4.4B]

Larry H. Bernstein, MD, FCAP, Author, Curator, Editor

http://pharmaceuticalintelligence.com/2015/8/11/larryhbern/Treatment-for-Chronic-Leukemias-[2.4.4B]

2.4.4B1 Treatment for CML

Chronic Myelogenous Leukemia Treatment (PDQ®)

http://www.cancer.gov/cancertopics/pdq/treatment/CML/Patient/page4

Treatment Option Overview

Key Points for This Section

There are different types of treatment for patients with chronic myelogenous leukemia.

Six types of standard treatment are used:

Targeted therapy
Chemotherapy
Biologic therapy
High-dose chemotherapy with stem cell transplant
Donor lymphocyte infusion (DLI)
Surgery

New types of treatment are being tested in clinical trials.

Patients may want to think about taking part in a clinical trial.

Patients can enter clinical trials before, during, or after starting their cancer treatment.

Follow-up tests may be needed.

There are different types of treatment for patients with chronic myelogenous leukemia.

Different types of treatment are available for patients with chronic myelogenous leukemia (CML). Some treatments are standard (the currently used treatment), and some are being tested in clinical trials. A treatment clinical trial is a research study meant to help improve current treatments or obtain information about new treatments for patients with cancer. When clinical trials show that a new treatment is better than the standard treatment, the new treatment may become the standard treatment. Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.

Six types of standard treatment are used:

Targeted therapy

Targeted therapy is a type of treatment that uses drugs or other substances to identify and attack specific cancer cells without harming normal cells. Tyrosine kinase inhibitors are targeted therapy drugs used to treat chronic myelogenous leukemia.

Imatinib mesylate, nilotinib, dasatinib, and ponatinib are tyrosine kinase inhibitors that are used to treat CML.

See Drugs Approved for Chronic Myelogenous Leukemia for more information.

Chemotherapy

Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy). When chemotherapy is placed directly into the cerebrospinal fluid, an organ, or a body cavity such as the abdomen, the drugs mainly affect cancer cells in those areas (regional chemotherapy). The way the chemotherapy is given depends on the type and stage of the cancer being treated.

See Drugs Approved for Chronic Myelogenous Leukemia for more information.

Biologic therapy

Biologic therapy is a treatment that uses the patient’s immune system to fight cancer. Substances made by the body or made in a laboratory are used to boost, direct, or restore the body’s natural defenses against cancer. This type of cancer treatment is also called biotherapy or immunotherapy.

See Drugs Approved for Chronic Myelogenous Leukemia for more information.

High-dose chemotherapy with stem cell transplant

High-dose chemotherapy with stem cell transplant is a method of giving high doses of chemotherapy and replacing blood-forming cells destroyed by the cancer treatment. Stem cells (immature blood cells) are removed from the blood or bone marrow of the patient or a donor and are frozen and stored. After the chemotherapy is completed, the stored stem cells are thawed and given back to the patient through an infusion. These reinfused stem cells grow into (and restore) the body’s blood cells.

See Drugs Approved for Chronic Myelogenous Leukemia for more information.

Donor lymphocyte infusion (DLI)

Donor lymphocyte infusion (DLI) is a cancer treatment that may be used after stem cell transplant.Lymphocytes (a type of white blood cell) from the stem cell transplant donor are removed from the donor’s blood and may be frozen for storage. The donor’s lymphocytes are thawed if they were frozen and then given to the patient through one or more infusions. The lymphocytes see the patient’s cancer cells as not belonging to the body and attack them.

Surgery

Splenectomy

What`s new in chronic myeloid leukemia research and treatment?

http://www.cancer.org/cancer/leukemia-chronicmyeloidcml/detailedguide/leukemia-chronic-myeloid-myelogenous-new-research

Combining the targeted drugs with other treatments

Imatinib and other drugs that target the BCR-ABL protein have proven to be very effective, but by themselves these drugs don’t help everyone. Studies are now in progress to see if combining these drugs with other treatments, such as chemotherapy, interferon, or cancer vaccines (see below) might be better than either one alone. One study showed that giving interferon with imatinib worked better than giving imatinib alone. The 2 drugs together had more side effects, though. It is also not clear if this combination is better than treatment with other tyrosine kinase inhibitors (TKIs), such as dasatinib and nilotinib. A study going on now is looking at combing interferon with nilotinib.

Other studies are looking at combining other drugs, such as cyclosporine or hydroxychloroquine, with a TKI.

New drugs for CML

Because researchers now know the main cause of CML (the BCR-ABL gene and its protein), they have been able to develop many new drugs that might work against it.

In some cases, CML cells develop a change in the BCR-ABL oncogene known as a T315I mutation, which makes them resistant to many of the current targeted therapies (imatinib, dasatinib, and nilotinib). Ponatinib is the only TKI that can work against T315I mutant cells. More drugs aimed at this mutation are now being tested.

Other drugs called farnesyl transferase inhibitors, such as lonafarnib and tipifarnib, seem to have some activity against CML and patients may respond when these drugs are combined with imatinib. These drugs are being studied further.

Other drugs being studied in CML include the histone deacetylase inhibitor panobinostat and the proteasome inhibitor bortezomib (Velcade).

Several vaccines are now being studied for use against CML.

2.4.4.B2 Chronic Lymphocytic Leukemia

Chronic Lymphocytic Leukemia Treatment (PDQ®)

General Information About Chronic Lymphocytic Leukemia

Key Points for This Section

Chronic lymphocytic leukemia is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell).
Leukemia may affect red blood cells, white blood cells, and platelets.
Older age can affect the risk of developing chronic lymphocytic leukemia.
Signs and symptoms of chronic lymphocytic leukemia include swollen lymph nodes and tiredness.
Tests that examine the blood, bone marrow, and lymph nodes are used to detect (find) and diagnose chronic lymphocytic leukemia.
Certain factors affect treatment options and prognosis (chance of recovery).
Chronic lymphocytic leukemia is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell).

Chronic lymphocytic leukemia (also called CLL) is a blood and bone marrow disease that usually gets worse slowly. CLL is one of the most common types of leukemia in adults. It often occurs during or after middle age; it rarely occurs in children.

http://www.cancer.gov/images/cdr/live/CDR755927-750.jpg

Anatomy of the bone; drawing shows spongy bone, red marrow, and yellow marrow. A cross section of the bone shows compact bone and blood vessels in the bone marrow. Also shown are red blood cells, white blood cells, platelets, and a blood stem cell.

Anatomy of the bone. The bone is made up of compact bone, spongy bone, and bone marrow. Compact bone makes up the outer layer of the bone. Spongy bone is found mostly at the ends of bones and contains red marrow. Bone marrow is found in the center of most bones and has many blood vessels. There are two types of bone marrow: red and yellow. Red marrow contains blood stem cells that can become red blood cells, white blood cells, or platelets. Yellow marrow is made mostly of fat.

Leukemia may affect red blood cells, white blood cells, and platelets.

Normally, the body makes blood stem cells (immature cells) that become mature blood cells over time. A blood stem cell may become a myeloid stem cell or a lymphoid stem cell.

A myeloid stem cell becomes one of three types of mature blood cells:

Red blood cells that carry oxygen and other substances to all tissues of the body.
White blood cells that fight infection and disease.
Platelets that form blood clots to stop bleeding.

A lymphoid stem cell becomes a lymphoblast cell and then one of three types of lymphocytes (white blood cells):

B lymphocytes that make antibodies to help fight infection.
T lymphocytes that help B lymphocytes make antibodies to fight infection.
Natural killer cells that attack cancer cells and viruses.

Blood cell development. CDR526538-750

http://www.cancer.gov/images/cdr/live/CDR526538-750.jpg

Blood cell development; drawing shows the steps a blood stem cell goes through to become a red blood cell, platelet, or white blood cell. A myeloid stem cell becomes a red blood cell, a platelet, or a myeloblast, which then becomes a granulocyte (the types of granulocytes are eosinophils, basophils, and neutrophils). A lymphoid stem cell becomes a lymphoblast and then becomes a B-lymphocyte, T-lymphocyte, or natural killer cell.

Blood cell development. A blood stem cell goes through several steps to become a red blood cell, platelet, or white blood cell.

In CLL, too many blood stem cells become abnormal lymphocytes and do not become healthy white blood cells. The abnormal lymphocytes may also be called leukemia cells. The lymphocytes are not able to fight infection very well. Also, as the number of lymphocytes increases in the blood and bone marrow, there is less room for healthy white blood cells, red blood cells, and platelets. This may cause infection, anemia, and easy bleeding.

