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Posts Tagged ‘Chemotherapy’

Exploring the role of vitamin C in Cancer therapy

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Human Immune System in Health and in Disease, Nutrition, tagged , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , on January 15, 2013| 15 Comments »

 Curator: Ritu Saxena, Ph.D.

Vitamin C or Ascorbic acid (AA) or Ascorbate

Biochemical role: AA serves a basic biochemical role of accelerating hydroxylation in several biochemical reactions. It provides electrons to metal ions, the reduced forms of which are required for the full enzymatic activity of some enzymes. Most emphasized role of AA is as a cofactor for the enzyme required for the biosynthesis of collagen.

Molecular structure and the oxidized form of AA, dihydroascorbic acid, bear similarity to that of glucose.

Biological role: AA is an essential vitamin for humans and its deficiency leads to disease called Scurvy characterized by initial symptoms of malaise and lethargy, followed by formation of spots on the skin, spongy gums, and bleeding from the mucous membranes. As scurvy advances, there can be open, suppurating wounds, loss of teeth, jaundice, fever, neuropathy and death. AA is water soluble and found in high concentrations in several tissues including eye lens, WBCs, adrenal glad and pituitary gland. Some of the roles of ascorbate include:

  1. Carnitine synthesis from lysine
  2. Neurotransmitter synthesis,
  3. Cytochrome P-450 activity,
  4. Cholesterol metabolism,
  5. Detoxification of exogenous compounds,
  6. Antioxidant
  7. Possibly an ergogenic aid (Ergogenic aids are substances, devices, or practices that enhance an individual’s energy use, production, or recovery.)

Vitamin C and Cancer

As early as in 1949, vitamin C was implicated in cancer therapy. Since then, several research articles have been published exploring the role of ascorbate in cancer therapy. Among the plethora of literature discussing the relationship between vitamin C and cancer, one of the very significant and comprehensive reviews was published in 1979 in Cancer Research (2).

Mechanisms of action of AA (1) with respect to cancer have been divided and subdivided into the following:

  1. Primary mechanisms
  2. Secondary mechanisms
  • Preventive mechanism

Ascorbate acts as a cancer preventive agent by virtue of its strong antioxidant activities. Being one of the strongest reductants and radical scavenger, it absorbs unstable oxygen, nitrogen, and sulphur-centered radicals. AA can prevent biomembranes from peroxidative damage from peroxyl radicals. Ascorbate can trap peroxyl radicals and lead to their peroxidation in the aqueous phase before they reach the lipid rich biomembranes and cause damage. Ascorbate has been speculated to have a biomembrane protective action by its synergistic antioxidant activity with vitamin E (tocopherol).  Vitamin E is lipid-soluble and tocopheroxyl radical is generated in the cell membranes as a result of its antioxidant activity.  Ascorbate reacts with the tocopheroxyl radical and regenerates tocopherol transferring the oxidative challenge to the aqueous phase. At this point, the less active ascorbate radical might be reduced to AA by an NADP-dependent system. The probably mechanism might explain the reduction of nitrates via ascorbate to prevent the formation of carcinogenic nitrosamines.

  • Anticancer mechanisms

1. Primary anticancer mechanisms

i.     Oxidative, oxidant and pro-oxidant properties: Ascorbate has been reported to be cytotoxic at high concentrations, which has been demonstrated in a number of malignant cell lines. Transcription factor NFkB is potentially activated via ascorbate and its radicals leading to the inhibition of cell growth. Also, ascorbate inhibits certain prostaglandins leading to decrease in cell proliferation.

ii.     Hydrogen peroxide: On oxidation with oxygen, ascorbate produces a hydrogen peroxide, a reactive oxygen species. Hydrogen peroxide can generate several other reactive species and can have several damaging effects on cells including decrease in cell viability by damaging cell membranes of malignant cells. The amount of these reactive species produced via oxidation is limited in healthy cells unlike that in malignant cells where they exist in large amounts. The amount of hydrogen peroxide generated has been correlated to the amount of ascorbate in the cells. The reactive species can lead to multiple negative effects on cells including DNA strand breaks, lipid peroxidation leading to membrane function disruption, cellular ATP depletion.

Authors state that “the failure to maintain high ATP production may be a consequence of oxidative inactivation of key enzymes especially those related to the Krebs cycle and the electron transport chain.” This might result in alteration of transmembrane potential and distortion of mitochondrial function, suggestive of the important role of mitochondria in the process of carcinogenesis. In this paper, vitamin C has been correlated with cancer with the involvement of altered mitochondrial function. In addition, ascorbate has been detected in mitochondria where it is also regenerated. Different aspects of mitochondrial involvement in cancer have been discussed in several posts published earlier (3-8).

iii.     Other oxidation products of AA: Other oxidation products of AA include 2,3-diketoglutonic acid, and 5-methyl 1-3, 4-dehydrotetrone and other degradation products, have demonstrated antitumor activity. Additionally, some degradation and oxidation products of AA, gamma-cronolactone and 3-hydroxyl-2-pyrone, have been found to inhibit tumor growth. The mechanism of their antitumor actions is complex and might involve multitude of steps, including generation of reactive oxygen species, lipid peroxidation, inducing structural changes in important cellular proteins, inhibition of mitosis and so on.

iv.     Intracellular transport of ascorbate and its tumor specificity: Oxidized ascorbate, dihydroascorbic acid, is transported intracellularly where it is reduced back to ascorbate. Owing to its structural similarity with glucose, dihydroascorbic transport is facilitated via glucose transporters (GLUTs). Ascrobate in its reduced form is transported through a sodium-dependent cotransporter in some cells. Tumor cells require large amounts of glucose, which leads to an increase in the number of GLUTs, hence, resulting in an increase in ascorbate concentration within cancer cells. Because of this selective increased uptake of ascorbate and its cytotoxic effects in cancer cells (generation of hydrogen peroxide, DNA damage, other cytotoxic effects), AA has become a selective, nontoxic chemotherapeutic agent. The difference in the levels of catalase enzyme has been found to lead to intracellular tumor selectivity in cancer cells.

Ascorbate induced cytotoxicity in cancer cells involves its final electron acceptor, oxygen, which interferes with the anaerobic respiration within malignant cells. This gives an important clue for the involvement of mitochondria in malignant cells.

v.     Intravenous AA: High concentrations of AA in plasma (>200mg/dL) have been found to be cytotoxic to cancer cells. Clinically high plasma concentrations of AA can be achieved by its intravenous administration. It was observed that 60g infusion of AA given to cancer patients for 60 minutes followed by 20g given over the next 60 minutes resulted in a 240 minutes high plasma AA concentration of >400mg/dL, that is known to be cytotoxic.

Lipoic acid when administered with AA, is able to reduce the high-dose requirement of AA for its cytotoxic activity reducing it from 700mg/dL to 120mg/dL. Lipoic acid can recycle vitamin C, mediate the reduction of dihydroascorbic acid and improves mitochondrial function. Thus, energy intermediates such as coenzyme Q, vitamin K3, B-complex vitamins, alpha-ketoglutarate aspartate, magnesium might aid in cancer therapy by intercting with ascorbate, directly or indirectly, thereby stimuating/interacting/correcting aerobic mitochondrial respiration.

Hence, the pro-oxidant activity of vitamin C is being referred to as the primary mechanism of anticancer action.

2. Secondary anticancer mechanisms

i.     AA and intracellular matrix: Collagen is an important constituent of the matrix and its concentration determines the strength of the tissue along with its resistance to the infiltration of malignant cancer cells. In Scurvy, a disease resulting from a chronic deficiency of vitamin C, there is generalized tissue disintegration, dissolution of intercellular ground substance and the disruption of collagen bundles. This disintegration leads to ulceration; bacterial colonization and general undifferentiated cellular proliferation with specialized cells reverting back to their primitive form, very much like cancer.  Lack of ascorbate causes a reduction in the hydroxylation of prolyl and lysyl residues into hydroxyproline and hydroxylysine, leading to instability of the collagen triple helix, a common feature in scurvy and also in cancer. Thus, a secondary mechanism of ascorbic acid anticancer mechanism would be to repair these sites, which is emphasized by its role in wound healing, including surgical recovery and other traumatic injuries.

ii.     Ascorbate and immunocompetence: Ascorbate plays several roles for the efficient functioning of immune system in ways that are invoved in both humoral and cell-mediated.  Ascorbate provides humoral immunocompetence as it is essential for immunoglobulin synthesis. In addition, lymphocytes, seminal cells involved in cell-mediated immunity have been found to contain high concentrations of ascorbate. Other immune system roles include, aid in active phagocytosis and enhancing of interferon production.

Classical vitamin C and Cancer controversy-A possible explanation

Conflicting results were obtained from the studies performed by Pauling (Pauling Institute) and Cameron (Mayo Clinic) with vitamin C and its effect on cancer, the issue was debated a few decades ago. Both the studies, however, used oral doses of ascorbate (10g). Gonzalez et al, authors of the review on which the post is based, analyzed and expressed their views on the controversy. They state that the plasma concentration cannot be replicated when the dose is given orally as opposed to when the dose is given intravenously. According to their research, when AA is administered intravenously, higher plasma levels of ascorbate are achieved that could be retained for longer time periods. Also, the authors advocate the use of substantially higher doses (25-200g) to be given intravenously for selective toxicity towards cancer cells.

Modern vitamin C and Cancer controversy-Chemotherapy and radiation

A recent concern regarding the antioxidants like vitamin C is that they might reduce the effectiveness of chemotherapy and radiation by reducing the potency of free radicals necessary for killing cells. A publication by Agus et al (13) has a major role to play in this misconception. The authors describe how cancer cells acquire and concentrate vitamin C providing malignant cells with metabolic advantage. However, details or explanations regarding the theory are missing. Some studies, on the other hand, explain that high concentrations of AA in cancer cells is cytotoxic and is achieved because of similarity in structure between AA and glucose. Cancer cells uptake AA derivative, dehydroascorbic acid via glucose transporters (GLUTs).

In a case report published in PNAS in 1985 (12), two patients with ovarian cancer stage IIIC were found to respond positively to chemotherapy along with high-dose of antioxidants. Antioxidant, AA was administered intravenously to maintain a high plasma dose of 200 mg/dL. The two patients didn’t show disease recurrence after three years of chemotherapy and vitamin C administration. Vast literature exists on the topic indicating that antioxidants, including ascorbate, provide beneficial effects in several cancers without reducing the efficacy of chemotherapy or radiation during treatment of these cancers. Some data, in fact, suggests increase in effectiveness of chemotherapy when supplemented with antioxidants along with an increase in adverse effects. The topic has been summarized and discussed in a series of articles by Lawson and Brignall (9-11).

REFERENCES

The post is primarily based on the following two review articles:

1. González MJ et al. Orthomolecular oncology review: ascorbic acid and cancer 25 years later.  Integr Cancer Ther. 2005 Mar;4(1):32-44.

2. Cameron E, Pauling L, Leibovitz B. Ascorbic acid and cancer: a review. Cancer Res. 1979 Mar;39(3):663-81.

Other articles  on Mitochondria and Cancer were published on this Open Source Online Scientific Journal

3. Ritu Saxena. Mitochondria and Cancer: An overview of mechanisms

4. Ritusaxena. β Integrin emerges as an important player in mitochondrial dysfunction associated Gastric Cancer.

5. Larry H Bernstein. Mitochondria: Origin from oxygen free environment, role in aerobic glycolysis, metabolic adaptation

6. Ritu Saxena. Mitochondria and Cancer: An overview of mechanisms

7. Larry H Bernstein. Mitochondrial Damage and Repair under Oxidative Stress

8. Larry H Bernstein. What can we expect of tumor therapeutic response?

Research articles:

9. Lamson DW, Brignall MS. Antioxidants and cancer, part 3: quercetin. Altern Med Rev. 2000 Jun;5(3):196-208. Review.

10. Lamson DW, Brignall MS. Antioxidants and cancer therapy II: quick reference guide. Altern Med Rev. 2000 Apr;5(2):152-63.

11. Lamson DW, Brignall MS. Antioxidants in cancer therapy; their actions and interactions with oncologic therapies. Altern Med Rev. 1999 Oct;4(5):304-29.

