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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

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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 »

Identification of Biomarkers that are Related to the Actin Cytoskeleton

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biomarkers & Medical Diagnostics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Genome Biology, International Global Work in Pharmaceutical, Molecular Genetics & Pharmaceutical, Pharmaceutical Industry Competitive Intelligence, Proteomics, Technology Transfer: Biotech and Pharmaceutical, tagged , , , , , , , , , , , , , , , , , , , , on December 10, 2012| 33 Comments »

Identification of Biomarkers that are Related to the Actin Cytoskeleton

Curator and Writer: Larry H Bernstein, MD, FCAP

Article I Identification of Biomarkers that are Related to the Actin Cytoskeleton

This is Part I in a series of articles on Calcium and Cell motility.

The Series consists of the following articles:

Part I: Identification of Biomarkers that are Related to the Actin Cytoskeleton

Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2012/12/10/identification-of-biomarkers-that-are-related-to-the-actin-cytoskeleton/

Part II: Role of Calcium, the Actin Skeleton, and Lipid Structures in Signaling and Cell Motility

Larry H. Bernstein, MD, FCAP, Stephen Williams, PhD and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/08/26/role-of-calcium-the-actin-skeleton-and-lipid-structures-in-signaling-and-cell-motility/

Part III: Renal Distal Tubular Ca2+ Exchange Mechanism in Health and Disease

Larry H. Bernstein, MD, FCAP, Stephen J. Williams, PhD
 and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/09/02/renal-distal-tubular-ca2-exchange-mechanism-in-health-and-disease/

Part IV: The Centrality of Ca(2+) Signaling and Cytoskeleton Involving Calmodulin Kinases and Ryanodine Receptors in Cardiac Failure, Arterial Smooth Muscle, Post-ischemic Arrhythmia, Similarities and Differences, and Pharmaceutical Targets

Larry H Bernstein, MD, FCAP, Justin Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/09/08/the-centrality-of-ca2-signaling-and-cytoskeleton-involving-calmodulin-kinases-and-ryanodine-receptors-in-cardiac-failure-arterial-smooth-muscle-post-ischemic-arrhythmia-similarities-and-differen/

Part V: Ca2+-Stimulated Exocytosis:  The Role of Calmodulin and Protein Kinase C in Ca2+ Regulation of Hormone and Neurotransmitter

Larry H Bernstein, MD, FCAP
and
Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/12/23/calmodulin-and-protein-kinase-c-drive-the-ca2-regulation-of-hormone-and-neurotransmitter-release-that-triggers-ca2-stimulated-exocytosis/

Part VI: Calcium Cycling (ATPase Pump) in Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension and Percutaneous Intra-coronary Artery Infusion for Heart Failure: Contributions by Roger J. Hajjar, MD

Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/08/01/calcium-molecule-in-cardiac-gene-therapy-inhalable-gene-therapy-for-pulmonary-arterial-hypertension-and-percutaneous-intra-coronary-artery-infusion-for-heart-failure-contributions-by-roger-j-hajjar/

Part VII: Cardiac Contractility & Myocardium Performance: Ventricular Arrhythmias and Non-ischemic Heart Failure – Therapeutic Implications for Cardiomyocyte Ryanopathy (Calcium Release-related Contractile Dysfunction) and Catecholamine Responses

Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/08/28/cardiac-contractility-myocardium-performance-ventricular-arrhythmias-and-non-ischemic-heart-failure-therapeutic-implications-for-cardiomyocyte-ryanopathy-calcium-release-related-contractile/

Part VIII: Disruption of Calcium Homeostasis: Cardiomyocytes and Vascular Smooth Muscle Cells: The Cardiac and Cardiovascular Calcium Signaling Mechanism

Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/09/12/disruption-of-calcium-homeostasis-cardiomyocytes-and-vascular-smooth-muscle-cells-the-cardiac-and-cardiovascular-calcium-signaling-mechanism/

Part IX: Calcium-Channel Blockers, Calcium Release-related Contractile Dysfunction (Ryanopathy) and Calcium as Neurotransmitter Sensor

Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

Part X: Synaptotagmin functions as a Calcium Sensor: How Calcium Ions Regulate the fusion of vesicles with cell membranes during Neurotransmission

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/09/10/synaptotagmin-functions-as-a-calcium-sensor-how-calcium-ions-regulate-the-fusion-of-vesicles-with-cell-membranes-during-neurotransmission/