This summary is about chronic lymphocytic leukemia. See the following PDQ summaries for more information about leukemia:

Adult Acute Lymphoblastic Leukemia Treatment.
Childhood Acute Lymphoblastic Leukemia Treatment.
Adult Acute Myeloid Leukemia Treatment.
Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment.
Chronic Myelogenous Leukemia Treatment.
Hairy Cell Leukemia Treatment

Older age can affect the risk of developing chronic lymphocytic leukemia.

Anything that increases your risk of getting a disease is called a risk factor. Having a risk factor does not mean that you will get cancer; not having risk factors doesn’t mean that you will not get cancer. Talk with your doctor if you think you may be at risk. Risk factors for CLL include the following:

Being middle-aged or older, male, or white.
A family history of CLL or cancer of the lymph system.
Having relatives who are Russian Jews or Eastern European Jews.

Signs and symptoms of chronic lymphocytic leukemia include swollen lymph nodes and tiredness.

Usually CLL does not cause any signs or symptoms and is found during a routine blood test. Signs and symptoms may be caused by CLL or by other conditions. Check with your doctor if you have any of the following:

Painless swelling of the lymph nodes in the neck, underarm, stomach, or groin.
Feeling very tired.
Pain or fullness below the ribs.
Fever and infection.
Weight loss for no known reason.

Tests that examine the blood, bone marrow, and lymph nodes are used to detect (find) and diagnose chronic lymphocytic leukemia.

The following tests and procedures may be used:

Physical exam and history : An exam of the body to check general signs of health, including checking for signs of disease, such as lumps or anything else that seems unusual. A history of the patient’s health habits and past illnesses and treatments will also be taken.

Complete blood count (CBC) with differential : A procedure in which a sample of blood is drawn and checked for the following:

The number of red blood cells and platelets.

The number and type of white blood cells.

The amount of hemoglobin (the protein that carries oxygen) in the red blood cells.

The portion of the blood sample made up of red blood cells.

Results from the Phase 3 Resonate™ Trial

Significantly improved progression free survival (PFS) vs ofatumumab in patients with previously treated CLL

Patients taking IMBRUVICA® had a 78% statistically significant reduction in the risk of disease progression or death compared with patients who received ofatumumab¹
In patients with previously treated del 17p CLL, median PFS was not yet reached with IMBRUVICA® vs 5.8 months with ofatumumab (HR 0.25; 95% CI: 0.14, 0.45)¹

Significantly prolonged overall survival (OS) with IMBRUVICA® vs ofatumumab in patients with previously treated CLL

In patients with previously treated CLL, those taking IMBRUVICA® had a 57% statistically significant reduction in the risk of death compared with those who received ofatumumab (HR 0.43; 95% CI: 0.24, 0.79; P<0.05)¹

Typical treatment of chronic lymphocytic leukemia

http://www.cancer.org/cancer/leukemia-chroniclymphocyticcll/detailedguide/leukemia-chronic-lymphocytic-treating-treatment-by-risk-group

Treatment options for chronic lymphocytic leukemia (CLL) vary greatly, depending on the person’s age, the disease risk group, and the reason for treating (for example, which symptoms it is causing). Many people live a long time with CLL, but in general it is very difficult to cure, and early treatment hasn’t been shown to help people live longer. Because of this and because treatment can cause side effects, doctors often advise waiting until the disease is progressing or bothersome symptoms appear, before starting treatment.

If treatment is needed, factors that should be taken into account include the patient’s age, general health, and prognostic factors such as the presence of chromosome 17 or chromosome 11 deletions or high levels of ZAP-70 and CD38.

Initial treatment

Patients who might not be able to tolerate the side effects of strong chemotherapy (chemo), are often treated with chlorambucil alone or with a monoclonal antibody targeting CD20 like rituximab (Rituxan) or obinutuzumab (Gazyva). Other options include rituximab alone or a corticosteroid like prednisione.

In stronger and healthier patients, there are many options for treatment. Commonly used treatments include:

FCR: fludarabine (Fludara), cyclophosphamide (Cytoxan), and rituximab
Bendamustine (sometimes with rituximab)
FR: fludarabine and rituximab
CVP: cyclophosphamide, vincristine, and prednisone (sometimes with rituximab)
CHOP: cyclophosphamide, doxorubicin, vincristine (Oncovin), and prednisone
Chlorambucil combined with prednisone, rituximab, obinutuzumab, or ofatumumab
PCR: pentostatin (Nipent), cyclophosphamide, and rituximab
Alemtuzumab (Campath)
Fludarabine (alone)

Other drugs or combinations of drugs may also be also used.

If the only problem is an enlarged spleen or swollen lymph nodes in one region of the body, localized treatment with low-dose radiation therapy may be used. Splenectomy (surgery to remove the spleen) is another option if the enlarged spleen is causing symptoms.

Sometimes very high numbers of leukemia cells in the blood cause problems with normal circulation. This is calledleukostasis. Chemo may not lower the number of cells until a few days after the first dose, so before the chemo is given, some of the cells may be removed from the blood with a procedure called leukapheresis. This treatment lowers blood counts right away. The effect lasts only for a short time, but it may help until the chemo has a chance to work. Leukapheresis is also sometimes used before chemo if there are very high numbers of leukemia cells (even when they aren’t causing problems) to prevent tumor lysis syndrome (this was discussed in the chemotherapy section).

Some people who have very high-risk disease (based on prognostic factors) may be referred for possible stem cell transplant (SCT) early in treatment.

Second-line treatment of CLL

If the initial treatment is no longer working or the disease comes back, another type of treatment may help. If the initial response to the treatment lasted a long time (usually at least a few years), the same treatment can often be used again. If the initial response wasn’t long-lasting, using the same treatment again isn’t as likely to be helpful. The options will depend on what the first-line treatment was and how well it worked, as well as the person’s health.

Many of the drugs and combinations listed above may be options as second-line treatments. For many people who have already had fludarabine, alemtuzumab seems to be helpful as second-line treatment, but it carries an increased risk of infections. Other purine analog drugs, such as pentostatin or cladribine (2-CdA), may also be tried. Newer drugs such as ofatumumab, ibrutinib (Imbruvica), and idelalisib (Zydelig) may be other options.

If the leukemia responds, stem cell transplant may be an option for some patients.

Some people may have a good response to first-line treatment (such as fludarabine) but may still have some evidence of a small number of leukemia cells in the blood, bone marrow, or lymph nodes. This is known as minimal residual disease. CLL can’t be cured, so doctors aren’t sure if further treatment right away will be helpful. Some small studies have shown that alemtuzumab can sometimes help get rid of these remaining cells, but it’s not yet clear if this improves survival.

Treating complications of CLL

One of the most serious complications of CLL is a change (transformation) of the leukemia to a high-grade or aggressive type of non-Hodgkin lymphoma called diffuse large cell lymphoma. This happens in about 5% of CLL cases, and is known as Richter syndrome. Treatment is often the same as it would be for lymphoma (see our document called Non-Hodgkin Lymphoma for more information), and may include stem cell transplant, as these cases are often hard to treat.

Less often, CLL may transform to prolymphocytic leukemia. As with Richter syndrome, these cases can be hard to treat. Some studies have suggested that certain drugs such as cladribine (2-CdA) and alemtuzumab may be helpful.

In rare cases, patients with CLL may have their leukemia transform into acute lymphocytic leukemia (ALL). If this happens, treatment is likely to be similar to that used for patients with ALL (see our document called Leukemia: Acute Lymphocytic).

Acute myeloid leukemia (AML) is another rare complication in patients who have been treated for CLL. Drugs such as chlorambucil and cyclophosphamide can damage the DNA of blood-forming cells. These damaged cells may go on to become cancerous, leading to AML, which is very aggressive and often hard to treat (see our document calledLeukemia: Acute Myeloid).

CLL can cause problems with low blood counts and infections. Treatment of these problems were discussed in the section “Supportive care in chronic lymphocytic leukemia.”

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Treatments other than Chemotherapy for Leukemias and Lymphomas [2.5]

Posted in Acute lymphocytic leukemia, Acute myelocytic leukemia, Autologous Cell Therapy, Automated Cell Processing, Biomarkers & Medical Diagnostics, Bone marrow derived cells, Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Circulating Progenitor Cells, Clinical Diagnostics, Clinical Genomics, Curation, Diagnostics and Lab Tests, Disease Biology, Evidence-based decision-making, Explanatory, Gene Regulation, Hematology, Hematopoiesis, Human Immune System in Health and in Disease, Imaging-based Cancer Patient Management, Lymphoma, Medical Imaging Technology, Myelodysplasia, Myelofibrosis, Regenerative Biology and Medicine, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Stem Cells for Regenerative Medicine, Technology Advance Assessment of, Translational Science, Umbilical cord cells, tagged allogeneic hemopoietic transplant, Autologous stem cell transplant, blood transfusion, hematological malignancies, nonchemotherapy support, Radiation therapy, stem cell therapy on August 11, 2015| Leave a Comment »

Treatments other than Chemotherapy for Leukemias and Lymphomas

Author, Curator, Editor: Larry H. Bernstein, MD, FCAP

2.5.1 Radiation Therapy

http://www.lls.org/treatment/types-of-treatment/radiation-therapy

Radiation therapy, also called radiotherapy or irradiation, can be used to treat leukemia, lymphoma, myeloma and myelodysplastic syndromes. The type of radiation used for radiotherapy (ionizing radiation) is the same that’s used for diagnostic x-rays. Radiotherapy, however, is given in higher doses.