12. Bensch KG, Fleming JE, Lohman W. The role of ascorbic acid in senile cataracts. Proc Natl Acad Sci USA 1985;82:7193-7196.

13. Agus DB, Vera JG, Golde DW. Stand allocation: a mechanism by which tumors obtain vitamin C. Cancer Res. 1999;59:4555-4558.

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Heroes in Medical Research: Barnett Rosenberg and the Discovery of Cisplatin

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Disease Biology, Small Molecules in Development of Therapeutic Drugs, FDA Regulatory Affairs, Health Economics and Outcomes Research, Pharmaceutical Analytics, Pharmaceutical Industry Competitive Intelligence, tagged , , , , , , , , , , on January 12, 2013| 4 Comments »

Heroes in Medical Research: Barnett Rosenberg and the Discovery of Cisplatin (Translating Basic Research to the Clinic)

Author/Writer: Stephen J. Williams, Ph.D.

This will be a regular posting which I hope people will find interesting.  I wish to highlight the basic research which led to seminal breakthroughs in the medical field, brought on by the result of basic inquiry, thorough and detailed investigation, meticulously following the scientific method, and eventually leading to development of important medical therapies.

This month I would like to highlight the research of Dr. Barnett Rosenberg and his discovery of one of the most used and effective chemotherapeutics, cisplatin.

Cisplatin_ALX-400-040

The compound cis-PtCl2(NH3)2 (seen in the Figure ) was first described by M. Peyrone in 1845, and known for a long time as Peyrone’s salt.[3] In 1965, Barnett Rosenberg, van Camp et al. of Michigan State University  had asked a simple question and noticed that electrical fields can inhibit the division and induce filamentous growth  of Escherichia coli (E. coli) bacteria. . Although bacterial cell growth continued, cell division was arrested, the bacteria growing as filaments up to 300 times their normal length.[5]  However, Dr. Roenberg did not stop at this finding and meticulously accounting for each variable which might explain this finding, including altering the metal composistion of the electrodes.  Dr. Rosenberg thought of the possibility it was not the electric field perse, which caused the growth inhibition, but a chemical produced in the media by electrolysis.  Eventually he discovered that electrolysis of platinum electrodes generated a soluble platinum complex which inhibited binary fission in Escherichia coli (E. coli) bacteria.  In addition he isolated this platinum complex and discovered that ammonium ions were required as well, owing to the full chemical structure of cisplatin as seen above (the nitrogens moieties are bioactivated to cations). This finding led to the observation that cis PtCl2(NH3)2 was indeed highly effective at regressing the mass of sarcomas in rats.[8] Confirmation of this discovery, and extension of testing to other tumour cell lines launched the medicinal applications of cisplatin. Cisplatin was approved for use in testicular and ovarian cancers by the U.S. Food and Drug Administration on December 19, 1978.[9]

  • ^ Peyrone M. (1844). “Ueber die Einwirkung des Ammoniaks auf Platinchlorür”. Ann Chemie Pharm 51 (1): 1–29. doi:10.1002/jlac.18440510102.
  • ^ a b c Stephen Trzaska (20 June 2005). “Cisplatin”. C&EN News 83 (25).
  • ^ Rosenberg, B.; Van Camp, L.; Krigas, T. (1965). “Inhibition of cell division in Escherichia coli by electrolysis products from a platinum electrode”. Nature 205 (4972): 698–699. doi:10.1038/205698a0. PMID 14287410.

Barnett Rosenberg

From Wikipedia, the free encyclopedia

403px-Nci-vol-8173-300_barnett_rosenberg

Barnett Rosenberg
Born November 16, 1926
New York, New York
Died August 8, 2009
Lansing, Michigan
Fields Physics/Biophysics
Institutions Michigan State University
Known for Cisplatin

Barnett Rosenberg (16 November 1926 – 8 August 2009) was an American chemist best known for the discovery of the anti-cancer drug cisplatin.[1]

Rosenberg graduated from Brooklyn College in 1948 and obtained his PhD in Physics at New York University (NYU) in 1956. He joined Michigan State University in 1961 and worked there until 1997.

In 1965, Rosenberg and his colleagues proved that certain platinum-containing compounds inhibited cell division and then in 1969 showed that they cured solid tumors. The chemotherapy drug that eventually resulted from this work, cisplatin, obtained US Food and Drug Administration (FDA) approval in 1978 and went on to become a widely used anticancer drug. The initial discovery was quite serendipitous. Rosenberg was looking into the effects of an electric field on the growth of bacteria. He noticed that bacteria ceased to divide when placed in an electric field and eventually pinned down the cause of this phenomenon to the platinum electrode he was using.[2]

He was awarded the Charles F. Kettering Prize in 1984 and the Harvey Prize in 1984. [3]

  1. ^ Rosenberg, B.; Van Camp, L.; Krigas, T. (1965). “Inhibition of Cell Division in Escherichia coli by Electrolysis Products from a Platinum Electrode”. Nature 205 (4972): 698–9. doi:10.1038/205698a0. PMID 14287410. edit
  2. ^ Petsko, G. A. (2002). “A christmas carol”. Genome biology 3 (1): COMMENT1001. PMC 150444. PMID 11806819. edit
  3. ^ http://visualsonline.cancer.gov/details.cfm?imageid=8173

Other posts of interest  in this site  include:

Interview with the co-discoverer of the structure of DNA: Watson on The Double Helix and his changing view of Rosalind Franklin

Otto Warburg, A Giant of Modern Cellular Biology

Inspiration From Dr. Maureen Cronin’s Achievements in Applying Genomic Sequencing to Cancer Diagnostics

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Differentiation Therapy – Epigenetics Tackles Solid Tumors

Posted in Biological Networks, Gene Regulation and Evolution, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Health Economics and Outcomes Research, Molecular Genetics & Pharmaceutical, tagged , , , , , , , , , , , , , , , , , , on January 3, 2013| 18 Comments »

Differentiation Therapy – Epigenetics Tackles Solid Tumors

Author-Writer: Stephen J. Williams, Ph.D.

Updated 4/27/2021

Screen Shot 2021-07-19 at 7.04.21 PM

Word Cloud By Danielle Smolyar

Genetic and epigenetic events within a cell which promote a block in normal development or differentiation coupled with unregulated proliferation are hallmarks of neoplastic transformation.  Differentiation therapy is a chemotherapeutic strategy directed at re-activating endogenous cellular differentiation programs in a tumor cell therefore driving the cancerous cell to a state closer resembling the normal or preneoplastic cell and therefore incurring loss of the tumorigenic phenotype.

This post will deal with:

  • Agents such as histone deacetylase inhibitors (HDACi), retinoids, and PPARϒ agonists which have been shown to reactivate terminal differentiation programs in solid tumors
  • Clinical trials in solid tumors
  • Issues regarding the use of differentiation therapy in solid tumors

This post is a follow-up post to Histone Deacetylase Inhibitors Induce Epithelial-to-Mesenchymal Transition in Prostate Cancer Cells

To put the need for alternate chemotherapeutic strategies in perspective, one is referred to the National Cancer Statistics from http://www.cancer.gov show that 33% of cancer patients, treated with standard cytolytic chemotherapy, will still die within five years (i.e. one in three will die within 5 years).  However the addition of the differentiation agent retinoic acid to standard chemotherapy regimen for treatment of acute promyelocytic leukemia (APML) had improved 5 year survival rates from a range of 50-80% up to near 90% complete remission rates while 75% become disease free, an astonishing success story.  For a review of APML please be referred to http://en.wikipedia.org/wiki/Acute_promyelocytic_leukemia.  Briefly, APML is predominantly a result of the chromosomal translocation producing a fusion gene between the promyelocytic leukemia (PML) and RARα receptor genes.  The PML-RARα fusion protein recruits transcriptional repressors, histone deacetylases (HDACs), and DNA methyltransferases.  Treatment with pharmacologic doses of retinoic acid dissociates the PML-RARα from HDACs and results in degradation of PML-RARα, eventually resulting in the differentiation of the myeloid cells in APML.

Dr. Igor Matushansky of Columbia University believes such differentiation therapy could be useful in soft tissue sarcomas, due to the existence of a connective tissue (mesenchymal) stem cell,  in vitro methods which can differentiate these cells into mature tissues, and, from a gene clustering analysis his group had performed, correlation of expression signatures of each liposarcoma subtype throughout the adipocytic differentiation spectrum, including early differentiated to more mature differentiated cells(1).   A parallel study by Riester and colleagues had been able to classify breast tumors and liposarcomas along a phylogenetic tree showing solid tumors can be reclassified based on cell of origin via expression patterns(2).  In addition, other solid tumors, such as ovarian cancer are easily classified, based both on pathologic, histologic, and expression analysis into well and poorly differentiated tumors, correlating differentiation status with prognosis.

Compound Classes which have potential in

differentiation therapy for solid tumors

A. Histone Deacetylase Inhibitors (HDACi)

In eukaryotes, epigenetic post-translational modification of histones is critical for regulation of chromatin structure and gene expression.  Histone deacetylation leads to chromatin compaction and is associated with transcriptional repression of tumor suppressors, cell growth and differentiation.  Therefore, HDACi are promising anti-tumor agents as they may affect the cell cycle, inhibit proliferation, stimulate differentiation and induce apoptotic cell death (3). In a review by Kniptein and Gore, entinostat was found to be a well-tolerated HDACi that demonstrates promising therapeutic potential in both solid and hematologic malignancies(4). The path to the discovery of suberoylanilide hydroxamic acid (SAHA, vorinostat) began over three decades ago with our studies designed to understand why dimethylsulfoxide causes terminal differentiation of the virus-transformed cells, murine erythroleukemia cells. SAHA can cause growth arrest and death of a broad variety of transformed cells both in vitro and in vivo at concentrations that have little or no toxic effects on normal cells (for references see (5). In fact, treatment of MCF-7 breast carcinoma cells with SAHA resulted in morphologic changes resembling epithelial mammary differentiation(6).

HDAC inhibitors

Figure.  Structures of some HDACi used in clinical trials for cancer (see section below)

hdacwithsaha

Figure.  HDAC with SAHA

B. Retinoids

Vitamin A and retinoids play significant roles in basic physiological processes such as vision, reproduction, growth, development, hematopoiesis and immunity (7). Retinoids are the natural derivatives and synthetic analogs of vitamin A. They have been shown to prevent mammary carcinogenesis in rodents (8), to inhibit the growth of human cancer cells in vitro  (9,10) and be effective chemopreventive and chemotherapeutic agents in a variety of human epithelial and hematopoietic tumors (11-14).

Retinoids cannot be synthesized de novo by higher animals and consequently must be consumed in the diet. The two sources of retinoids are animal products that contain retinol and retinyl esters, and plant-derived carotenoids (provitamin A). b-carotene is the most potent vitamin A precursor and has been shown to be an active inhibitor of both tumor initiation and promotion (15).

A major function of retinol, relevant to cancer, is its function as an antioxidant. The antioxidant properties of vitamin A have been shown both in vitro and in vivo (16,17). Retinol deficiency causes oxidative damage to liver mitochondria in rats that can be reversed by vitamin A supplementation (18). A caveat to this is in vitro and in vivo evidence of chronic hypervitaminosis A inducing oxidative DNA damage, as well (19-21). Therefore, it is evident that maintaining the vitamin A concentration within a physiological range is critical to normal cell function because either a deficiency or an excess of vitamin A induces oxidative stress (22). Retinoic acids (RA) (all-trans, 9-cis and 13-cis) are the major biologically active retinoids and exert their effects by regulation of gene expression by binding two families of ligand-activated nuclear retinoid receptors (23). Retinoic acid receptors (RARs) and retinoid X receptors (RXRs) regulate the transcription of a large number of target genes that contain retinoic acid response elements (RAREs) in their promoters. Many of these genes are involved in cancer (13,24) and differentiation (24-26).

Several lines of evidence suggest involvement of defects in retinol signaling in cancer, from the observation that a vitamin A-deficient (VAD) diet leads to an increase in the number of spontaneous and chemically induced tumors in animals (27-29) to the observation that RA itself can induce  differentiation and inhibit the growth of many tumor cells (30-32), as well as the identification that components of the RA signaling pathway are absent in cancer cells (33). Vitamin A and its metabolites have been proposed to have a dual effect in cancer prevention, as antioxidants (16,17,19,34) and differentiating agents (35-37). as it is well accepted that retinoid signaling is integral in maintaining the differentiated state of many cell types (13,38). Additionally, current rationale for chemoprevention with retinoids is based, in part, on the hypothesis that some tumors, may arise due to loss of normal somatic differentiation during tissue repair.