Part XI: Sensors and Signaling in Oxidative Stress

Larry H. Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2013/11/01/sensors-and-signaling-in-oxidative-stress/

Part XII: Atherosclerosis Independence: Genetic Polymorphisms of Ion Channels Role in the Pathogenesis of Coronary Microvascular Dysfunction and Myocardial Ischemia (Coronary Artery Disease (CAD))

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2013/12/21/genetic-polymorphisms-of-ion-channels-have-a-role-in-the-pathogenesis-of-coronary-microvascular-dysfunction-and-ischemic-heart-disease/

In this article the Author will cover two types of biomarker on the function of actin in cytoskeleton mobility in situ.

  • First, is an application in developing the actin or other component, for a biotarget and then, to be able to follow it as

(a) a biomarker either for diagnosis, or

(b) for the potential treatment prediction of disease free survival.

  • Second, is mostly in the context of MI, for which there is an abundance of work to reference, and a substantial body of knowledge about

(a) treatment and long term effects of diet, exercise, and

(b) underlying effects of therapeutic drugs.

1.  Cell Membrane (cytoskeletal) Plasticity

Refer to … Squeezing Ovarian Cancer Cells to Predict Metastatic Potential: Cell Stiffness as Possible Biomarker

Reporter/curator: Prabodh Kandala, PhD

New Georgia Tech research shows that cell stiffness could be a valuable clue for doctors as they search for and treat cancerous cells before they’re able to spread. The findings, which are published in the journal PLoS One, found that highly metastatic ovarian cancer cells are several times softer than less metastatic ovarian cancer cells. This study used atomic force microscopy (AFM) to study the mechanical properties of various ovarian cell lines. A soft mechanical probe “tapped” healthy, malignant and metastatic ovarian cells to measure their stiffness. In order to spread, metastatic cells must push themselves into the bloodstream. As a result, they must be highly deformable and softer. This study results indicate that cell stiffness may be a useful biomarker to evaluate the relative metastatic potential of ovarian and perhaps other types of cancer cells.

Comparative gene expression analyses indicate that the reduced stiffness of highly metastatic HEY A8 cells is associated with actin cytoskeleton remodeling and microscopic examination of actin fiber structure in these cell lines is consistent with this prediction.   The results suggest either of two approaches. Atomic Force Microscopy is not normally used by pathologists in diagnostics. Electron microscopy requires space for making and cutting the embedded specimen, and a separate room for the instrument. The instrument is large and the technique was not suitable for anything other than research initially until EM gained importance in Renal Pathology. It has not otherwise been used.  This new method looks like it might be more justified over a spectrum of cases.

A.  Atomic Force Microscopy

So the first point related to microscopy is whether AFM has feasibility for routine clinical use in the pathologists’ hands. This requires:

  1. suitable size of equipment
  2.  suitable manipulation of the specimen
  3. The question of whether you are using overnight fixed specimen, or whether the material is used unfixed
  4. Nothing is said about staining of cells for identification.
  5. Then there is the question about whether this will increase the number of Pathologist Assistants used across the country, which I am not against.   This would be the end of “house” trained PAs, and gives more credence to the too few PA programs across the country. The PA programs have to be reviewed and accredited by NAACLS (I served 8 years on the Board). A PA is represented on the Board, and programs are inspected by qualified peers.   There is no academic recognition given to this for tenure and promotion in Pathology Departments, and a pathologist is selected for a medical advisory role by the ASCP, and must be a Medical Advisor to a MLS accredited Program.   The fact is that PAs do gross anatomic dictation of selected specimens, and they do autopsies under the guidance of a pathologist. This is the reality of the profession today. The pathologist has to be in attendance at a variety of quality review conferences, for surgical morbidity and mortality to obstetrics review, and the Cancer Review. Cytopathology and cytogenetics are in the pathology domain.   In the case of tumors of the throat, cervix, and accessible orifices, it seems plausible to receive a swab for preparation. However, sampling error is greater than for a biopsy. A directed needle biopsy or a MIS specimen is needed for the ovary.

B.  identification of biomarkers that are related to the actin cytoskeleton

The alternative to the first approach is the identification of biomarkers that are related to the actin cytoskeleton, perhaps in the nature of the lipid or apoprotein isoform that gives the cell membrane deformability. The method measuring by Atomic Force Microscopy is shown with the current method of cytological screening, and I call attention to cells clustered together that have a scant cytoplasm surrounding nuclei occupying 1/2 to 3/4 of the cell radius.  The cells are not anaplastic, but the clumps are suggestive of glnad forming epithelium.