Radiotherapy works by damaging the genetic material (DNA) within cells, which prevents them from growing and reproducing. Although the radiotherapy is directed at cancer cells, it can also damage nearby healthy cells. However, current methods of radiotherapy have been improved upon, minimizing “scatter” to nearby tissues. Therefore its benefit (destroying the cancer cells) outweighs its risk (harming healthy cells).

When radiotherapy is used for blood cancer treatment, it’s usually part of a treatment plan that includes drug therapy. Radiotherapy can also be used to relieve pain or discomfort caused by an enlarged liver, lymph node(s) or spleen.

Radiotherapy, either alone or with chemotherapy, is sometimes given as conditioning treatment to prepare a patient for a blood or marrow stem cell transplant. The most common types used to treat blood cancer are external beam radiation (see below) and radioimmunotherapy.
External Beam Radiation

External beam radiation is the type of radiotherapy used most often for people with blood cancers. A focused radiation beam is delivered outside the body by a machine called a linear accelerator, or linac for short. The linear accelerator moves around the body to deliver radiation from various angles. Linear accelerators make it possible to decrease or avoid skin reactions and deliver targeted radiation to lessen “scatter” of radiation to nearby tissues.

The dose (total amount) of radiation used during treatment depends on various factors regarding the patient, disease and reason for treatment, and is established by a radiation oncologist. You may receive radiotherapy during a series of visits, spread over several weeks (from two to 10 weeks, on average). This approach, called dose fractionation, lessens side effects. External beam radiation does not make you radioactive.

2.5.2 Bone marrow (BM) transplantation

http://www.nlm.nih.gov/medlineplus/ency/article/003009.htm

There are three kinds of bone marrow transplants:

Autologous bone marrow transplant: The term auto means self. Stem cells are removed from you before you receive high-dose chemotherapy or radiation treatment. The stem cells are stored in a freezer (cryopreservation). After high-dose chemotherapy or radiation treatments, your stems cells are put back in your body to make (regenerate) normal blood cells. This is called a rescue transplant.

Allogeneic bone marrow transplant: The term allo means other. Stem cells are removed from another person, called a donor. Most times, the donor’s genes must at least partly match your genes. Special blood tests are done to see if a donor is a good match for you. A brother or sister is most likely to be a good match. Sometimes parents, children, and other relatives are good matches. Donors who are not related to you may be found through national bone marrow registries.

Umbilical cord blood transplant: This is a type of allogeneic transplant. Stem cells are removed from a newborn baby’s umbilical cord right after birth. The stem cells are frozen and stored until they are needed for a transplant. Umbilical cord blood cells are very immature so there is less of a need for matching. But blood counts take much longer to recover.

Before the transplant, chemotherapy, radiation, or both may be given. This may be done in two ways:

Ablative (myeloablative) treatment: High-dose chemotherapy, radiation, or both are given to kill any cancer cells. This also kills all healthy bone marrow that remains, and allows new stem cells to grow in the bone marrow.

Reduced intensity treatment, also called a mini transplant: Patients receive lower doses of chemotherapy and radiation before a transplant. This allows older patients, and those with other health problems to have a transplant.

A stem cell transplant is usually done after chemotherapy and radiation is complete. The stem cells are delivered into your bloodstream usually through a tube called a central venous catheter. The process is similar to getting a blood transfusion. The stem cells travel through the blood into the bone marrow. Most times, no surgery is needed.

Donor stem cells can be collected in two ways:

Bone marrow harvest. This minor surgery is done under general anesthesia. This means the donor will be asleep and pain-free during the procedure. The bone marrow is removed from the back of both hip bones. The amount of marrow removed depends on the weight of the person who is receiving it.
Leukapheresis. First, the donor is given 5 days of shots to help stem cells move from the bone marrow into the blood. During leukapheresis, blood is removed from the donor through an IV line in a vein. The part of white blood cells that contains stem cells is then separated in a machine and removed to be later given to the recipient. The red blood cells are returned to the donor.

Why the Procedure is Performed

A bone marrow transplant replaces bone marrow that either is not working properly or has been destroyed (ablated) by chemotherapy or radiation. Doctors believe that for many cancers, the donor’s white blood cells can attach to any remaining cancer cells, similar to when white cells attach to bacteria or viruses when fighting an infection.

Your doctor may recommend a bone marrow transplant if you have:

Certain cancers, such as leukemia, lymphoma, and multiple myeloma

A disease that affects the production of bone marrow cells, such as aplastic anemia, congenital neutropenia, severe immunodeficiency syndromes, sickle cell anemia, thalassemia

Had chemotherapy that destroyed your bone

2.5.3 Autologous stem cell transplantation

Phase II trial of ¹³¹I-B1 (anti-CD20) antibody therapy with autologous stem cell transplantation for relapsed B cell lymphomas

O.W Press, F Appelbaum, P.J Martin, et al.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(95)92225-3/abstract

25 patients with relapsed B-cell lymphomas were evaluated with trace-labelled doses (2·5 mg/kg, 185-370 MBq [5-10 mCi]) of 131I-labelled anti-CD20 (B1) antibody in a phase II trial. 22 patients achieved 131I-B1 biodistributions delivering higher doses of radiation to tumor sites than to normal organs and 21 of these were treated with therapeutic infusions of 131I-B1 (12·765-29·045 GBq) followed by autologous hemopoietic stem cell reinfusion. 18 of the 21 treated patients had objective responses, including 16 complete remissions. One patient died of progressive lymphoma and one died of sepsis. Analysis of our phase I and II trials with 131I-labelled B1 reveal a progression-free survival of 62% and an overall survival of 93% with a median follow-up of 2 years. 131I-anti-CD20 (B1) antibody therapy produces complete responses of long duration in most patients with relapsed B-cell lymphomas when given at maximally tolerated doses with autologous stem cell rescue.

Autologous (Self) Transplants

http://www.leukaemia.org.au/treatments/stem-cell-transplants/autologous-self-transplants

An autologous transplant (or rescue) is a type of transplant that uses the person’s own stem cells. These cells are collected in advance and returned at a later stage. They are used to replace stem cells that have been damaged by high doses of chemotherapy, used to treat the person’s underlying disease.

In most cases, stem cells are collected directly from the bloodstream. While stem cells normally live in your marrow, a combination of chemotherapy and a growth factor (a drug that stimulates stem cells) called Granulocyte Colony Stimulating Factor (G-CSF) is used to expand the number of stem cells in the marrow and cause them to spill out into the circulating blood. From here they can be collected from a vein by passing the blood through a special machine called a cell separator, in a process similar to dialysis.

Most of the side effects of an autologous transplant are caused by the conditioning therapy used. Although they can be very unpleasant at times it is important to remember that most of them are temporary and reversible.

Procedure of Hematopoietic Stem Cell Transplantation

Hematopoietic stem cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood. It may be autologous (the patient’s own stem cells are used) or allogeneic (the stem cells come from a donor).

Hematopoietic Stem Cell Transplantation

Author: Ajay Perumbeti, MD, FAAP; Chief Editor: Emmanuel C Besa, MD
http://emedicine.medscape.com/article/208954-overview

Hematopoietic stem cell transplantation (HSCT) involves the intravenous (IV) infusion of autologous or allogeneic stem cells to reestablish hematopoietic function in patients whose bone marrow or immune system is damaged or defective.

The image below illustrates an algorithm for typically preferred hematopoietic stem cell transplantation cell source for treatment of malignancy.

An algorithm for typically preferred hematopoietic stem cell transplantation cell source for treatment of malignancy: If a matched sibling donor is not available, then a MUD is selected; if a MUD is not available, then choices include a mismatched unrelated donor, umbilical cord donor(s), and a haploidentical donor.

Supportive Therapies

2.5.4 Blood transfusions – risks and complications of a blood transfusion

Allogeneic transfusion reaction (acute or delayed hemolytic reaction)
Allergic reaction
Viruses Infectious Diseases

The risk of catching a virus from a blood transfusion is very low.