C. PPARϒ Agonists

Peroxisome proliferator-activated receptor ϒ (PPARϒ) is a member of the steroid hormone receptor superfamily that responds to changes in lipid and glucose homeostasis but has increasing roles in differentiation and tumorigenesis. The first PPAR (PPARα) was discovered during the search of a molecular target for a group of agents then referred to as peroxisome proliferators, as they increased peroxisomal numbers in rodent liver tissue, apart from improving insulin sensitivity.  One of the first agents, developed in the early 80’s for treatment of hyperlipidemia and hperlipoproteinemia, was clofibrate.  All PPAR subtypes heterodimerize with the retinoid-x-receptor (RXR) and, upon binding of ATRA, activate target genes.

PPARϒ agonists have shown potential as a therapeutic in a variety of cancer types including bladder cancer (39), colon cancer(40),  breast cancer(41), prostate cancer(42).  There are numerous studies showing that PPARϒ agonists have anti-tumorigenic activity via anti-proliferative, pro-differentiation and anti-angiogenic mechanisms of action(43). For example, Papi et al. observed that agonists for the retinoid X receptor (6-OH-11-O-hydroxyphenanthrene), retinoic acid receptor (all-trans retinoic acid (RA)) and peroxisome proliferator-activated receptor (PPAR)-γ (pioglitazone (PGZ)), reduce the survival of MS generated from breast cancer tissues and MCF7 cells, but not from normal mammary gland or MCF10 cells(44) with concomitant upregulation of differentiation markers.

A great website for further information on PPAR is Dr. Jack Vanden Heuvel, Professor of Toxicology at Penn State University at http://ppar.cas.psu.edu/general_information.html.

D. Trabectedin

Trabectedin (ecteinascidin-743 (ET-743); Yondelis) is derived from the Caribbean tunicate Ecteinascidia turbinacta has antitumor activity by binding to the DNA minor groove thus disrupting binding of transcription factors and inhibiting DNA synthesis.  However, it has also been shown, in myxoid liposarcoma (MLS) cells, to cause dissociation of transcription factor TLS-CHOP from promoter sequences resulting in downregulation of target genes such as CHOP, PTX3 and FN1 and induces an adipogenic differentiation program by enhancing activation of CAAT/enhancer binding protein (C/EBP) family of genes.  In MLS, TLS-CHOP sequesters C/EBPβ resulting in block of differentiation programs while trabectedin disrupts this association freeing up C/EBPβ to act as transcriptional activator of genes related to differentiation.

Ongoing Cancer Clinical Trials with HDAC Inhibitors

The following is a listing of some clinical trials using histone deacetylase inhibitors in combination with approved chemotherapeutics in various tumors.  This data was taken from the New Medicine Oncology Knowledge Base ( at http://www.nmok.net).

hdactrial1 hdactrial2

Issues and Future of Differentiation-based Therapy

In the review by Filemon Dela Cruz and Igor Matushansky(1), the authors suggest that, like days of old of cytotoxic monotherapy, differentiation therapy would not evolve as a simplistic one-size-fits –all but mirror an extremely complicated process.  Therefore they suggest three theoretical mechanisms in which differentiation therapy may occur:

  1. Cancer directed differentiation: differentiation pathways are activated without correcting the underlying oncogenic mechanisms which produced the initial differentiation block
  2. Cancer reverted differentiation: correction of the underlying oncogenic mechanism results in restoration of endogenous differentiation pathways
  3. Cancer diverted differentiation: cancer cell is redirected to an earlier stage of differentiation

Finally the authors suggest that “the potential for reversion of the malignant cancer phenotype to a more benign, or at the very least a lower grade of biological aggressiveness, may serve as a critical clinical and biologic transition of a uniformly fatal cancer into one more amenable to management or to treatment using conventional therapeutic approaches.”

References:

1.            Cruz, F. D., and Matushansky, I. (2012) Oncotarget 3, 559-567

2.            Riester, M., Stephan-Otto Attolini, C., Downey, R. J., Singer, S., and Michor, F. (2010) PLoS computational biology 6, e1000777

3.            Seidel, C., Schnekenburger, M., Dicato, M., and Diederich, M. (2012) Genes & nutrition 7, 357-367

4.            Knipstein, J., and Gore, L. (2011) Expert opinion on investigational drugs 20, 1455-1467

5.            Marks, P. A. (2007) Oncogene 26, 1351-1356

6.            Munster, P. N., Troso-Sandoval, T., Rosen, N., Rifkind, R., Marks, P. A., and Richon, V. M. (2001) Cancer research 61, 8492-8497

7.            Napoli, J. L. (1999) Biochim Biophys Acta 1440, 139-162

8.            Moon, R., Metha, R., and Rao, K. (1994) Retinoids and cancer in experimental animals. in The Retinoids: Biology, Chemistry, and Medicine (Sporn, M., Roberts, A., and Goodman, D. eds.), 2 Ed., Raven Press, New York. pp 573-596

9.            De Luca, L. M. (1991) Faseb J 5, 2924-2933

10.          Gudas, L. J. (1992) Cell Growth Differ 3, 655-662

11.          Degos, L., and Parkinson, D. (1995) Retinoids in Oncology, Springer-Verlag, Berlin

12.          Lotan, R. (1996) Faseb J 10, 1031-1039

13.          Zhang, D., Holmes, W. F., Wu, S., Soprano, D. R., and Soprano, K. J. (2000) J Cell Physiol 185, 1-20

14.          Fontana, J. A., and Rishi, A. K. (2002) Leukemia 16, 463-472

15.          Suda, D., Schwartz, J., and Shklar, G. (1986) Carcinogenesis 7, 711-715

16.          Ciaccio, M., Valenza, M., Tesoriere, L., Bongiorno, A., Albiero, R., and Livrea, M. A. (1993) Arch Biochem Biophys 302, 103-108

17.          Palacios, A., Piergiacomi, V. A., and Catala, A. (1996) Mol Cell Biochem 154, 77-82

18.          Barber, T., Borras, E., Torres, L., Garcia, C., Cabezuelo, F., Lloret, A., Pallardo, F. V., and Vina, J. R. (2000) Free Radic Biol Med 29, 1-7

19.          Borras, E., Zaragoza, R., Morante, M., Garcia, C., Gimeno, A., Lopez-Rodas, G., Barber, T., Miralles, V. J., Vina, J. R., and Torres, L. (2003) Eur J Biochem 270, 1493-1501

20.          Omenn, G. S., Goodman, G. E., Thornquist, M. D., Balmes, J., Cullen, M. R., Glass, A., Keogh, J. P., Meyskens, F. L., Jr., Valanis, B., Williams, J. H., Jr., Barnhart, S., Cherniack, M. G., Brodkin, C. A., and Hammar, S. (1996) J Natl Cancer Inst 88, 1550-1559

21.          Murata, M., and Kawanishi, S. (2000) J Biol Chem 275, 2003-2008

22.          Schwartz, J. L. (1996) J Nutr 126, 1221S-1227S

23.          Chambon, P. (1996) Faseb J 10, 940-954

24.          Freemantle, S. J., Kerley, J. S., Olsen, S. L., Gross, R. H., and Spinella, M. J. (2002) Oncogene 21, 2880-2889

25.          Collins, S. J., Robertson, K. A., and Mueller, L. (1990) Mol Cell Biol 10, 2154-2163

26.          Grunt, T. W., Somay, C., Oeller, H., Dittrich, E., and Dittrich, C. (1992) J Cell Sci 103 ( Pt 2), 501-509

27.          Lasnitzki, I. (1955) Br J Cancer 9, 434-441

28.          Moore, T. (1965) Proc Nutr Soc 24, 129-135

29.          Saffiotti, U., Montesano, R., Sellakumar, A. R., and Borg, S. A. (1967) Cancer 20, 857-864

30.          Strickland, S., and Mahdavi, V. (1978) Cell 15, 393-403

31.          Breitman, T. R., Selonick, S. E., and Collins, S. J. (1980) Proc Natl Acad Sci U S A 77, 2936-2940

32.          Breitman, T. R., Collins, S. J., and Keene, B. R. (1981) Blood 57, 1000-1004

33.          Niles, R. M. (2000) Nutrition 16, 573-576

34.          Monagham, B., and Schmitt, F. (1932) J Biol Chem 96, 387-395

35.          Miller, W. H., Jr. (1998) Cancer 83, 1471-1482

36.          Miyauchi, J. (1999) Leuk Lymphoma 33, 267-280

37.          Reynolds, C. P. (2000) Curr Oncol Rep 2, 511-518

38.          Ortiz, M. A., Bayon, Y., Lopez-Hernandez, F. J., and Piedrafita, F. J. (2002) Drug Resist Updat 5, 162-175

39.          Mansure, J. J., Nassim, R., and Kassouf, W. (2009) Cancer biology & therapy 8, 6-15

40.          Osawa, E., Nakajima, A., Wada, K., Ishimine, S., Fujisawa, N., Kawamori, T., Matsuhashi, N., Kadowaki, T., Ochiai, M., Sekihara, H., and Nakagama, H. (2003) Gastroenterology 124, 361-367

41.          Stoll, B. A. (2002) Eur J Cancer Prev 11, 319-325

42.          Smith, M. R., and Kantoff, P. W. (2002) Investigational new drugs 20, 195-200

43.          Rumi, M. A., Ishihara, S., Kazumori, H., Kadowaki, Y., and Kinoshita, Y. (2004) Current medicinal chemistry. Anti-cancer agents 4, 465-477

44.          Papi, A., Guarnieri, T., Storci, G., Santini, D., Ceccarelli, C., Taffurelli, M., De Carolis, S., Avenia, N., Sanguinetti, A., Sidoni, A., Orlandi, M., and Bonafe, M. (2012) Cell death and differentiation 19, 1208-1219

Updated 4/27/2021

Epizyme’s EZH2 blocker boosts immuno-oncology response in prostate cancer models

Source: https://www.fiercebiotech.com/research/epizyme-s-ezh2-blocker-boosts-immuno-oncology-response-prostate-cancer-models

cancer cell surrounded by killer T cells
Inhibiting EZH2 either genetically or with a chemical inhibitor signaled the immune system to respond to PD-1 inhibition in prostate cancer. (NIH)

The protein EZH2 has long been known as a major driver of prostate cancer because of its ability to inactivate genes that would normally suppress tumor growth. Now, a team at Cedars-Sinai Cancer has shown in preclinical models of the disease that blocking EZH2 reduces resistance to immune-boosting checkpoint inhibitors—and they did it with the help of Epizyme, which won FDA approval for the first EZH2 blocker last year.

The Cedars-Sinai team inhibited EZH2 in preclinical prostate cancer models, activating interferon-stimulated genes in the immune system. The interferons then boosted the immune response and reversed resistance to drugs that inhibit the checkpoint PD-1, they reported in the journal Nature Cancer.

By inhibiting EZH2 either genetically or with a chemical inhibitor donated by Epizyme, the researchers used a technique called “viral mimicry” to “reopen” parts of the genome that are typically inactive, they explained in a statement. That signaled the immune system to respond to PD-1 inhibition.

Checkpoint inhibitors have been approved to treat several cancer types, but they’ve been largely disappointing in prostate cancer. Hence several research groups have been exploring combination strategies. They include the University of Texas MD Anderson Cancer Center, which published research in 2019 showing early evidence that combining checkpoint inhibition with anti-TGF-beta drug could be effective in prostate cancer.

More recently, bispecific antibodies have shown early promise in prostate cancer. Last September, Amgen presented data from a phase 1 study of AMG 160, a bispecific targeting PSMA and CD3 on T cells. The company said that 68.6% of patients experienced a decline in PSA, and eight out of 15 patients evaluated showed stable disease.