English: Animation showing 3-D nature of clust...

English: Animation showing 3-D nature of cluster. Image:Serous carcinoma 2a – cytology.jpg (Photo credit: Wikipedia)

The cell membrane, also called the plasma memb...

The cell membrane, also called the plasma membrane or plasmalemma, is a semipermeable lipid bilayer common to all living cells. It contains a variety of biological molecules, primarily proteins and lipids, which are involved in a vast array of cellular processes. It also serves as the attachment point for both the intracellular cytoskeleton and, if present, the cell wall. (Photo credit: Wikipedia)

English: AFM bema detection

AFM non contact mode

AFM non contact mode (Photo credit: Wikipedia)

C.  The diagnosis of ovarian cancer can be problematic because it can have a long period of growth undetected.

On the other hand, it is easily accessible once there is reason to suspect it. They are terrible to deal with because they metastasize along the abdominal peritoneum and form a solid cake. It is a problem of location and silence until it is late. Once they do announce a presence on the abdominal wall, there is probably a serous effusion. It was not possible to rely on a single marker, but when CA125 was introduced, Dr. Marguerite Pinto, Chief of Cytology at Bridgeport Hospital-Yale New Haven Health came to the immnunochemistry lab and we worked out a method for analyzing effusions, as we had already done with carcinoembryonic antigen.       The use of CEA and CA125 was published by Pinto and Bernstein as a first that had an impact.  This was followed by a study with the Chief of Oncology, Dr. Martin Rosman, that showed that the 30 month survival of patients post treatment is predicted by the half-life of disappearance of CA125 in serum.  At the time of this writing, I am not sure of the extent of its use 20 years later. History has taught us that adoption can be slow, depending very much on dissemination from major academic medical centers.  On the other hand, concepts can also be stuck at academic medical centers because of a rigid and unprepared mindset in the professional community.  The best example of this is the story of Ignaz Semmelweis, the best student of Rokitansky in Vienna for discovering the cause and prevention of childbirth fever at a time that nursemaids had far better results at obstetrical delivery than physicians.  Contrary to this, Edward Jenner, the best student of John Hunter (anatomist, surgeon, and physician to James Hume), discovered vaccination from the observation that milkmaids did not get smallpox (cowpox was a better alternative).
Only this year a Nobel Prize in Physics was awarded to an Israeli scientist who, working in the US, was unable to convince his associates of his discovery of PSEUDOCRYSTALS. – Diagnostic efficiency of carcinoembryonic antigen and CA125 in the cytological evaluation of effusions. M M Pinto, L H Bernstein, R A Rudolph, D A Brogan, M Rosman Arch Pathol Lab Med 1992; 116(6):626-631 ICID: 825503 Article type: Review article – Immunoradiometric assay of CA 125 in effusions. Comparison with carcinoembryonic antigen. M M Pinto, L H Bernstein, D A Brogan, E Criscuolo Cancer 1987; 59(2):218-222 ICID: 825555 Article type: Review article – Carcinoembryonic antigen in effusions. A diagnostic adjunct to cytology. M M Pinto, L H Bernstein, D A Brogan, E M Criscuolo Acta Cytologica 1987; 31(2):113-118 ICID: 825557

Predictive Modeling

Ovarian Cancer a plot of the CA125 elimination half-life vs the Kullback-Liebler distance

Ca125 half-life vs Kullback Entropy                                                          HL vs Survival KM plot 

Troponin(s) T, I, C  and the contractile apparatus  (contributed by Aviva Lev-Ari, PhD, RN)

 

For 2012 – 2013 Frontier Contribution in Cardiology on Gene Therapy Solutions for Improving Myocardial Contractility, see

Lev-Ari, A. 8/1/2013 Calcium Cycling (ATPase Pump) in Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension and Percutaneous Intra-coronary Artery Infusion for Heart Failure: Contributions by Roger J. Hajjar, MD

http://pharmaceuticalintelligence.com/2013/08/01/calcium-molecule-in-cardiac-gene-therapy-inhalable-gene-therapy-for-pulmonary-arterial-hypertension-and-percutaneous-intra-coronary-artery-infusion-for-heart-failure-contributions-by-roger-j-hajjar/