HIV. Your risk of getting HIV from a blood transfusion is lower than your risk of getting killed by lightning. Only about 1 in 2 million donations might carry HIV and transmit HIV if given to a patient.

Hepatitis B and C. The risk of having a donation that carries hepatitis B is about 1 in 205,000. The risk for hepatitis C is 1 in 2 million. If you receive blood during a transfusion that contains hepatitis, you’ll likely develop the virus.

Variant Creutzfeldt-Jakob disease (vCJD). This disease is the human version of Mad Cow Disease. It’s a very rare, yet fatal brain disorder. There is a possible risk of getting vCJD from a blood transfusion, although the risk is very low. Because of this, people who may have been exposed to vCJD aren’t eligible blood donors.

Fever
Iron Overload
Lung Injury
Graft-Versus-Host Disease

Graft-versus-host disease (GVHD) is a condition in which white blood cells in the new blood attack your tissues.

2.5.5 Erythropoietin

Erythropoietin, (/ɨ ˌ r ɪ θ r ɵ ˈ p ɔɪ .ɨ t ɨ n /, UK /ɛ ˌ r ɪ θ r oʊ .p oʊ ˈ iː t ɪ n /) also known as EPO, is a glycoprotein hormone that controls erythropoiesis, or red blood cell production. It is a cytokine (protein signaling molecule) for erythrocyte (red blood cell) precursors in the bone marrow. Human EPO has a molecular weight of 34 kDa.

Also called hematopoietin or hemopoietin, it is produced by interstitial fibroblasts in the kidney in close association with peritubular capillary and proximal convoluted tubule. It is also produced in perisinusoidal cells in the liver. While liver production predominates in the fetal and perinatal period, renal production is predominant during adulthood. In addition to erythropoiesis, erythropoietin also has other known biological functions. For example, it plays an important role in the brain’s response to neuronal injury.^[1] EPO is also involved in the wound healing process.^[2]

Exogenous erythropoietin is produced by recombinant DNA technology in cell culture. Several different pharmaceutical agents are available with a variety ofglycosylation patterns, and are collectively called erythropoiesis-stimulating agents (ESA). The specific details for labelled use vary between the package inserts, but ESAs have been used in the treatment of anemia in chronic kidney disease, anemia in myelodysplasia, and in anemia from cancer chemotherapy. Boxed warnings include a risk of death, myocardial infarction, stroke, venous thromboembolism, and tumor recurrence.^[3]

2.5.6 G-CSF (granulocyte-colony stimulating factor)

Granulocyte-colony stimulating factor (G-CSF or GCSF), also known as colony-stimulating factor 3 (CSF 3), is a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells and release them into the bloodstream.

There are different types, including

Lenograstim (Granocyte)
Filgrastim (Neupogen, Zarzio, Nivestim, Ratiograstim)
Long acting (pegylated) filgrastim (pegfilgrastim, Neulasta) and lipegfilgrastim (Longquex)

Pegylated G-CSF stays in the body for longer so you have treatment less often than with the other types of G-CSF.

2.5.7 Plasma Exchange (plasmapheresis)

http://emedicine.medscape.com/article/1895577-overview

Plasmapheresis is a term used to refer to a broad range of procedures in which extracorporeal separation of blood components results in a filtered plasma product.^{[1, 2]}The filtering of plasma from whole blood can be accomplished via centrifugation or semipermeable membranes.^[3]Centrifugation takes advantage of the different specific gravities inherent to various blood products such as red cells, white cells, platelets, and plasma.^[4]Membrane plasma separation uses differences in particle size to filter plasma from the cellular components of blood.^[3]

Traditionally, in the United States, most plasmapheresis takes place using automated centrifuge-based technology.^[5]In certain instances, in particular in patients already undergoing hemodialysis, plasmapheresis can be carried out using semipermeable membranes to filter plasma.^[4]

In therapeutic plasma exchange, using an automated centrifuge, filtered plasma is discarded and red blood cells along with replacement colloid such as donor plasma or albumin is returned to the patient. In membrane plasma filtration, secondary membrane plasma fractionation can selectively remove undesired macromolecules, which then allows for return of the processed plasma to the patient instead of donor plasma or albumin. Examples of secondary membrane plasma fractionation include cascade filtration,^[6]thermofiltration, cryofiltration,^[7]and low-density lipoprotein pheresis.

The Apheresis Applications Committee of the American Society for Apheresis periodically evaluates potential indications for apheresis and categorizes them from I to IV based on the available medical literature. The following are some of the indications, and their categorization, from the society’s 2010 guidelines.[2]

The only Category I indication for hemopoietic malignancy is Hyperviscosity in monoclonal gammopathies

2.5.8 Platelet Transfusions

Indications for platelet transfusion in children with acute leukemia

Scott Murphy, Samuel Litwin, Leonard M. Herring, Penelope Koch, et al.
Am J Hematol Jun 1982; 12(4): 347–356
http://onlinelibrary.wiley.com/doi/10.1002/ajh.2830120406/abstract;jsessionid=A6001D9D865EA1EBC667EF98382EF20C.f03t01
http://dx.doi.org:/10.1002/ajh.2830120406

In an attempt to determine the indications for platelet transfusion in thrombocytopenic patients, we randomized 56 children with acute leukemia to one of two regimens of platelet transfusion. The prophylactic group received platelets when the platelet count fell below 20,000 per mm3 irrespective of clinical events. The therapeutic group was transfused only when significant bleeding occurred and not for thrombocytopenia alone. The time to first bleeding episode was significantly longer and the number of bleeding episodes were significantly reduced in the prophylactic group. The survival curves of the two groups could not be distinguished from each other. Prior to the last month of life, the total number of days on which bleeding was present was significantly reduced by prophylactic therapy. However, in the terminal phase (last month of life), the duration of bleeding episodes was significantly longer in the prophylactic group. This may have been due to a higher incidence of immunologic refractoriness to platelet transfusion. Because of this terminal bleeding, comparison of the two groups for total number of days on which bleeding was present did not show a significant difference over the entire study period.

Clinical and Laboratory Aspects of Platelet Transfusion Therapy
Yuan S, Goldfinger D
http://www.uptodate.com/contents/clinical-and-laboratory-aspects-of-platelet-transfusion-therapy

INTRODUCTION — Hemostasis depends on an adequate number of functional platelets, together with an intact coagulation (clotting factor) system. This topic covers the logistics of platelet use and the indications for platelet transfusion in adults. The approach to the bleeding patient, refractoriness to platelet transfusion, and platelet transfusion in neonates are discussed elsewhere.

Pooled Platelets – A single unit of platelets can be isolated from every unit of donated blood, by centrifuging the blood within the closed collection system to separate the platelets from the red blood cells (RBC). The number of platelets per unit varies according to the platelet count of the donor; a yield of 7 x 10¹⁰ platelets is typical [1]. Since this number is inadequate to raise the platelet count in an adult recipient, four to six units are pooled to allow transfusion of 3 to 4 x 10¹¹ platelets per transfusion [2]. These are called whole blood-derived or random donor pooled platelets.

Advantages of pooled platelets include lower cost and ease of collection and processing (a separate donation procedure and pheresis equipment are not required). The major disadvantage is recipient exposure to multiple donors in a single transfusion and logistic issues related to bacterial testing.

Apheresis (single donor) Platelets – Platelets can also be collected from volunteer donors in the blood bank, in a one- to two-hour pheresis procedure. Platelets and some white blood cells are removed, and red blood cells and plasma are returned to the donor. A typical apheresis platelet unit provides the equivalent of six or more units of platelets from whole blood (ie, 3 to 6 x 10¹¹ platelets) [2]. In larger donors with high platelet counts, up to three units can be collected in one session. These are called apheresis or single donor platelets.

Advantages of single donor platelets are exposure of the recipient to a single donor rather than multiple donors, and the ability to match donor and recipient characteristics such as HLA type, cytomegalovirus (CMV) status, and blood type for certain recipients.

Both pooled and apheresis platelets contain some white blood cells (WBC) that were collected along with the platelets. These WBC can cause febrile non-hemolytic transfusion reactions (FNHTR), alloimmunization, and transfusion-associated graft-versus-host disease (ta-GVHD) in some patients.

Platelet products also contain plasma, which can be implicated in adverse reactions including transfusion-related acute lung injury (TRALI) and anaphylaxis. (See ‘Complications of platelet transfusion’ .)