Regeneron is also developing a bispecific antibody for prostate cancer, targeting PSMA and CD28. The drug is being tested as a solo therapy and in combination with Regeneron’s PD-1 inhibitor Libtayo in a phase 1/2 clinical trial enrolling men with metastatic castration-resistant prostate cancer.

As for Epizyme’s EZH2 inhibitor, Tazverik, its path to market hasn’t been perfectly smooth. An advisory committee to the FDA questioned its efficacy and safety in its initial indication, metastatic or locally advanced epithelioid sarcoma. Still, the company got the go-ahead to market the drug in adult patients with the rare cancer last January. Then the FDA added follicular lymphoma to the label in June. The drug’s takeoff has been slower than expected, however, largely because the pandemic has prevented face-to-face interactions between the sales force and physicians.

The company is currently testing Tazverik in several other cancer types, including as a combination with standard-of-care treatments in castration-resistant prostate cancer.

Other research papers on Cancer and Cancer Therapeutics were published on this Scientific Web site as follows:

Histone Deacetylase Inhibitors Induce Epithelial-to-Mesenchymal Transition in Prostate Cancer Cells

PIK3CA mutation in Colorectal Cancer may serve as a Predictive Molecular Biomarker for adjuvant Aspirin therapy

Nanotechnology Tackles Brain Cancer

Response to Multiple Cancer Drugs through Regulation of TGF-β Receptor Signaling: a MED12 Control

Personalized medicine-based cure for cancer might not be far away

GSK for Personalized Medicine using Cancer Drugs needs Alacris systems biology model to determine the in silico effect of the inhibitor in its “virtual clinical trial”

Lung Cancer (NSCLC), drug administration and nanotechnology

Non-small Cell Lung Cancer drugs – where does the Future lie?

Cancer Innovations from across the Web

arrayMap: Genomic Feature Mining of Cancer Entities of Copy Number Abnormalities (CNAs) Data

How mobile elements in “Junk” DNA promote cancer. Part 1: Transposon-mediated tumorigenesis.

Cancer Genomics – Leading the Way by Cancer Genomics Program at UC Santa Cruz

Closing the gap towards real-time, imaging-guided treatment of cancer patients.

Closing the gap towards real-time, imaging-guided treatment of cancer patients.

mRNA interference with cancer expression

Search Results for ‘cancer’ on this web site

Cancer Genomics – Leading the Way by Cancer Genomics Program at UC Santa Cruz

Closing the gap towards real-time, imaging-guided treatment of cancer patients.

Lipid Profile, Saturated Fats, Raman Spectrosopy, Cancer Cytology

mRNA interference with cancer expression

Pancreatic cancer genomes: Axon guidance pathway genes – aberrations revealed

Biomarker tool development for Early Diagnosis of Pancreatic Cancer: Van Andel Institute and Emory University

Is the Warburg Effect the cause or the effect of cancer: A 21st Century View?

Crucial role of Nitric Oxide in Cancer

Targeting Glucose Deprived Network Along with Targeted Cancer Therapy Can be a Possible Method of Treatment

Read Full Post »

Prostate Cancer Cells: Histone Deacetylase Inhibitors Induce Epithelial-to-Mesenchymal Transition

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biological Networks, Gene Regulation and Evolution, BioSimilars, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Health Economics and Outcomes Research, Pharmaceutical Analytics, Stem Cells for Regenerative Medicine, tagged , , , , , , , , , , , , , , , , , , , , , , , , , , on November 30, 2012| 21 Comments »

Histone Deacetylase Inhibitors Induce Epithelial-to-Mesenchymal Transition in Prostate Cancer Cells(1)

Screen Shot 2021-07-19 at 7.44.44 PM

Word Cloud By Danielle Smolyar

Authors: Dejuan Kong, Aamir Ahmad, Bin Bao, Yiwei Li, Sanjeev Banarjee, Fazlul H. Sarkar, Wayne State University School of Medicine

Reporter-Curator: Stephen J. Williams, Ph.D.

Clinically, there has not been much success in treating solid tumors with histone deacetylase inhibitors (HDACi). Histone acetylation and deacetylation play an important role in transcriptional regulation of genes and increased activity is associated with many cancers, therefore it was thought that HDAC inhibition might be fruitful as a therapy.  There have been several phase I and II clinical trials using HDACi for treatment of various malignancies, including hematological and solid malignancies(2), with most success seen in hematologic malignancies such as cutaneous T-cell lymphoma and peripheral T-cell lymphoma and little or no positive outcome with solid tumors.  Many mechanisms of resistance to HDACi in solid tumors have been described, most of which are seen with other chemotherapeutics such as increased multidrug resistance gene MDR1, increased anti-apoptotic proteins and activation of cell survival pathways(3).

A report in PLOS One by Dr. Dejuan Kong, Dr. Fazlul Sarkar, and colleagues from Wayne State University School of Medicine, demonstrate another possible mechanism of resistance to HDACi in prostate cancer, by induction of the epithelial-to-mesenchymal transition (EMT), which has been associated with the development of resistance to chemotherapies in other malignancies of epithelial origin(4,5).

EMT is an important differentiation process in embryogenesis and felt to be important in progression of cancer.  Epithelial cells will acquire a mesenchymal morphology (on plastic this looks like a cuboidal epithelial cell gaining a more flattened, elongated, tri-corner morphology; see paper Figure 1) and down-regulate epithelial markers such as cytokeratin, up-regulation of mesenchymal markers, increased migration and invasiveness in standard assays, and increased resistance to chemotherapeutics, and similarity to cancer stem cells(6-10).

ImageFigure 1. HDACis led to the induction of EMT phemotype. (A and B) PC3 cells treated with TSA and SAHA for 24 h at indicated doses.  The photomicrographs of PC3 cells treated with TSA and SAHA exhibited a fibroblastic-type phenotype, while cells treated with DMAO control displayed rounded epithelial cell morphology (original magnification, x 100). (C) Treated PC3 cells show increased mesenchymal markers vimentin and ZEB1 and F-actin reorganization.  Figure taken from Kong, D., Ahmad, A., Bao, B., Li, Y., Banerjee, S., and Sarkar, F. H. (2012) PloS one 7, e45045

In this study the authors found that treatment of prostate carcinoma cells with two different HDACis (trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA)) induced EMT phenotype mediated through up-regulation of transcription factors ZEB1, ZEB2 and Slug, increased expression of mesenchymal markers vimentin, N-cadherin and fibronectin by promoting histone 3 acetylation on gene promoters.  In addition TSA increased the stem cell markers Sox2 and Nanog with concomitant EMT morphology and increased cell motility.

Below is the abstract of this paper(1):

ABSTRACT

Clinical experience of histone deacetylase inhibitors (HDACIs) in patients with solid tumors has been disappointing; however, the molecular mechanism of treatment failure is not known. Therefore, we sought to investigate the molecular mechanism of treatment failure of HDACIs in the present study. We found that HDACIs Trichostatin A (TSA) and Suberoylanilide hydroxamic acid (SAHA) could induce epithelial-to-mesenchymal transition (EMT) phenotype in prostate cancer (PCa) cells, which was associated with changes in cellular morphology consistent with increased expression of transcription factors ZEB1, ZEB2 and Slug, and mesenchymal markers such as vimentin, N-cadherin and Fibronectin. CHIP assay showed acetylation of histone 3 on proximal promoters of selected genes, which was in part responsible for increased expression of EMT markers. Moreover, TSA treatment led to further increase in the expression of Sox2 and Nanog in PCa cells with EMT phenotype, which was associated with cancer stem-like cell (CSLC) characteristics consistent with increased cell motility. Our results suggest that HDACIs alone would lead to tumor aggressiveness, and thus strategies for reverting EMT-phenotype to mesenchymal-to-epithelial transition (MET) phenotype or the reversal of CSLC characteristics prior to the use of HDACIs would be beneficial to realize the value of HDACIs for the treatment of solid tumors especially PCa.

Highlights of the research include:

  • TSA and SAHA induce morphologic changes  in prostate carcinoma LNCaP and PC3 cells related to EMT by microscopy as well as accumulation of mesenchymal markers ZEB1, vimentin, and F-actin reorganization shown by immunofluorescence microscopy and increased expression of these markers shown by real-time PCR
  • Western blotting showed TSA treatment resulted in hyperacetyulation of histone 3 whi8le CHIP analysis revealed increased histone 3 acetylation on the promoters of vimentin, ZEB2, Slug, and MMP2
  • Western analysis revealed that HDACi not only induced EMT but increased the expression of cancer stem cell markers associated with increased motility such as Sox2 and Nanog.  Increased cell migration was measured by Transwell migration assays and increased cell motility was measured via cell detachment assays

1.            Kong, D., Ahmad, A., Bao, B., Li, Y., Banerjee, S., and Sarkar, F. H. (2012) PloS one 7, e45045

2.            Bertino, E. M., and Otterson, G. A. (2011) Expert opinion on investigational drugs 20, 1151-1158

3.            Robey, R. W., Chakraborty, A. R., Basseville, A., Luchenko, V., Bahr, J., Zhan, Z., and Bates, S. E. (2011) Molecular pharmaceutics 8, 2021-2031

4.            Wang, Z., Li, Y., Kong, D., Banerjee, S., Ahmad, A., Azmi, A. S., Ali, S., Abbruzzese, J. L., Gallick, G. E., and Sarkar, F. H. (2009) Cancer research 69, 2400-2407

5.            Wang, Z., Li, Y., Ahmad, A., Azmi, A. S., Kong, D., Banerjee, S., and Sarkar, F. H. (2010) Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy 13, 109-118

6.            Hugo, H., Ackland, M. L., Blick, T., Lawrence, M. G., Clements, J. A., Williams, E. D., and Thompson, E. W. (2007) Journal of cellular physiology 213, 374-383

7.            Thiery, J. P. (2002) Nature reviews. Cancer 2, 442-454

8.            Kong, D., Banerjee, S., Ahmad, A., Li, Y., Wang, Z., Sethi, S., and Sarkar, F. H. (2010) PloS one 5, e12445

9.            Kong, D., Li, Y., Wang, Z., and Sarkar, F. H. (2011) Cancers 3, 716-729

10.          Bao, B., Wang, Z., Ali, S., Kong, D., Li, Y., Ahmad, A., Banerjee, S., Azmi, A. S., Miele, L., and Sarkar, F. H. (2011) Cancer letters 307, 26-36

Other research papers on Cancer and Cancer Therapeutics were published on this Scientific Web site as follows:

PIK3CA mutation in Colorectal Cancer may serve as a Predictive Molecular Biomarker for adjuvant Aspirin therapy

Nanotechnology Tackles Brain Cancer

Response to Multiple Cancer Drugs through Regulation of TGF-β Receptor Signaling: a MED12 Control

Personalized medicine-based cure for cancer might not be far away

GSK for Personalized Medicine using Cancer Drugs needs Alacris systems biology model to determine the in silico effect of the inhibitor in its “virtual clinical trial”

Lung Cancer (NSCLC), drug administration and nanotechnology

Non-small Cell Lung Cancer drugs – where does the Future lie?

Cancer Innovations from across the Web

arrayMap: Genomic Feature Mining of Cancer Entities of Copy Number Abnormalities (CNAs) Data

How mobile elements in “Junk” DNA promote cancer. Part 1: Transposon-mediated tumorigenesis.

Cancer Genomics – Leading the Way by Cancer Genomics Program at UC Santa Cruz

Closing the gap towards real-time, imaging-guided treatment of cancer patients.

Closing the gap towards real-time, imaging-guided treatment of cancer patients.

mRNA interference with cancer expression

Search Results for ‘cancer’ on this web site

Cancer Genomics – Leading the Way by Cancer Genomics Program at UC Santa Cruz

Closing the gap towards real-time, imaging-guided treatment of cancer patients.

Lipid Profile, Saturated Fats, Raman Spectrosopy, Cancer Cytology

mRNA interference with cancer expression

Pancreatic cancer genomes: Axon guidance pathway genes – aberrations revealed

Biomarker tool development for Early Diagnosis of Pancreatic Cancer: Van Andel Institute and Emory University

Is the Warburg Effect the cause or the effect of cancer: A 21st Century View?