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Treatments for Leukemias and Lymphomas [2.4.4]

Posted in Academic Publishing, Best evidence, Genetics & Pharmaceutical, Genome Biology, Genomic Testing: Methodology for Diagnosis, Hematology, Imaging-based Cancer Patient Management, Immunodiagnostics, Lymphoma, Pharmaceutical Drug Discovery, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Translational Effectiveness, Translational Research, Translational Science, tagged Hodgkin's lymphoma, Non-Hodgkin lymphoma, treatment of lymphomas on August 11, 2015| Leave a Comment »

Treatments for Lymphomas and Leukemias

Curator and Editor: Larry H. Bernstein, MD, FCAP

2.4.4 Treatments for leukemia by type

2.4.4.1 Acute Lymphocytic Leukemias

Treatment of Acute Lymphoblastic Leukemia

Ching-Hon Pu, and William E. Evans
N Engl J Med Jan 12, 2006; 354:166-178
http://dx.doi.org:/10.1056/NEJMra052603

Although the overall cure rate of acute lymphoblastic leukemia (ALL) in children is about 80 percent, affected adults fare less well. This review considers recent advances in the treatment of ALL, emphasizing issues that need to be addressed if treatment outcome is to improve further.

Acute Lymphoblastic Leukemia

Ching-Hon Pui, Mary V. Relling, and James R. Downing
N Engl J Med Apr 8, 2004; 350:1535-1548
http://dx.doi.org:/10.1056/NEJMra023001

This comprehensive survey emphasizes how recent advances in the knowledge of molecular mechanisms involved in acute lymphoblastic leukemia have influenced diagnosis, prognosis, and treatment.

Gene-Expression Patterns in Drug-Resistant Acute Lymphoblastic Leukemia Cells and Response to Treatment

Amy Holleman, Meyling H. Cheok, Monique L. den Boer, et al.
N Engl J Med 2004; 351:533-42

Childhood acute lymphoblastic leukemia (ALL) is curable with chemotherapy in approximately 80 percent of patients. However, the cause of treatment failure in the remaining 20 percent of patients is largely unknown.

Methods We tested leukemia cells from 173 children for sensitivity in vitro to prednisolone, vincristine, asparaginase, and daunorubicin. The cells were then subjected to an assessment of gene expression with the use of 14,500 probe sets to identify differentially expressed genes in drug-sensitive and drug-resistant ALL. Gene-expression patterns that differed according to sensitivity or resistance to the four drugs were compared with treatment outcome in the original 173 patients and an independent cohort of 98 children treated with the same drugs at another institution.

Results We identified sets of differentially expressed genes in B-lineage ALL that were sensitive or resistant to prednisolone (33 genes), vincristine (40 genes), asparaginase (35 genes), or daunorubicin (20 genes). A combined gene-expression score of resistance to the four drugs, as compared with sensitivity to the four, was significantly and independently related to treatment outcome in a multivariate analysis (hazard ratio for relapse, 3.0; P=0.027). Results were confirmed in an independent population of patients treated with the same medications (hazard ratio for relapse, 11.85; P=0.019). Of the 124 genes identified, 121 have not previously been associated with resistance to the four drugs we tested.

Conclusions Differential expression of a relatively small number of genes is associated with drug resistance and treatment outcome in childhood ALL.

Leukemias Treatment & Management

Author: Lihteh Wu, MD; Chief Editor: Hampton Roy Sr
http://emedicine.medscape.com/article/1201870-treatment

The treatment of leukemia is in constant flux, evolving and changing rapidly over the past few years. Most treatment protocols use systemic chemotherapy with or without radiotherapy. The basic strategy is to eliminate all detectable disease by using cytotoxic agents. To attain this goal, 3 phases are typically used, as follows: remission induction phase, consolidation phase, and maintenance therapy phase.

Chemotherapeutic agents are chosen that interfere with cell division. Tumor cells usually divide more rapidly than host cells, making them more vulnerable to the effects of chemotherapy. Primary treatment will be under the direction of a medical oncologist, radiation oncologist, and primary care physician. Although a general treatment plan will be outlined, the ophthalmologist does not prescribe or manage such treatment.

The initial treatment of ALL uses various combinations of vincristine, prednisone, and L-asparaginase until a complete remission is obtained.
Maintenance therapy with mercaptopurine is continued for 2-3 years following remission.
Use of intrathecal methotrexate with or without cranial irradiation to cover the CNS varies from facility to facility.
Daunorubicin, cytarabine, and thioguanine currently are used to obtain induction and remission of AML.
Maintenance therapy for 8 months may lengthen remission. Once relapse has occurred, AML generally is curable only by bone marrow transplantation.
Presently, treatment of CLL is palliative.
CML is characterized by a leukocytosis greater than 100,000 cells. Emergent treatment with leukopheresis sometimes is necessary when leukostastic complications are present. Otherwise, busulfan or hydroxyurea may control WBC counts. During the chronic phase, treatment is palliative.
When CML converts to the blastic phase, approximately one third of cases behave as ALL and respond to treatment with vincristine and prednisone. The remaining two thirds resemble AML but respond poorly to AML therapy.
Allogeneic bone marrow transplant is the only curative therapy for CML. However, it carries a high early mortality rate.
Leukemic retinopathy usually is not treated directly. As the hematological parameters normalize with systemic treatment, many of the ophthalmic signs resolve. There are reports that leukopheresis for hyperviscosity also may alleviate intraocular manifestations.
When definite intraocular leukemic infiltrates fail to respond to systemic chemotherapy, direct radiation therapy is recommended.
Relapse, manifested by anterior segment involvement, should be treated by radiation. In certain cases, subconjunctival chemotherapeutic agents have been injected.
Optic nerve head infiltration in patients with ALL is an emergency and requires prompt radiation therapy to try to salvage some vision.

Treatments and drugs

http://www.mayoclinic.org/diseases-conditions/leukemia/basics/
treatment/con-20024914

Common treatments used to fight leukemia include:

Chemotherapy. Chemotherapy is the major form of treatment for leukemia. This drug treatment uses chemicals to kill leukemia cells.

Depending on the type of leukemia you have, you may receive a single drug or a combination of drugs. These drugs may come in a pill form, or they may be injected directly into a vein.

Biological therapy. Biological therapy works by using treatments that help your immune system recognize and attack leukemia cells.
Targeted therapy. Targeted therapy uses drugs that attack specific vulnerabilities within your cancer cells.

For example, the drug imatinib (Gleevec) stops the action of a protein within the leukemia cells of people with chronic myelogenous leukemia. This can help control the disease.

Radiation therapy. Radiation therapy uses X-rays or other high-energy beams to damage leukemia cells and stop their growth. During radiation therapy, you lie on a table while a large machine moves around you, directing the radiation to precise points on your body.

You may receive radiation in one specific area of your body where there is a collection of leukemia cells, or you may receive radiation over your whole body. Radiation therapy may be used to prepare for a stem cell transplant.

Stem cell transplant. A stem cell transplant is a procedure to replace your diseased bone marrow with healthy bone marrow.

Before a stem cell transplant, you receive high doses of chemotherapy or radiation therapy to destroy your diseased bone marrow. Then you receive an infusion of blood-forming stem cells that help to rebuild your bone marrow.

You may receive stem cells from a donor, or in some cases you may be able to use your own stem cells. A stem cell transplant is very similar to a bone marrow transplant.

2.4.4.2 Acute Myeloid Leukemia

New treatment approaches in acute myeloid leukemia: review of recent clinical studies.

Norsworthy K¹, Luznik L, Gojo I.
Rev Recent Clin Trials. 2012 Aug; 7(3):224-37.
http://www.ncbi.nlm.nih.gov/pubmed/22540908

Standard chemotherapy can cure only a fraction (30-40%) of younger and very few older patients with acute myeloid leukemia (AML). While conventional allografting can extend the cure rates, its application remains limited mostly to younger patients and those in remission. Limited efficacy of current therapies and improved understanding of the disease biology provided a spur for clinical trials examining novel agents and therapeutic strategies in AML. Clinical studies with novel chemotherapeutics, antibodies, different signal transduction inhibitors, and epigenetic modulators demonstrated their clinical activity; however, it remains unclear how to successfully integrate novel agents either alone or in combination with chemotherapy into the overall therapeutic schema for AML. Further studies are needed to examine their role in relation to standard chemotherapy and their applicability to select patient populations based on recognition of unique disease and patient characteristics, including the development of predictive biomarkers of response. With increasing use of nonmyeloablative or reduced intensity conditioning and alternative graft sources such as haploidentical donors and cord blood transplants, the benefits of allografting may extend to a broader patient population, including older AML patients and those lacking a HLA-matched donor. We will review here recent clinical studies that examined novel pharmacologic and immunologic approaches to AML therapy.

Novel approaches to the treatment of acute myeloid leukemia.

Roboz GJ¹Hematology Am Soc Hematol Educ Program. 2011:43-50.
http://dx.doi.org:/10.1182/asheducation-2011.1.43.