Crucial role of Nitric Oxide in Cancer

Targeting Glucose Deprived Network Along with Targeted Cancer Therapy Can be a Possible Method of Treatment

Read Full Post »

Response to Multiple Cancer Drugs through Regulation of TGF-β Receptor Signaling: a MED12 Control

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, tagged , , , , , , , on November 21, 2012| 4 Comments »

Reporter: Aviva Lev-Ari, PhD, RN

 

MED12 Controls the Response to Multiple Cancer Drugs through Regulation of TGF-β Receptor Signaling

Cell, Volume 151, Issue 5, 937-950, 21 November 2012
Copyright © 2012 Elsevier Inc. All rights reserved.
10.1016/j.cell.2012.10.035

Referred to by: A Mediator Lost in the War on Cancer

Authors

  • Highlights
  • MED12 loss causes resistance to many cancer drugs through enhanced TGF-β signaling
  • MED12 inhibits TGF-β receptor signaling through physical interaction in the cytoplasm
  • MED12-regulated genes are predictive for responses to cancer drugs in patients
  • MED12-deficient tumors may benefit from therapy that includes a TGF-β inhibitor

Summary

Inhibitors of the ALK and EGF receptor tyrosine kinases provoke dramatic but short-lived responses in lung cancers harboring EML4-ALK translocations or activating mutations of EGFR, respectively. We used a large-scale RNAi screen to identify MED12, a component of the transcriptional MEDIATOR complex that is mutated in cancers, as a determinant of response to ALK and EGFR inhibitors. MED12 is in part cytoplasmic where it negatively regulates TGF-βR2 through physical interaction. MED12 suppression therefore results in activation of TGF-βR signaling, which is both necessary and sufficient for drug resistance. TGF-β signaling causes MEK/ERK activation, and consequently MED12 suppression also confers resistance to MEK and BRAF inhibitors in other cancers. MED12 loss induces an EMT-like phenotype, which is associated with chemotherapy resistance in colon cancer patients and to gefitinib in lung cancer. Inhibition of TGF-βR signaling restores drug responsiveness in MED12KD cells, suggesting a strategy to treat drug-resistant tumors that have lost MED12.

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GSK for Personalized Medicine using Cancer Drugs needs Alacris systems biology model to determine the in silico effect of the inhibitor in its “virtual clinical trial”

Posted in Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, CANCER BIOLOGY & Innovations in Cancer Therapy, Chemical Genetics, Computational Biology/Systems and Bioinformatics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Genome Biology, Genomic Testing: Methodology for Diagnosis, Medical and Population Genetics, Personalized and Precision Medicine & Genomic Research, Population Health Management, Genetics & Pharmaceutical, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Technology Transfer: Biotech and Pharmaceutical, tagged , , , , , , on November 14, 2012| 8 Comments »

GSK for Personalized Medicine using Cancer Drugs needs Alacris systems biology model to determine the in silico effect of the inhibitor in its “virtual clinical trial”

Reporter: Aviva Lev-Ari, PhD, RN

Article-7.3.5. GSK for Personalized Medicine using Cancer Drugs needs Alacris systems biology model to determine the in silico effect of the inhibitor in its virtual clinical trial

German firm Alacris Theranostics today announced a deal with GlaxoSmithKline for the application of Alacris’ Modcell System for drug stratification.

The technology, which was developed at the Max Planck Institute for Molecular Genetics and is licensed exclusively to Alacris, will be used by GSK for early stage cancer drug discovery. GSK will provide Alacris with preclinical biology data from a cancer drug discovery project. Alacris will apply its systems biology model to determine the in silico effect of the inhibitor in its “virtual clinical trial,” and then suggest cancer cell lines, as well as cancers, that may be likely responders to the inhibitor.

The process will be based on whole-genome and transcriptome data integrated in Alacris’ cancer model ModCell.

Financial terms of the deal were not disclosed.

Based in Berlin, Alacris develops personalized medicine approaches directed at cancer. Its ModCell approach is based on next-generation sequencing and kinetic pathway information, as well as mutation and drug databases.

SOURCE:

http://www.genomeweb.com//node/1153161?hq_e=el&hq_m=1408239&hq_l=2&hq_v=e1df6f3681

What is the strategy of the Competition

Foundation Medicine, AstraZeneca to ID Genetic Mutations for Cancer Drug Development

November 12, 2012

NEW YORK (GenomeWeb News) – Foundation Medicine today announced a deal with AstraZeneca aimed at predicting a patient’s response or resistance to targeted medicines.

The firms are partnering to identify genomic mutations in cancer-related tumor genes that may prove helpful to AstraZeneca in developing new therapies for patients. Foundation Medicine also was granted right of first negotiation for developing potential diagnostic products.

According to Susan Galbraith, vice president and head of the AstraZeneca Oncology Innovative Medicines Unit, the collaboration will allow the drug firm to “identify tumor-specific defects and alterations that can be used for patient segmentation.”

Financial and other terms of the agreement were not disclosed.

“We are helping companies like AstraZeneca achieve deeper insight into their programs and trials with our unique cancer expertise and our ability to provide genomic information that can impact clinical treatment decisions,” Michael Pellini, president and CEO of Foundation Medicine, said in a statement. “Together, we expect to enable a more individualized, targeted approach to cancer drug development and clinical trials.”

The partnership is the most recent in a string of deals that Cambridge, Mass.-based Foundation Medicine has forged in recent months with drug firms. It follows a collaboration with Eisai last month, Clovis Oncologyin August, and Novartis in June.

SOURCE:

 

Life Tech to Partner with Bristol-Myers Squibb for CDx Development

September 17, 2012
 

NEW YORK (GenomeWeb News) – Life Technologies said today that it would collaborate with Bristol-Myers Squibb to develop companion diagnostics. Initially, the companies will partner on an oncology project with the option to expand collaborative efforts across a range of disease areas.

Life Tech will utilize a variety of its technology platforms including both next-generation and Sanger sequencing instruments, qPCR, flow cytometry, and immuno-histochemistry.

“The pharmaceutical industry is increasingly turning its focus to discovering and delivering targeted, personalized medications,” Life Tech’s President of Medical Sciences, Ronnie Andrews, said in a statement. “As more and more targeted drugs come onto the market in the next decade, there will be a growing need for diagnostics that can help predict which patients will benefit from which drugs.”

The agreement is part of Life Tech’s strategy to expand and develop its diagnostic business through both internal development and also partnerships and acquisitions.

Internally, the company has said that it plans to build out its medical sciences business across multiple technologies and develop assays across five disease areas: oncology, inherited disease, neurological disorders, transplant diagnostics, and infectious diseases.

In addition, in July it acquired direct-to-consumer genomic testing company Navigenics, which gave Life Tech access to its CLIA certified laboratory.

SOURCE:

http://www.genomeweb.com/sequencing/life-tech-partner-bristol-myers-squibb-cdx-development

Life Tech, Boston Children’s Hospital to Develop Sequencing Workflows on Ion Proton in CLIA Lab

June 20, 2012
 

NEW YORK (GenomeWeb News) – Life Technologies said today that it will collaborate with Boston Children’s Hospital to develop next-generation sequencing workflows in a CLIA and CAP certified laboratory.

As part of the collaboration, the hospital plans to purchase Life Tech’s Ion Proton, a benchtop, semiconductor sequencing machine.

David Margulies, director of the Gene Partnership Program at Boston Children’s Hospital, said in statement that the deal is an “important first step toward providing informed, personalized care for patients whose conditions are difficult to treat.”

The deal is Life Tech’s second announced this week to develop sequencing protocols for the Ion Proton in collaboration with a children’s hospital. Earlier this week, it said it would work with the Hospital for Sick Children in Toronto, which has launched a new Centre for Genetic Medicine and plans to install four Proton machines.

Paul Billings, Life Tech’s chief medical officer, commented in a statement that these kinds of partnerships are “essential to our medical sciences strategy as we seek to assist researchers in discovering improved diagnostics and treatments for genetic conditions.”

In a separate announcement today, Life Tech said that it is collaborating with the University of North Texas Health Science Center’s Institute of Applied Genetics to use the firm’s Ion Personal Genome Machine system to further the center’s forensic DNA research. Life Tech said that it will collaborate with the center to train forensic analysts in applying next-gen sequencing to their research.

Foundation Medicine, Novartis Ink New Deal for Clinical Oncology Programs

June 07, 2012
 

NEW YORK (GenomeWeb News) – Foundation Medicine today said it and Novartis have reached a new agreement to use Foundation’s clinical grade, next-generation sequencing to support the drug firm’s clinical oncology programs.

The three-year agreement builds on a 2011 deal between the firms and calls for the use of Foundation Medicine’s molecular information platform across many of Novartis’ Phase 1 and Phase 2 oncology clinical programs. The initial collaboration generated “very interesting” data, and this type of tumor genomic profiling has become an important part of Novartis’ clinical trials, Foundation Medicine said.

Foundation Medicine’s sequencing capabilities allow for the rapid analysis of hundreds of cancer-related genes from formalin-fixed, paraffin-embedded tumor samples, and earlier this year its laboratory in Cambridge, Mass., gained Clinical Laboratory Improvement Amendments certification. Novartis plans to use the technology to align clinical trial enrollment and outcome analysis with the genomic profile of patient tumors, accelerating the development of Novartis’ portfolio of targeted cancer therapeutics and expanding treatment options for patients.

Foundation Medicine added that it may develop additional diagnostic products from the partnership.

“The comprehensive molecular assessment of Novartis’ Oncology clinical trial samples is expected to help to bring potentially lifesaving therapies to the right patients more quickly, and we expect that the wealth of molecular information will help fundamentally improve the way cancer is understood and treated,” Michael Pellini, president and CEO of Foundation Medicine, said in a statement.

Financial and other terms of the deal were not disclosed.

SOURCE:

 

Carestream Teams with Beatson Institute on Molecular Imaging Efforts

May 14, 2012
NEW YORK (GenomeWeb News) – Carestream Molecular Imaging announced today that it will collaborate with the Beatson Institute for Cancer Research on preclinical imaging approaches in oncology.

The partners will use Carestream’s Alibri trimodal imaging system, which combines PET, SPECT, and CT modalities in one platform. The system is being used by the Beatson Institute in its research into cancer cell behavior, as well as the development of new therapeutic, diagnostic, and prognostic tools.

The Beatson Institute, which is a core-funded institute of Cancer Research UK and is based in Glasgow, Scotland, said the Carestream technology would be used by its own researchers, as well as its close collaborators including the West of Scotland Cancer Center.

“The combination of PET, SPECT, and CT technologies in one instrument provides investigators at our institutions the flexibility to support research programs across many areas of cancer research such as biomarker, theranostics, and drug development,” Kurt Anderson, research professor and director of the Beatson Advanced Imaging Resource, said in a statement.

 

 

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Non-small Cell Lung Cancer drugs – where does the Future lie?

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Disease Biology, Small Molecules in Development of Therapeutic Drugs, FDA Regulatory Affairs, International Global Work in Pharmaceutical, Medical and Population Genetics, Pharmaceutical Analytics, Pharmaceutical Industry Competitive Intelligence, Pharmaceutical R&D Investment, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Uncategorized, tagged , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , on November 6, 2012| 21 Comments »

Non-small Cell Lung Cancer drugs – where does the Future lie?

In focus: Tarceva, Avastin and Dacomitinib

 

UPDATED on July 5, 2013

(from reports published in New England Journal of Medicine on drug, crizotinib)

 

Curator: Ritu Saxena, Ph.D.

 

Introduction

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and usually grows and spreads more slowly than small cell lung cancer.

There are three common forms of NSCLC:

  • Adenocarcinomas are often found in an outer area of the lung.
  • Squamous cell carcinomas are usually found in the center of the lung next to an air tube (bronchus).
  • Large cell carcinomas can occur in any part of the lung. They tend to grow and spread faster than the other two types.

Lung cancer is by far the leading cause of cancer death among both men and women. Each year, more people die of lung cancer than of colon, breast, and prostate cancers combined. The American Cancer Society’s most recent estimates for lung cancer in the United States for 2012 reveal that about 226,160 new cases of lung cancer will be diagnosed (116,470 in men and 109,690 in women), and there will be an estimated 160,340 deaths from lung cancer (87,750 in men and 72,590 among women), accounting for about 28% of all cancer deaths.