Approximately 12 000 adults are diagnosed with acute myeloid leukemia (AML) in the United States annually, the majority of whom die from their disease. The mainstay of initial treatment, cytosine arabinoside (ara-C) combined with an anthracycline, was developed nearly 40 years ago and remains the worldwide standard of care. Advances in genomics technologies have identified AML as a genetically heterogeneous disease, and many patients can now be categorized into clinicopathologic subgroups on the basis of their underlying molecular genetic defects. It is hoped that enhanced specificity of diagnostic classification will result in more effective application of targeted agents and the ability to create individualized treatment strategies. This review describes the current treatment standards for induction, consolidation, and stem cell transplantation; special considerations in the management of older AML patients; novel agents; emerging data on the detection and management of minimal residual disease (MRD); and strategies to improve the design and implementation of AML clinical trials.

Age ≥ 60 years has consistently been identified as an independent adverse prognostic factor in AML, and there are very few long-term survivors in this age group.5 Poor outcomes in elderly AML patients have been attributed to both host- and disease-related factors, including medical comorbidities, physical frailty, increased incidence of antecedent myelodysplastic syndrome and myeloproliferative disorders, and higher frequency of adverse cytogenetics.28 Older patients with multiple poor-risk factors have a high probability of early death and little chance of long-term disease-free survival with standard chemotherapy. In a retrospective analysis of 998 older patients treated with intensive induction at the M.D. Anderson Cancer Center, multivariate analysis identified age ≥ 75 years, unfavorable karyotype, poor performance status, creatinine > 1.3 mg/dL, duration of antecedent hematologic disorder > 6 months, and treatment outside a laminar airflow room as adverse prognostic indicators.29 Patients with 3 or more of these factors had expected complete remission rates of < 20%, 8-week mortality > 50%, and 1-year survival < 10%. The Medical Research Council (MRC) identified cytogenetics, WBC count at diagnosis, age, and de novo versus secondary disease as critical factors influencing survival in > 2000 older patients with AML, but cautioned in their conclusions that less objective factors, such as clinical assessment of “fitness” for chemotherapy, may be equally important in making treatment decisions in this patient population.30 It is hoped that data from comprehensive geriatric assessments of functional status, cognition, mood, quality of life, and other measures obtained during ongoing cooperative group trials will improve our ability to predict how older patients will tolerate treatment.

Current treatment of acute myeloid leukemia.

Roboz GJ¹.
Curr Opin Oncol. 2012 Nov; 24(6):711-9.
http://dx.doi.org:/10.1097/CCO.0b013e328358f62d.

The objectives of this review are to discuss standard and investigational nontransplant treatment strategies for acute myeloid leukemia (AML), excluding acute promyelocytic leukemia.

RECENT FINDINGS: Most adults with AML die from their disease. The standard treatment paradigm for AML is remission induction chemotherapy with an anthracycline/cytarabine combination, followed by either consolidation chemotherapy or allogeneic stem cell transplantation, depending on the patient’s ability to tolerate intensive treatment and the likelihood of cure with chemotherapy alone. Although this approach has changed little in the last three decades, increased understanding of the pathogenesis of AML and improvements in molecular genomic technologies are leading to novel drug targets and the development of personalized, risk-adapted treatment strategies. Recent findings related to prognostically relevant and potentially ‘druggable’ molecular targets are reviewed.

SUMMARY: At the present time, AML remains a devastating and mostly incurable disease, but the combination of optimized chemotherapeutics and molecularly targeted agents holds significant promise for the future.

Adult Acute Myeloid Leukemia Treatment (PDQ®)
http://www.cancer.gov/cancertopics/pdq/treatment/adultAML/healthprofessional/page9

About This PDQ Summary

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

be discussed at a meeting,
be cited with text, or
replace or update an existing article that is already cited.

Treatment Option Overview for AML

Successful treatment of acute myeloid leukemia (AML) requires the control of bone marrow and systemic disease and specific treatment of central nervous system (CNS) disease, if present. The cornerstone of this strategy includes systemically administered combination chemotherapy. Because only 5% of patients with AML develop CNS disease, prophylactic treatment is not indicated.[1–3]

Treatment is divided into two phases: remission induction (to attain remission) and postremission (to maintain remission). Maintenance therapy for AML was previously administered for several years but is not included in most current treatment clinical trials in the United States, other than for acute promyelocytic leukemia. (Refer to the Adult Acute Myeloid Leukemia in Remission section of this summary for more information.) Other studies have used more intensive postremission therapy administered for a shorter duration of time after which treatment is discontinued.[4] Postremission therapy appears to be effective when given immediately after remission is achieved.[4]

Since myelosuppression is an anticipated consequence of both the leukemia and its treatment with chemotherapy, patients must be closely monitored during therapy. Facilities must be available for hematologic support with multiple blood fractions including platelet transfusions and for the treatment of related infectious complications.[5] Randomized trials have shown similar outcomes for patients who received prophylactic platelet transfusions at a level of 10,000/mm3 rather than 20,000/mm3.[6] The incidence of platelet alloimmunization was similar among groups randomly assigned to receive pooled platelet concentrates from random donors; filtered, pooled platelet concentrates from random donors; ultraviolet B-irradiated, pooled platelet concentrates from random donors; or filtered platelets obtained by apheresis from single random donors.[7] Colony-stimulating factors, for example, granulocyte colony–stimulating factor (G-CSF) and granulocyte-macrophage colony–stimulating factor (GM-CSF), have been studied in an effort to shorten the period of granulocytopenia associated with leukemia treatment.[8] If used, these agents are administered after completion of induction therapy. GM-CSF was shown to improve survival in a randomized trial of AML in patients aged 55 to 70 years (median survival was 10.6 months vs. 4.8 months). In this Eastern Cooperative Oncology Group (ECOG) (EST-1490) trial, patients were randomly assigned to receive GM-CSF or placebo following demonstration of leukemic clearance of the bone marrow;[9] however, GM-CSF did not show benefit in a separate similar randomized trial in patients older than 60 years.[10] In the latter study, clearance of the marrow was not required before initiating cytokine therapy. In a Southwest Oncology Group (NCT00023777) randomized trial of G-CSF given following induction therapy to patients older than 65 years, complete response was higher in patients who received G-CSF because of a decreased incidence of primary leukemic resistance. Growth factor administration did not impact on mortality or on survival.[11,12] Because the majority of randomized clinical trials have not shown an impact of growth factors on survival, their use is not routinely recommended in the remission induction setting.

The administration of GM-CSF or other myeloid growth factors before and during induction therapy, to augment the effects of cytotoxic therapy through the recruitment of leukemic blasts into cell cycle (growth factor priming), has been an area of active clinical research. Evidence from randomized studies of GM-CSF priming have come to opposite conclusions. A randomized study of GM-CSF priming during conventional induction and postremission therapy showed no difference in outcomes between patients who received GM-CSF and those who did not receive growth factor priming.[13,14][Level of evidence: 1iiA] In contrast, a similar randomized placebo-controlled study of GM-CSF priming in patients with AML aged 55 to 75 years showed improved disease-free survival (DFS) in the group receiving GM-CSF (median DFS for patients who achieved complete remission was 23 months vs. 11 months; 2-year DFS was 48% vs. 21%), with a trend towards improvement in overall survival (2-year survival was 39% vs. 27%, P = .082) for patients aged 55 to 64 years.[15][Level of evidence: 1iiDii]