Treatment

Different types of treatments are available for non-small cell lung cancer. Treatment depends on the stage of the cancer. For patients in whom the cancer has not spread to nearby lymph nodes are recommended surgery. Surgeon may remove- one of the lobes (lobectomy), only a small portion of the lung (wedge removal), or the entire lung (pneumonectomy). Some patients require chemotherapy that uses drugs to kill cancer cells and stop new cells from growing.

FDA approved drugs for NSCLC

Abitrexate (Methotrexate)
Abraxane (Paclitaxel Albumin-stabilized Nanoparticle Formulation) 
Alimta (Pemetrexed Disodium)
Avastin (Bevacizumab)
Bevacizumab
Carboplatin
Cisplatin
Crizotinib
Erlotinib Hydrochloride
Folex (Methotrexate)
Folex PFS (Methotrexate)
Gefitinib
Gemcitabine Hydrochloride
Gemzar (Gemcitabine Hydrochloride)
Iressa (Gefitinib)
Methotrexate
Methotrexate LPF (Methotrexate)
Mexate (Methotrexate)
Mexate-AQ (Methotrexate)
Paclitaxel
Paclitaxel Albumin-stabilized Nanoparticle Formulation
Paraplat (Carboplatin)
Paraplatin (Carboplatin)
Pemetrexed Disodium
Platinol (Cisplatin)
Platinol-AQ (Cisplatin)
Tarceva (Erlotinib Hydrochloride)
Taxol (Paclitaxel)
Xalkori (Crizotinib)

On the basis of target, the drugs have been classified as follows:

Image

NSCLC Drug Market Analysis

NSCLC drug market expected to grow from $4.2 billion in 2010 to $5.4 billion in 2020

Although, a whole list of agents is available for the treatment of NSCLC, the market for NSCLC drugs is expected to expand from $4.2 billion in 2010 to $5.4 billion in 2020 in the United States, France, Germany, Italy, Spain, the United Kingdom and Japan.   

However, drug sales for metastatic/advanced squamous cell non-small-cell lung cancer, which comprises only a small fraction of the market, will decrease from nearly 17 percent in 2010 to approximately 13 percent in 2020. According to surveyed U.S. oncologists and MCO pharmacy directors, increasing overall survival is one of the greatest unmet needs in first-line advanced squamous non-small-cell lung cancer.

In 2009, antimetabolites dominated the NSCLC market, with Eli Lilly’s Alimta (Pemetrexed) accounting for nearly three-quarters of sales within this drug class. Since then, Alimta has faced tough competition from a number of similar drugs and from emerging therapies. It was speculated that the antimetabolites market share would reduce significantly making it the second-largest drug class in NSCLC, while the epidermal growth factor receptor (EGFR) inhibitor class will garner the top market share by 2019.

Genentech/OSI Pharmaceuticals/Roche/Chugai Pharmaceutical’s Tarceva belongs to the EGFR inhibitor class, and has been prescribed principally along with Eli Lilly’s Alimta, to NSCLC patients.Both these drugs have dominated the NSCLC market till 2010, however, their market hold is expected to weaken from 2015-2020, as claimed by Decision Resources Analyst Karen Pomeranz, Ph.D. Decision Resources is a research and advisory firms for pharmaceutical and healthcare issues.

Tarceva (Erlotinib)

Generic Name: Erlotinib, Brand Name: Tarceva

Other Designation: CP 358774, OSI-774, R1415, RG1415, NSC 718781

Mechanism of Action: Tarceva, a small molecule quinazoline, directly and reversibly inhibits the epidermal growth factor receptor (EGFr) tyrosine kinase. Detailed information on how it works could be found at the Macmillian Cancer support website.

Tarceva has been approved for different cancers and several indications have been filed-

  • non-small cell lung cancer (nsclc), locally advanced or metastatic, second line, after failure of at least one prior chemotherapy regimen (2004)
  • pancreatic cancer, locally advanced or metastatic, in combination with gemcitabine, first line (2005)
  • non-small cell lung cancer (nsclc), advanced, maintenance therapy in responders following first line treatment with platinum-based chemotherapy (2010)
  • non-small cell lung cancer (nsclc) harboring epidermal growth factor (EGFr)-activating mutations, first line treatment in advanced disease

Sales of Tarceva 

May, 2012 sales of Tarceva in the US have been reported to be around $564.2 million.

In a recent article published by Vergnenègre et al in the Clinicoeconomic Outcomes Research journal (2012), cross-market cost-effectiveness of Erlotinib was analyzed. The study aimed at estimating the incremental cost-effectiveness of Erlotinib (150 mg/day) versus best supportive care when used as first-line maintenance therapy for patients with locally advanced or metastatic NSCLC and stable disease.

It was determined that treatment with erlotinib in first-line maintenance resulted in a mean life expectancy of 1.39 years in all countries, compared with a mean 1.11 years with best supportive care, which represents 0.28 life-years (3.4 life-months) gained with erlotinib versus best supportive care.

According to the authors analysis, there was a gain in the costs per-life year as $50,882, $60,025, and $35,669 in France, Germany, and Italy, respectively. Hence, on the basis of the study it was concluded that Erlotinib is a cost-effective treatment option when used as first-line maintenance therapy for locally advanced or metastatic NSCLC.

Avastin (Bevacizumab)

Generic Name: Avastin, Brand Name: Bevacizumab

Other Designation: rhuMAb-VEGF, NSC-704865, R435, RG435

Mechanism of Action

Bevacizumab is a recombinant humanized Mab antagonist of vascular endothelial growth factor A (VEGFA) acting as an angiogenesis inhibitor.

Targets

Vascular endothelial growth factor (VEGF, VEGF-A, VEGFA)

Avastin is the only currently approved VEGF inhibitor that selectively targets VEGF-A.

Three other approved oral drugs, pazopanib (Votrient; GlaxoSmithKline), sunitinib (Sutent; Pfizer) and sorafenib (Nexavar; Onyx Pharmaceuticals) are orally available multi-targeted receptor tyrosine kinase inhibitors that include VEGF receptors among their tar­gets.

Avastin has been approved for different cancers and several indications have been filed:

  • colorectal cancer, advanced, metastatic, first line, in combination with a 5-FU based chemotherapy regimen
  • colorectal cancer, relapsed, metastatic, second line, in combintion with 5-FU-based chemotherapy (2004)
  • non-small cell lung cancer (nsclc), non-squamous, inoperable, locally advanced, recurrent or metastatic, in combination with carboplatin and paclitaxel chemotherapy, first line (2006)
  • breast cancer, chemotherapy naive, first line, locally recurrent or metastatic, in combination with taxane chemotherapy (2008, revoked in 2011)
  • non-small cell lung cancer (nsclc), non-squamous, inoperable, locally advanced, recurrent or metastatic, in combination with platinum-based chemotherapy, first line
  • renal cell carcinoma (RCC), metastatic, in combination with interferon (IFN) alpha, first line (2009)
  • glioblastoma multiforme (GBM), relapsed after first line chemoradiotherapy
  • breast cancer, chemotherapy naive, first line, locally recurrent or metastatic, HEr2 negative, in combination with capecitabine (2009)
  • ovarian cancer, in combination with standard chemotherapy (carboplatin and paclitaxel) as a first line treatment following surgery for women with advanced (Stage IIIb/c or Stage IV) epithelial ovarian, primary peritoneal or fallopian tube cancer
  • ovarian cancer, in combination with carboplatin and gemcitabine as a treatment for women with recurrent, platinum-sensitive ovarian cancer

SOURCE:

New medicine Oncology Knowledge Base

Sales of Avastin 

As of May, 2012, sales of Avastin in the US have been reported to be around $2.66 billion.

It attracted a lot of attention over the past few years after its use as a breast cancer treatment. Avastin was approved by the FDA under its fast-track program. However, the data released by the FDA from follow-up studies led to questioning the use of Avastin as a breast cancer drug. Infact, Genentech pulled the indication from Avastin’s label. Henceforth, the FDA did cancel that approval in late 2011. Doctors, however, can still prescribe it off-label. Potential adverse effects of Avastin that came under scrutiny along with unfavorable cost benefit analyses might pose challenges to its growth potential and continued widespread use. However, the sales of Avastin have continued to increase and it has been reported by Fierce Pharma as one of the 15 best-selling cancer drugs list. (Fierce Pharma)

Dacomitinib: New promising drug for NSCLC

Generic Name: Dacomitinib

Other Designation: PF-299804, PF-00299804, PF-299,804, PF00299804

PF-299804 is an orally available irreversible pan-HEr tyrosine kinase inhibitor.

Dacomitinib is a promising new drug on the market. Phase III trials are ongoing for advanced and refractory NSCLC, locally advanced or metastatic NSCLC and the EGFr mutation containing locally advanced or metastatic NSCLC in several countries including those in Europe, Asia, and America.

SOURCE:

New medicine Oncology Knowledge base

Dacomitinib bests Erlotinib in advanced NSCLC:  Comparison of its Progression-Free Survival (PFS) with the NSCLC marketed drug, Erlotinib.

In September of 2012, a study was published by Ramalingam et al in the Journal of Clinical Oncology, which was a randomized open-label trial comparing dacomitinib with erlotinib in patients with advanced NSCLC. On the basis of the study it was concluded that dacomitinib demonstrated significantly improved progression-free survival (PFS*) as compared to erlotinib, with a certain degree of toxicity.

SOURCE:

Randomized Phase II Study of Dacomitinib Versus Erlotinib in Patients With Advanced Non-Small-Cell Lung Cancer

The results indicated indicated the following:

  • Median PFS was significantly greater with Dacomitinib than Erlotinib, at 2.86 versus 1.91.
  • Mean duration of response was 16.56 months for dacomitinib and 9.23 months for erlotinib.

Patients were divided into groups by tumor type and following results were obtained:

  • Median PFS was 3.71 months with dacomitinib and 1.91 with erlotinib in patients with KRAS wild-type tumors
  • Median PFS was 2.21 months and 1.68 months, in patients with KRAS wild-type/EGFR wild-type tumors.
  • PFS was significantly better in the molecular subgroups harboring a mutant EGFR genotype.

The study also highlighted the side effects which might be more of concern and probably limiting for Dacomitinib.

Although adverse side effects were uncommon in both the groups, certain side effects such as:

  • mouth sores,
  • nailbed infections, and
  • diarrhea

were more common and tended to be more severe with Dacomitinib as compared to Tarceva.

Therefore, for patients for whom side effects of Tarceva seem challenging might face more difficulty with Dacomitinib treatment. Nonetheless, the results of PFS were promising enough and provide a greater efficacy in several clinical and molecular subgroups targeting a larger population than Tarceva. Authors, thus, suggested a larger, randomized phase III trial with the same design.

Current status of Dacomitinib

Based on positive performance of Dacomitinib published in research studies, Pfizer has entered into a collaborative development agreement with the SFJ Pharmaceuticals Group to conduct a phase III clinical trial across multiple sites in Asia and Europe, to evaluate dacomitinib (PF-00299804) as a first line treatment in patients with locally advanced or metastatic non-small cell lung cancer (nsclc) with activating mutations in the epidermal growth factor receptor (EGFr). Under the terms of the agreement, SFJ will provide the funding and clinical development supervision to generate the clinical data necessary to support a registration dossier on Dacomitinib for marketing authorization by regulatory authorities for this indication. If approved for this indication, SFJ will be eligible to receive milestone and earn-out payments.

SOURCE:

New medicine Oncology Knowledge base

*PFS or Progression-free survival is defined as the length of time during and after the treatment of as disease, such as cancer, that a patient lives with the disease but it does not get worse. In a clinical trial, measuring the progression-free survival is one way to see how well a new treatment works.

REFERENCES

Recently, another drug PF-02341066 (crizotinib), was tested on patients with non-small cell lung cancer and the results were published in New England Journal of Medicine (2013). Crizotinib is an orally available aminopyridine-based inhibitor of the) and the c-Met/hepatocyte growth factor receptor (HGFR). Crizotinib, in an ATP-competitive manner, binds to and inhibits ALK kinase and ALK fusion proteins. In addition, crizotinib inhibits c-Met kinase, and disrupts the c-Met signaling pathway. Altogether, this agent inhibits tumor cell growth.

  • Shaw and colleagues (2013) investigated whether crizotinib is superior to standard chemotherapy with respect to efficacy. To answer the question, Pfizer launched a phase III clinical trial (NCT00932893; http://clinicaltrials.gov/show/NCT00932893) comparing the safety and anti-tumor activity of PF-02341066 (crizotinib) versus pemetrexed or docetaxel in patients with advanced non-small cell lung cancer harboring a translocation or inversion event involving the ALK gene. Shaw and colleagues (2013) published the results of the clinical trial in a recent issue of New England Journal of Medicine.  A total of 347 patients with locally advanced or metastatic ALK-positive lung cancer who had received one prior platinum-based regimen were recruited for the trial and patients were randomly assigned to receive oral treatment with crizotinib (250 mg) twice daily or intravenous chemotherapy with either pemetrexed (500 mg per square meter of body-surface area) or docetaxel (75 mg per square meter) every 3 weeks. Patients in the chemotherapy group who had disease progression were permitted to cross over to crizotinib as part of a separate study. The primary end point was progression-free survival. According to the results, the median progression-free survival was 7.7 months in the crizotinib group and 3.0 months in the chemotherapy group. Hazard ratio (HR) for progression or death with crizotinib was 0.49 (95% CI, P<0.001). The response rates were 65% with crizotinib, as compared with 20% with chemotherapy (P<0.001). An interim analysis of overall survival showed no significant improvement with crizotinib as compared with chemotherapy (hazard ratio for death in the crizotinib group, 1.02; 95% CI, P=0.54). Common adverse events associated with crizotinib were visual disorder, gastrointestinal side effects, and elevated liver aminotransferase levels, whereas common adverse events with chemotherapy were fatigue, alopecia, and dyspnea. Patients reported greater reductions in symptoms of lung cancer and greater improvement in global quality of life with crizotinib than with chemotherapy.In conclusion, the results from the trial indicate that crizotinib is superior to standard chemotherapy in patients with previously treated, advanced non–small-cell lung cancer with ALK rearrangement. (Shaw AT, et al, Crizotinib versus Chemotherapy in Advanced ALK-Positive Lung Cancer. N Engl J Med 2013; 20 June, 368:2385-2394; http://www.ncbi.nlm.nih.gov/pubmed/23724913).

However, in the same issue of New England Journal of Medicine, Awad and colleagues (2013) reported from a phase I clinical trial (NCT00585195; http://clinicaltrials.gov/show/NCT00585195), that a patient with metastatic lung adenocarcioma harboring a CD74-ROS1 rearrangement who had initially shown a dramatic response to treatment, showed resistance to crizotinib. Biopsy of the resistant tumor identified an acquired mutation leading to a glycine-to-arginine substitution at codon 2032 in the ROS1 kinase domain. Although this mutation does not lie at the gatekeeper residue, it confers resistance to ROS1 kinase inhibition through steric interference with drug binding. The same resistance mutation was observed at all the metastatic sites that were examined at autopsy, suggesting that this mutation was an early event in the clonal evolution of resistance. The study was funded by Pfizer (Awad MM, et al, Acquired resistance to crizotinib from a mutation in CD74-ROS1. N Engl J Med. 2013 Jun 20;368(25):2395-401; http://www.ncbi.nlm.nih.gov/pubmed/23724914)

Reference: 

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Personalized Pancreatic Cancer Treatment Option

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Genome Biology, Genomic Testing: Methodology for Diagnosis, Glycobiology: Biopharmaceutical Production, Pharmacodynamics and Pharmacokinetics, Human Immune System in Health and in Disease, Imaging-based Cancer Patient Management, Liver & Digestive Diseases Research, Medical and Population Genetics, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Industry Competitive Intelligence, Pharmaceutical R&D Investment, Population Health Management, Genetics & Pharmaceutical, Reproductive Andrology, Embryology, Genomic Endocrinology, Preimplantation Genetic Diagnosis and Reproductive Genomics, Technology Transfer: Biotech and Pharmaceutical, tagged , , , , , , on October 16, 2012| 6 Comments »

Personalized Pancreatic Cancer Treatment Option

Reporter: Aviva Lev-Ari, PhD, RN

Article-7.3.6. Personalized Pancreatic Cancer Treatment Option

Clovis on Track to Unveil Data on New Personalized Pancreatic Cancer Treatment Option by Year End

October 10, 2012
 

Drug developer Clovis Oncology is planning to report data from a clinical trial later this year that may yield a new treatment option for pancreatic cancer patients who are poor responders to gemcitabine.

Clovis is conducting a study, called LEAP, of 360 chemotherapy-naïve metastatic pancreatic cancer patients who are randomized to receive the current standard of care gemcitabine, or the investigational CO-101, a gemcitabine-lipid conjugate. The study investigators are hypothesizing that unlike gemcitabine, CO-101 won’t depend on the expression levels of the protein cellular transporter hENT1 to enter and destroy tumor cells.

Gemcitabine, currently the first-line standard chemotherapy treatment for metastatic pancreatic cancer patients, requires a transport mechanism to help it enter tumor cells. Previously published data suggest that patients with high hENT1 expression respond well to gemcitabine, while those with low expression — about two-thirds of pancreatic cancer patients — respond poorly to the chemotherapeutic.

LEAP researchers have prospectively collected biopsy samples and have enrolled both high- and low-hENT1 expressers. Study investigators will be blind to the hENT1 expression status of patients until the end of the trial. Clovis is working with Roche subsidiary Ventana Medical Systems to simultaneously develop and validate a companion diagnostic that can gauge low and high hENT1 expression. The primary outcome that study investigators are measuring in LEAP is overall survival in the hENT1-low population.

“The question really is whether the lipid, which facilitates entry into the cell through passive diffusion, is going to be able to deliver gemcitabine as efficiently as when a nucleoside transporter is present,” Clovis CEO Patrick Mahaffy told PGx Reporter. “The answer is we don’t know, but we’ll find out in the study.”

The study may reveal that since CO-101 doesn’t depend on hENT1 to enter tumor cells, all metastatic pancreatic cancer patients, regardless of low or high expression of this protein, derive a level of benefit from the new treatment. Still, Clovis is using a companion test to stratify patients after factoring in reimbursement and cost-effectiveness considerations, which currently are perhaps the biggest barriers to the adoption of personalized treatments.

“Nothing we know suggests that we would be better than gemcitabine … in the hENT1 high population. Given the evolving reimbursement environment and the fact that gemcitabine is generic and is priced as such, pending a successful outcome we anticipate that [CO-101] would be used primarily, if not solely, in the hENT1 low population where we anticipate poor outcomes for gemcitabine,” Mahaffy said. “We anticipate that gemcitabine would continue to be the favored product on price alone even if we were to show equivalence to CO-101 in the hENT1 high population.”

Clovis Oncology will commercialize CO-101 globally. The company is currently setting up commercialization infrastructure in the US for the drug, anticipating a launch as early as next year. Clovis won’t necessarily co-promote CO-101 and the companion test with Ventana. The test developer will be in charge of commercializing the test, and Clovis will market the drug with its sales representatives, who will also be educating oncologists about the need for a companion test.

Ventana will submit its premarket approval application for the hENT1 expression test at the same time that Clovis submits its new drug application for CO-101. The test will be marketed as not just a companion diagnostic to assess whether pancreatic cancer patients have low levels of hENT1 and would therefore respond to CO-101, but Ventana will also be able to market the diagnostic as a tool to determine which high-hENT1 expressing patients should be given gemcitabine.

“The [LEAP] trial will clinically validate the diagnostic both for determining response to both gemcitabine and CO-101,” Mahaffy said.

There are around 120,000 cases of pancreatic cancer each year in the US, EU, and Japan, and around 24 percent of patients survive for one year. Around 80 percent of pancreatic cancer patients receive gemcitabine as monotherapy or in combination with other cytotoxic agents. Based on the low incidence of metastatic pancreatic cancer, Clovis has garnered Orphan Drug status for CO-101 from US and European regulatory authorities.

Although a number of retrospective trials have demonstrated that hENT1 expression levels impact outcomes in pancreatic cancer patients in the metastatic and adjuvant setting, LEAP will be the first prospective validation of this observation. “That’s why this trial is so important to the pancreatic cancer community,” Mahaffy said. “Because not only are we going to learn about CO-101, but we’re going to learn prospectively about the role hENT1 plays in determining the outcome for patients’ treatment with gemcitabine alone.”

Testing for hENT1 expression status is not widely conducted by doctors in the care of pancreatic patients. “In fact, it’s not even widely known in the broader community setting,” noted Mahaffy, adding that academic oncologists are increasingly aware of the association between hENT1 expression and gemcitabine efficacy. After LEAP concludes and if the trial is successful, Clovis plans to initiate discussions with treatment guideline-setting bodies.

In addition to looking at CO-101 as a first-line metastatic pancreatic cancer treatment in hENT1-low patients, Clovis is also studying the drug-conjugate as a second-line treatment in metastatic pancreatic cancer (Phase II), as well as in non-small cell lung cancer (Phase I).

Personalized NSCLC Drug

In addition to CO-101, Clovis has a number of investigational agents in its pipeline that it is developing in molecularly defined patient subsets. For example, CO-1686 is a selective covalent inhibitor of EGFR mutations that the firm is exploring in patients with NSCLC. Currently Clovis is conducting a dose-finding Phase I/II trial involving CO-1686 in NSCLC patients with T790M mutations. Patients with these “gatekeeper” mutations become resistant to treatment to widely prescribed EGFR-inhibiting NSCLC drugs, Roche/Genentech’s Tarceva and AstraZeneca’s Iressa.

CO-1686 “is a very potent inhibitor of T790M … [mutations in] which occur in 50 percent of lung cancer patients, after treatment with Tarceva,” Mahaffy said. After the dose-finding portion of the Phase I/II trial, Clovis plans to initiate an expansion cohort looking at T790M mutation-positive patients who are resistant to Tarceva. “If we see the kind of results we hope to in that expansion cohort, we would initiate a registration study beginning in 2014 in Tarceva-failed patients with T790M mutations,” he said.

While CO-1686 is an inhibitor of T790M mutations and other activating mutations of EGFR, the drug doesn’t inhibit wild-type EGFR like Tarceva and Iressa do, which can make NSCLC patients prone to serious side effects. “What is interesting about [CO-1686] is it is a very potent inhibitor of activating mutations of EGFR, the same targets that Tarceva or Iressa address, but unlike those drugs, [CO-1686] does not inhibit wild-type EGFR,” Mahaffy said. With CO-1686, “we should see very limited rash and diarrhea side effects associated with Tarceva and Iressa.”

First, Clovis will study CO-1686 as a second-line treatment in NSCLC patients with T790M mutations. Eventually, Clovis plans to study the drug head-to-head against Tarceva in the first-line setting. “Given the activity of our drug in animal models so far, we think we may have the ability to demonstrate superiority in terms of efficacy and from the side effects of Tarceva,” Mahaffy said. “We would hope to demonstrate in addition to a cleaner safety profile, a longer duration of benefit, because we would prevent that primary resistance mechanism in T790M from emerging.”

Roche Molecular Systems has partnered with Clovis to develop a companion diagnostic for CO-1686.

Meanwhile, last year, the European Commission approved the use of Roche/Genentech’s Tarceva as a first-line treatment for NSCLC in patients with EGFR mutations (PGx Reporter 9/7/2012). Last month, UK’s National Institute for Health and Clinical Excellence issued a draft guidance recommending that the country’s National Health Service pay for Tarceva as an option for this patient population. The company is in discussions with the US Food and Drug Administration about launching Tarceva in this population (PGx Reporter 06/08/2011).

Additionally, Boehringer Ingelheim is developing afatinib, a drug intended for advanced NSCLC patients with EGFR mutation-positive tumors (PGx Reporter 6/6/2012). Boehringer is working with Qiagen to advance a companion test for its drug.

An NGS-Based Companion Dx?

Another drug in Clovis’ pipeline is an inhibitor of PARP 1 and PARP 2, called rucaparib, which the company licensed from Pfizer. Rucaparib is currently undergoing Phase I/II trials in breast and ovarian cancer. The company is investigating the efficacy and safety of the drug in patients who lack the ability to repair damaged DNA that cancer cells need to thrive.