References

Kebriaei P, Champlin R, deLima M, et al.: Management of acute leukemias. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011, pp 1928-54.
Wiernik PH: Diagnosis and treatment of acute nonlymphocytic leukemia. In: Wiernik PH, Canellos GP, Dutcher JP, et al., eds.: Neoplastic Diseases of the Blood. 3rd ed. New York, NY: Churchill Livingstone, 1996, pp 283-302.
Morrison FS, Kopecky KJ, Head DR, et al.: Late intensification with POMP chemotherapy prolongs survival in acute myelogenous leukemia–results of a Southwest Oncology Group study of rubidazone versus adriamycin for remission induction, prophylactic intrathecal therapy, late intensification, and levamisole maintenance. Leukemia 6 (7): 708-14, 1992. [PUBMED Abstract]
Cassileth PA, Lynch E, Hines JD, et al.: Varying intensity of postremission therapy in acute myeloid leukemia. Blood 79 (8): 1924-30, 1992. [PUBMED Abstract]
Supportive Care. In: Wiernik PH, Canellos GP, Dutcher JP, et al., eds.: Neoplastic Diseases of the Blood. 3rd ed. New York, NY: Churchill Livingstone, 1996, pp 779-967.
Rebulla P, Finazzi G, Marangoni F, et al.: The threshold for prophylactic platelet transfusions in adults with acute myeloid leukemia. Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto. N Engl J Med 337 (26): 1870-5, 1997. [PUBMED Abstract]
Leukocyte reduction and ultraviolet B irradiation of platelets to prevent alloimmunization and refractoriness to platelet transfusions. The Trial to Reduce Alloimmunization to Platelets Study Group. N Engl J Med 337 (26): 1861-9, 1997. [PUBMED Abstract]
Geller RB: Use of cytokines in the treatment of acute myelocytic leukemia: a critical review. J Clin Oncol 14 (4): 1371-82, 1996. [PUBMED Abstract]
Rowe JM, Andersen JW, Mazza JJ, et al.: A randomized placebo-controlled phase III study of granulocyte-macrophage colony-stimulating factor in adult patients (> 55 to 70 years of age) with acute myelogenous leukemia: a study of the Eastern Cooperative Oncology Group (E1490). Blood 86 (2): 457-62, 1995. [PUBMED Abstract]
Stone RM, Berg DT, George SL, et al.: Granulocyte-macrophage colony-stimulating factor after initial chemotherapy for elderly patients with primary acute myelogenous leukemia. Cancer and Leukemia Group B. N Engl J Med 332 (25): 1671-7, 1995. [PUBMED Abstract]
Dombret H, Chastang C, Fenaux P, et al.: A controlled study of recombinant human granulocyte colony-stimulating factor in elderly patients after treatment for acute myelogenous leukemia. AML Cooperative Study Group. N Engl J Med 332 (25): 1678-83, 1995. [PUBMED Abstract]
Godwin JE, Kopecky KJ, Head DR, et al.: A double-blind placebo-controlled trial of granulocyte colony-stimulating factor in elderly patients with previously untreated acute myeloid leukemia: a Southwest oncology group study (9031). Blood 91 (10): 3607-15, 1998. [PUBMED Abstract]
Buchner T, Hiddemann W, Wormann B, et al.: GM-CSF multiple course priming and long-term administration in newly diagnosed AML: hematologic and therapeutic effects. [Abstract] Blood 84 (10 Suppl 1): A-95, 27a, 1994.
Löwenberg B, Boogaerts MA, Daenen SM, et al.: Value of different modalities of granulocyte-macrophage colony-stimulating factor applied during or after induction therapy of acute myeloid leukemia. J Clin Oncol 15 (12): 3496-506, 1997. [PUBMED Abstract]
Witz F, Sadoun A, Perrin MC, et al.: A placebo-controlled study of recombinant human granulocyte-macrophage colony-stimulating factor administered during and after induction treatment for de novo acute myelogenous leukemia in elderly patients. Groupe Ouest Est Leucémies Aiguës Myéloblastiques (GOELAM). Blood 91 (8): 2722-30, 1998. [PUBMED Abstract]

2.4.4.3 Treatment for CML

Chronic Myelogenous Leukemia Treatment (PDQ®)

http://www.cancer.gov/cancertopics/pdq/treatment/CML/Patient/page4

Treatment Option Overview

Key Points for This Section

There are different types of treatment for patients with chronic myelogenous leukemia.

Six types of standard treatment are used:

Targeted therapy
Chemotherapy
Biologic therapy
High-dose chemotherapy with stem cell transplant
Donor lymphocyte infusion (DLI)
Surgery

New types of treatment are being tested in clinical trials.

Patients may want to think about taking part in a clinical trial.

Patients can enter clinical trials before, during, or after starting their cancer treatment.

Follow-up tests may be needed.

There are different types of treatment for patients with chronic myelogenous leukemia.

Six types of standard treatment are used:

Targeted therapy

Imatinib mesylate, nilotinib, dasatinib, and ponatinib are tyrosine kinase inhibitors that are used to treat CML.

See Drugs Approved for Chronic Myelogenous Leukemia for more information.

Chemotherapy

See Drugs Approved for Chronic Myelogenous Leukemia for more information.

Biologic therapy

See Drugs Approved for Chronic Myelogenous Leukemia for more information.

High-dose chemotherapy with stem cell transplant

See Drugs Approved for Chronic Myelogenous Leukemia for more information.

Donor lymphocyte infusion (DLI)

Surgery

Splenectomy

What`s new in chronic myeloid leukemia research and treatment?

http://www.cancer.org/cancer/leukemia-chronicmyeloidcml/detailedguide/leukemia-chronic-myeloid-myelogenous-new-research

Combining the targeted drugs with other treatments

Other studies are looking at combining other drugs, such as cyclosporine or hydroxychloroquine, with a TKI.

New drugs for CML

Because researchers now know the main cause of CML (the BCR-ABL gene and its protein), they have been able to develop many new drugs that might work against it.

Other drugs being studied in CML include the histone deacetylase inhibitor panobinostat and the proteasome inhibitor bortezomib (Velcade).

Several vaccines are now being studied for use against CML.

2.4.4.4. Chronic Lymphocytic Leukemia

Chronic Lymphocytic Leukemia Treatment (PDQ®)

General Information About Chronic Lymphocytic Leukemia

Key Points for This Section

Chronic lymphocytic leukemia is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell).
Leukemia may affect red blood cells, white blood cells, and platelets.
Older age can affect the risk of developing chronic lymphocytic leukemia.
Signs and symptoms of chronic lymphocytic leukemia include swollen lymph nodes and tiredness.
Tests that examine the blood, bone marrow, and lymph nodes are used to detect (find) and diagnose chronic lymphocytic leukemia.
Certain factors affect treatment options and prognosis (chance of recovery).
Chronic lymphocytic leukemia is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell).

http://www.cancer.gov/images/cdr/live/CDR755927-750.jpg

Leukemia may affect red blood cells, white blood cells, and platelets.

Normally, the body makes blood stem cells (immature cells) that become mature blood cells over time. A blood stem cell may become a myeloid stem cell or a lymphoid stem cell.

A myeloid stem cell becomes one of three types of mature blood cells:

Red blood cells that carry oxygen and other substances to all tissues of the body.
White blood cells that fight infection and disease.
Platelets that form blood clots to stop bleeding.

A lymphoid stem cell becomes a lymphoblast cell and then one of three types of lymphocytes (white blood cells):

B lymphocytes that make antibodies to help fight infection.
T lymphocytes that help B lymphocytes make antibodies to fight infection.
Natural killer cells that attack cancer cells and viruses.

Blood cell development. CDR526538-750

http://www.cancer.gov/images/cdr/live/CDR526538-750.jpg

Blood cell development. A blood stem cell goes through several steps to become a red blood cell, platelet, or white blood cell.

This summary is about chronic lymphocytic leukemia. See the following PDQ summaries for more information about leukemia:

Adult Acute Lymphoblastic Leukemia Treatment.
Childhood Acute Lymphoblastic Leukemia Treatment.
Adult Acute Myeloid Leukemia Treatment.
Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment.
Chronic Myelogenous Leukemia Treatment.
Hairy Cell Leukemia Treatment

Older age can affect the risk of developing chronic lymphocytic leukemia.

Being middle-aged or older, male, or white.
A family history of CLL or cancer of the lymph system.
Having relatives who are Russian Jews or Eastern European Jews.

Signs and symptoms of chronic lymphocytic leukemia include swollen lymph nodes and tiredness.

Painless swelling of the lymph nodes in the neck, underarm, stomach, or groin.
Feeling very tired.
Pain or fullness below the ribs.
Fever and infection.
Weight loss for no known reason.

Tests that examine the blood, bone marrow, and lymph nodes are used to detect (find) and diagnose chronic lymphocytic leukemia.

The following tests and procedures may be used:

Complete blood count (CBC) with differential : A procedure in which a sample of blood is drawn and checked for the following:
The number of red blood cells and platelets.
The number and type of white blood cells.
The amount of hemoglobin (the protein that carries oxygen) in the red blood cells.
The portion of the blood sample made up of red blood cells.

Results from the Phase 3 Resonate™ Trial

Significantly improved progression free survival (PFS) vs ofatumumab in patients with previously treated CLL

Patients taking IMBRUVICA® had a 78% statistically significant reduction in the risk of disease progression or death compared with patients who received ofatumumab¹
In patients with previously treated del 17p CLL, median PFS was not yet reached with IMBRUVICA® vs 5.8 months with ofatumumab (HR 0.25; 95% CI: 0.14, 0.45)¹

Significantly prolonged overall survival (OS) with IMBRUVICA® vs ofatumumab in patients with previously treated CLL

In patients with previously treated CLL, those taking IMBRUVICA® had a 57% statistically significant reduction in the risk of death compared with those who received ofatumumab (HR 0.43; 95% CI: 0.24, 0.79; P<0.05)¹

Typical treatment of chronic lymphocytic leukemia

http://www.cancer.org/cancer/leukemia-chroniclymphocyticcll/detailedguide/leukemia-chronic-lymphocytic-treating-treatment-by-risk-group

Initial treatment

In stronger and healthier patients, there are many options for treatment. Commonly used treatments include:

FCR: fludarabine (Fludara), cyclophosphamide (Cytoxan), and rituximab
Bendamustine (sometimes with rituximab)
FR: fludarabine and rituximab
CVP: cyclophosphamide, vincristine, and prednisone (sometimes with rituximab)
CHOP: cyclophosphamide, doxorubicin, vincristine (Oncovin), and prednisone
Chlorambucil combined with prednisone, rituximab, obinutuzumab, or ofatumumab
PCR: pentostatin (Nipent), cyclophosphamide, and rituximab
Alemtuzumab (Campath)
Fludarabine (alone)

Other drugs or combinations of drugs may also be also used.