Mahaffy highlighted that Clovis is currently continuing a dose-finding Phase I study initiated by Pfizer combining rucaparib with carboplatin, and is conducting a Phase I trial investigating the drug as a monotherapy. This latter study will include an extension cohort of ovarian cancer patients with germline BRCA mutations.

Clovis is among a handful of drug developers, including Abbott and AstraZeneca, that are advancing PARP inhibitors with a personalized medicine strategy, betting that patients with BRCA 1/2 mutations will respond better to this class of drugs than those without these mutations. Previous studies have demonstrated that the PARP 1 enzyme and the BRCA gene work in concert to repair DNA damage, enabling survival of cancer tumors. Patients with BRCA mutations can’t repair DNA damage in this way, so then PARP inhibitors can be more effective in stopping cancer growth.

Abbott and AstraZeneca are using a companion test developed by Myriad Genetics to study their PARP inhibitors in BRCA-mutated patients with these diseases. Myriad markets BRACAnalysis, a test that gauges germline BRCA mutations associated with hereditary breast and ovarian cancer. However, gene alternations other than germline BRCA 1/2 mutations are linked to faulty DNA repair and PARP inhibitor response. For example, Clovis estimates that around 15 percent of women with ovarian cancer harbor germline BRCA 1/2 mutations, but another 8 percent of patients have somatic mutations in BRCA. Meanwhile, germline BRCA 1/2 mutations comprise only 5 percent of breast cancers.

When Pfizer was developing rucaparib, it was working with MDxHealth to explore methylation-specific markers associated with DNA damage repair and response to PARP inhibiters (PGx Reporter 2/2/2011). According to MDxHealth both methylation and mutation testing can characterize BRCA gene activity. The company previously estimated that BRCA methylation appears in about 40 percent to 50 percent of triple-negative breast cancer patients, and in about 10 percent to 30 percent in sporadic breast cancers.

Clovis has an open contract with MDxHealth looking at methylation profiles in breast and ovarian cancer, and will continue to explore this approach, specifically for methylated BRCA in triple-negative breast cancer. Additionally, Clovis is “considering the opportunity to look at both germline and somatic mutations of BRCA, based on a tissue-based assay,” Mahaffy said.

Beyond this, in August, Clovis and Foundation Medicine announced they are working together to investigate other genetic defects related to DNA repair deficiency.

“We went with Foundation Medicine … because it will allow us to reach a broader population,” Mahaffy said. For example, in ovarian cancer, Foundation Medicine’s next-generation sequencing platform could identify other mechanisms of DNA repair deficiencies that could potentially increase the intent-to-treat population for rucaparib from 15 percent of ovarian cancer patients with germline BRCA mutations to as much as 50 percent of the population that has somatic mutations in 28 additional genes that have been described as conferring “BRCA-ness” or as having a BRCA-like effect on DNA repair.

Clovis plans to develop a companion test for rucaparib on Foundation Medicine’s Foundation One targeted NGS platform. However, one challenge for Clovis is that the FDA hasn’t yet elucidated how it plans to regulate NGS-based tests. “Clearly, there is a seismic shift underway, and we may be one of the first to have plans to go forward on a premarket approval path with next-gen sequencing,” Mahaffy said. “But clearly the FDA and everyone else knows this tidal wave is coming.”

Clovis hopes to initiate a registration trial in the second half of next year looking at rucaparib as a maintenance therapy in ovarian cancer patients sensitive to platinum-based chemotherapy who have alterations in BRCA and deficiencies in other DNA repair genes. Foundation Medicine and Clovis have separately initiated discussions with the FDA about getting taking NGS-based tests through regulatory approval, Mahaffy said.

      Turna Ray is the editor of GenomeWeb’s Pharmacogenomics Reporter. She covers pharmacogenomics, personalized medicine, and companion diagnostics. E-mail her here or follow her GenomeWeb Twitter account at @PGxReporter.

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Carboranes to aid the ability of the cancer drug

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, tagged , , , , , , , on September 1, 2012| 2 Comments »

Reported by: Dr. Venkat S. Karra, Ph.D

Carboranes to aid the ability of the cancer drug (it appears applicable to any drug)

Legend has it that Ralph Waldo Emerson once said, “Build a better mousetrap, and the world will beat a path to your door.” University of Missouri researchers are doing just that, but instead of building mousetraps, the scientists are targeting cancer drugs. In a new study, MU medicinal chemists have taken an existing drug that is being developed for use in fighting certain types of cancer, added a special structure to it, and created a more potent, efficient weapon against cancer.

“Over the past decade, we have seen an increasing interest in using carboranes in drug design,” said Mark W. Lee Jr., assistant professor of chemistry in College of Arts and Science. “Carboranes are clusters of three elements—boron, carbon and hydrogen. Carboranes don’t fight cancer directly, but they aid in the ability of a drug to bind more tightly to its target, creating a more potent mechanism for destroying the cancer cells.”

In the study, Lee and his research team used carboranes to build new drugs designed to shut off a cancer cell‘s energy production, which is vital for the cell’s survival. All cells produce energy through complex, multi-step processes. The key to an effective drug is targeting the process that cancer cells depend on more than healthy cells. By increasing the binding strength of a drug, a smaller dose is required, minimizing side effects and increasing the effectiveness of the therapy. With carboranes, Lee found that the drug is able to bind 10 times more powerfully.

“The reason why these drugs bind stronger to their target is because carboranes exploit a unique and very strong form of hydrogen bonding, the strongest form of interactions for drugs,” Lee said.

Lee said that this discovery also will lead to further uses for the drug.

“Too often, after radiation or chemotherapy, cancer cells repair themselves and reinvade the body,” Lee said. “This drug not only selectively shuts off the energy production for the cancer cells, but it also inhibits the processes that allow those cancer cells to repair themselves. When we tested our carborane-based drugs, we found that they were unimaginably potent. So far, we have tested this on breast, lung and colon cancer, all with exceptional results.”

According to Lee, this is the first study to show systematically how carboranes can improve the activity of a drug. Lee believes this discovery will open additional possibilities of improving drugs that are used to treat other diseases, not just cancer.

“The end result is that these new drugs could be many thousands of times more potent than the drugs that are used in the clinics today,” Lee said.

While it will be several years before the new drug would be available on the market, Lee said that clinical trials could begin within the next two years. Additionally, further testing on other types of cancer is underway. The study was published in the Journal of Medicinal Chemistry, a publication of the American Chemical Society.

Source:

rdmag

University of Missouri

 

 

 

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The Incentive for “Imaging based cancer patient’ management”

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biomarkers & Medical Diagnostics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, FDA Regulatory Affairs, Health Economics and Outcomes Research, HealthCare IT, Imaging-based Cancer Patient Management, International Global Work in Pharmaceutical, Medical Devices R&D Investment, Personalized and Precision Medicine & Genomic Research, Pharmaceutical R&D Investment, Population Health Management, Genetics & Pharmaceutical, Scientist: Career considerations, Statistical Methods for Research Evaluation, Technology Transfer: Biotech and Pharmaceutical, tagged , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , on August 27, 2012| 15 Comments »

The Incentive for “Imaging based cancer patient’ management”

Author and Curator: Dror Nir, PhD

Article 11.1 Introduction by Dror Nir PhD

Image taken from http://www.breastthermography.com/breast_thermography_mf.htm

It is generally agreed by radiologists and oncologists that in order to provide a comprehensive work-flow that complies with the principles of personalized medicine, future cancer patients’ management will heavily rely on “smart imaging” applications. These could be accompanied by highly sensitive and specific bio-markers, which are expected to be delivered by pharmaceutical companies in the upcoming decade. In the context of this post, smart imaging refers to imaging systems that are enhanced with tissue characterization and computerized image interpretation applications. It is expected that such systems will enable gathering of comprehensive clinical information on cancer tumors, such as location, size and rate of growth.

What is the main incentive for promoting cancer patients’ management based on smart imaging? 

It promises to enable personalized cancer patient management by providing the medical practitioner with a non-invasive and non-destructive tool to detect, stage and follow up cancer tumors in a standardized and reproducible manner. Furthermore, applying smart imaging that provides valuable disease-related information throughout the management pathway of cancer patient will eventually result in reducing the growing burden of health-care costs related to cancer patients’ treatment.

Let’s briefly review the segments that are common to all cancer patients’ pathway: screening, treatment and costs.

 

Screening for cancer: It is well known that one of the important factors in cancer treatment success is the specific disease staging. Often this is dependent on when the patient is diagnosed as a cancer patient. In order to detect cancer as early as possible, i.e. before any symptoms appear, leaders in cancer patients’ management came up with the idea of screening. To date, two screening programs are the most spoken of: the “officially approved and budgeted” breast cancer screening; and the unofficial, but still extremely costly, prostate cancer screening. After 20 years of practice, both are causing serious controversies:

In trend analysis of WHO mortality data base [1], the authors, Autier P, Boniol M, Gavin A and Vatten LJ, argue that breast cancer mortality in neighboring European countries with different levels of screening but similar access to treatment is the same: “The contrast between the time differences in implementation of mammography screening and the similarity in reductions in mortality between the country pairs suggest that screening did not play a direct part in the reductions in breast cancer mortality”.

In prostate cancer mortality at 11 years of follow-up [2],  the authors,Schröder FH et. al. argue regarding prostate cancer patients’ overdiagnosis and overtreatment: “To prevent one death from prostate cancer at 11 years of follow-up, 1055 men would need to be invited for screening and 37 cancers would need to be detected”.

The lobbying campaign (see picture below)  that AdmeTech (http://www.admetech.org/) is conducting in order to raise the USA administration’s awareness and get funding to improve prostate cancer treatment is a tribute to patients’ and practitioners’ frustration.

 

 

 

Treatment: Current state of the art in oncology is characterized by a shift in  the decision-making process from an evidence-based guidelines approach toward personalized medicine. Information gathered from large clinical trials with regard to individual biological cancer characteristics leads to a more comprehensive understanding of cancer.

Quoting from the National cancer institute (http://www.cancer.gov/) website: “Advances accrued over the past decade of cancer research have fundamentally changed the conversations that Americans can have about cancer. Although many still think of a single disease affecting different parts of the body, research tells us through new tools and technologies, massive computing power, and new insights from other fields that cancer is, in fact, a collection of many diseases whose ultimate number, causes, and treatment represent a challenging biomedical puzzle. Yet cancer’s complexity also provides a range of opportunities to confront its many incarnations”.

Personalized medicine, whether it uses cytostatics, hormones, growth inhibitors, monoclonal antibodies, and loco-regional medical devices, proves more efficient, less toxic, less expensive, and creates new opportunities for cancer patients and health care providers, including the medical industry.

To date, at least 50 types of systemic oncological treatments can be offered with much more quality and efficiency through patient selection and treatment outcome prediction.

Figure taken from presentation given by Prof. Jaak Janssens at the INTERVENTIONAL ONCOLOGY SOCIETY meeting held in Brussels in October 2011

For oncologists, recent technological developments in medical imaging-guided tissue acquisition technology (biopsy) create opportunities to provide representative fresh biological materials in a large enough quantity for all kinds of diagnostic tests.

 

Health-care economics: We are living in an era where life expectancy is increasing while national treasuries are over their limits in supporting health care costs. In the USA, of the nation’s 10 most expensive medical conditions, cancer has the highest cost per person. The total cost of treating cancer in the U.S. rose from about $95.5 billion in 2000 to $124.6 billion in 2010, the National Cancer Institute (www.camcer.gov) estimates. The true sum is probably higher as this estimate is based on average costs from 2001-2006, before many expensive treatments came out; quoting from www.usatoday.com : “new drugs often cost $100,000 or more a year. Patients are being put on them sooner in the course of their illness and for a longer time, sometimes for the rest of their lives.”

With such high costs at stake, solutions to reduce the overall cost of cancer patients’ management should be considered. My experience is that introducing smart imaging applications into routine use could contribute to significant savings in the overall cost of cancer patients’ management, by enabling personalized treatment choice and timely monitoring of tumors’ response to treatment.

 

 References

  1. 1.      BMJ. 2011 Jul 28;343:d4411. doi: 10.1136/bmj.d4411
  2. 2.      (N Engl J Med. 2012 Mar 15;366(11):981-90):

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