Some people who have very high-risk disease (based on prognostic factors) may be referred for possible stem cell transplant (SCT) early in treatment.

Second-line treatment of CLL

If the leukemia responds, stem cell transplant may be an option for some patients.

Treating complications of CLL

CLL can cause problems with low blood counts and infections. Treatment of these problems were discussed in the section “Supportive care in chronic lymphocytic leukemia.”

2.4.4.5 Lymphoma treatment

Overview

http://www.emedicinehealth.com/lymphoma/page8_em.htm#lymphoma_treatment

The most widely used therapies are combinations of chemotherapy and radiation therapy.

Biological therapy, which targets key features of the lymphoma cells, is used in many cases nowadays.

The goal of medical therapy in lymphoma is complete remission. This means that all signs of the disease have disappeared after treatment. Remission is not the same as cure. In remission, one may still have lymphoma cells in the body, but they are undetectable and cause no symptoms.

When in remission, the lymphoma may come back. This is called recurrence.
The duration of remission depends on the type, stage, and grade of the lymphoma. A remission may last a few months, a few years, or may continue throughout one’s life.
Remission that lasts a long time is called durable remission, and this is the goal of therapy.
The duration of remission is a good indicator of the aggressiveness of the lymphoma and of the prognosis. A longer remission generally indicates a better prognosis.

Remission can also be partial. This means that the tumor shrinks after treatment to less than half its size before treatment.

The following terms are used to describe the lymphoma’s response to treatment:

Improvement: The lymphoma shrinks but is still greater than half its original size.
Stable disease: The lymphoma stays the same.
Progression: The lymphoma worsens during treatment.
Refractory disease: The lymphoma is resistant to treatment.

The following terms to refer to therapy:

Induction therapy is designed to induce a remission.
If this treatment does not induce a complete remission, new or different therapy will be initiated. This is usually referred to as salvage therapy.
Once in remission, one may be given yet another treatment to prevent recurrence. This is called maintenance therapy.

Chemotherapy

Many different types of chemotherapy may be used for Hodgkin lymphoma. The most commonly used combination of drugs in the United States is called ABVD. Another combination of drugs, known as BEACOPP, is now widely used in Europe and is being used more often in the United States. There are other combinations that are less commonly used and not listed here. The drugs that make up these two more common combinations of chemotherapy are listed below.

ABVD: Doxorubicin (Adriamycin), bleomycin (Blenoxane), vinblastine (Velban, Velsar), and dacarbazine (DTIC-Dome). ABVD chemotherapy is usually given every two weeks for two to eight months.

BEACOPP: Bleomycin, etoposide (Toposar, VePesid), doxorubicin, cyclophosphamide (Cytoxan, Neosar), vincristine (Vincasar PFS, Oncovin), procarbazine (Matulane), and prednisone (multiple brand names). There are several different treatment schedules, but different drugs are usually given every two weeks.

The type of chemotherapy, number of cycles of chemotherapy, and the additional use of radiation therapy are based on the stage of the Hodgkin lymphoma and the type and number of prognostic factors.

Adult Non-Hodgkin Lymphoma Treatment (PDQ®)

http://www.cancer.gov/cancertopics/pdq/treatment/adult-non-hodgkins/Patient/page1

Key Points for This Section

Adult non-Hodgkin Lymphoma is a disease in which malignant (cancer) cells form in the lymph system.

Because lymph tissue is found throughout the body, adult non-Hodgkin lymphoma can begin in almost any part of the body. Cancer can spread to the liver and many other organs and tissues.

Non-Hodgkin lymphoma in pregnant women is the same as the disease in nonpregnant women of childbearing age. However, treatment is different for pregnant women. This summary includes information on the treatment of non-Hodgkin lymphoma during pregnancy

Non-Hodgkin lymphoma can occur in both adults and children. Treatment for children, however, is different than treatment for adults. (See the PDQ summary on Childhood Non-Hodgkin Lymphoma Treatment for more information.)

There are many different types of lymphoma.

Lymphomas are divided into two general types: Hodgkin lymphoma and non-Hodgkin lymphoma. This summary is about the treatment of adult non-Hodgkin lymphoma. For information about other types of lymphoma, see the following PDQ summaries:

Age, gender, and a weakened immune system can affect the risk of adult non-Hodgkin lymphoma.

If cancer is found, the following tests may be done to study the cancer cells:

Immunohistochemistry : A test that uses antibodies to check for certain antigens in a sample of tissue. The antibody is usually linked to a radioactive substance or a dye that causes the tissue to light up under a microscope. This type of test may be used to tell the difference between different types of cancer.
Cytogenetic analysis : A laboratory test in which cells in a sample of tissue are viewed under a microscope to look for certain changes in the chromosomes.
Immunophenotyping : A process used to identify cells, based on the types of antigens ormarkers on the surface of the cell. This process is used to diagnose specific types of leukemia and lymphoma by comparing the cancer cells to normal cells of the immune system.

Certain factors affect prognosis (chance of recovery) and treatment options.

The prognosis (chance of recovery) and treatment options depend on the following:

The stage of the cancer.
The type of non-Hodgkin lymphoma.
The amount of lactate dehydrogenase (LDH) in the blood.
The amount of beta-2-microglobulin in the blood (for Waldenström macroglobulinemia).
The patient’s age and general health.
Whether the lymphoma has just been diagnosed or has recurred (come back).

Stages of adult non-Hodgkin lymphoma may include E and S.

Adult non-Hodgkin lymphoma may be described as follows:

E: “E” stands for extranodal and means the cancer is found in an area or organ other than the lymph nodes or has spread to tissues beyond, but near, the major lymphatic areas.

S: “S” stands for spleen and means the cancer is found in the spleen.

Stage I adult non-Hodgkin lymphoma is divided into stage I and stage IE.

Stage I: Cancer is found in one lymphatic area (lymph node group, tonsils and nearby tissue, thymus, or spleen).
Stage IE: Cancer is found in one organ or area outside the lymph nodes.

Stage II adult non-Hodgkin lymphoma is divided into stage II and stage IIE.

Stage II: Cancer is found in two or more lymph node groups either above or below the diaphragm (the thin muscle below the lungs that helps breathing and separates the chest from the abdomen).
Stage IIE: Cancer is found in one or more lymph node groups either above or below the diaphragm. Cancer is also found outside the lymph nodes in one organ or area on the same side of the diaphragm as the affected lymph nodes.

Stage III adult non-Hodgkin lymphoma is divided into stage III, stage IIIE, stage IIIS, and stage IIIE+S.

Stage III: Cancer is found in lymph node groups above and below the diaphragm (the thin muscle below the lungs that helps breathing and separates the chest from the abdomen).
Stage IIIE: Cancer is found in lymph node groups above and below the diaphragm and outside the lymph nodes in a nearby organ or area.
Stage IIIS: Cancer is found in lymph node groups above and below the diaphragm, and in the spleen.
Stage IIIE+S: Cancer is found in lymph node groups above and below the diaphragm, outside the lymph nodes in a nearby organ or area, and in the spleen.

In stage IV adult non-Hodgkin lymphoma, the cancer:

is found throughout one or more organs that are not part of a lymphatic area (lymph node group, tonsils and nearby tissue, thymus, or spleen), and may be in lymph nodes near those organs; or
is found in one organ that is not part of a lymphatic area and has spread to organs or lymph nodes far away from that organ; or
is found in the liver, bone marrow, cerebrospinal fluid (CSF), or lungs (other than cancer that has spread to the lungs from nearby areas).

Adult non-Hodgkin lymphomas are also described based on how fast they grow and where the affected lymph nodes are in the body. Indolent & aggressive.

The treatment plan depends mainly on the following:

The type of non-Hodgkin’s lymphoma
Its stage (where the lymphoma is found)
How quickly the cancer is growing
The patient’s age
Whether the patient has other health problems
If there are symptoms present such as fever and night sweats (see above)

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