For explanation of Conduction prior to Myocardial Contractility, see

Lev-Ari, A. 4/28/2013 Genetics of Conduction Disease: Atrioventricular (AV) Conduction Disease (block): Gene Mutations – Transcription, Excitability, and Energy Homeostasis

http://pharmaceuticalintelligence.com/2013/04/28/genetics-of-conduction-disease-atrioventricular-av-conduction-disease-block-gene-mutations-transcription-excitability-and-energy-homeostasis/

The contraction of skeletal muscle is triggered by nerve impulses, which stimulate the release of Ca2+ from the sarcoplasmic reticulum—a specialized network of internal membranes, similar to the endoplasmic reticulum, that stores high concentrations of Ca2+ ions. The release of Ca2+ from the sarcoplasmic reticulum increases the concentration of Ca2+ in the cytosol from approximately 10-7 to 10-5 M. The increased Ca2+ concentration signals muscle contraction via the action of two accessory proteins bound to the actin filaments: tropomyosin and troponin (Figure 11.25). Tropomyosin is a fibrous protein that binds lengthwise along the groove of actin filaments. In striated muscle, each tropomyosin molecule is bound to troponin, which is a complex of three polypeptides: troponin C (Ca2+-binding), troponin I (inhibitory), and troponin T (tropomyosin-binding).

  • When the concentration of Ca2+ is low, the complex of the troponins with tropomyosin blocks the interaction of actin and myosin, so the muscle does not contract.
  • At high concentrations, Ca2+ binding to troponin C shifts the position of the complex, relieving this inhibition and allowing contraction to proceed.

Figure 11.25

Association of tropomyosin and troponins with actin filaments. (A) Tropomyosin binds lengthwise along actin filaments and, in striated muscle, is associated with a complex of three troponins: troponin I (TnI), troponin C (TnC), and troponin T (TnT). In (more…)
Contractile Assemblies of Actin and Myosin in Nonmuscle Cells

Contractile assemblies of actin and myosin, resembling small-scale versions of muscle fibers, are present also in nonmuscle cells. As in muscle, the actin filaments in these contractile assemblies are interdigitated with bipolar filaments of myosin II, consisting of 15 to 20 myosin II molecules, which produce contraction by sliding the actin filaments relative to one another (Figure 11.26). The actin filaments in contractile bundles in nonmuscle cells are also associated with tropomyosin, which facilitates their interaction with myosin II, probably by competing with filamin for binding sites on actin.

Figure 11.26

Contractile assemblies in nonmuscle cells. Bipolar filaments of myosin II produce contraction by sliding actin filaments in opposite directions.

Two examples of contractile assemblies in nonmuscle cells, stress fibers and adhesion belts, were discussed earlier with respect to attachment of the actin cytoskeleton to regions of cell-substrate and cell-cell contacts (see Figures 11.13 and 11.14). The contraction of stress fibers produces tension across the cell, allowing the cell to pull on a substrate (e.g., the extracellular matrix) to which it is anchored. The contraction of adhesion belts alters the shape of epithelial cell sheets: a process that is particularly important during embryonic development, when sheets of epithelial cells fold into structures such as tubes.

The most dramatic example of actin-myosin contraction in nonmuscle cells, however, is provided by cytokinesis—the division of a cell into two following mitosis (Figure 11.27). Toward the end of mitosis in animal cells, a contractile ring consisting of actin filaments and myosin II assembles just underneath the plasma membrane. Its contraction pulls the plasma membrane progressively inward, constricting the center of the cell and pinching it in two. Interestingly, the thickness of the contractile ring remains constant as it contracts, implying that actin filaments disassemble as contraction proceeds. The ring then disperses completely following cell division.

Figure 11.27

Cytokinesis. Following completion of mitosis (nuclear division), a contractile ring consisting of actin filaments and myosin II divides the cell in two.

http://www.ncbi.nlm.nih.gov/books/NBK9961/

2.  Use of Troponin(s) in Diagnosis

Troponins T and I are released into the circulation at the time of an acute coronary syndrome (ACS).  Troponin T was first introduced by Roche (developed in Germany) for the Roche platform as a superior biomarker for identifying acute myocardial infarction (AMI), because of a monoclonal specificity to the cardiac troponin T.  It could not be measured on any other platform (limited license patent), so the Washington University Clinical Chemistry group developed a myocardiocyte specific troponin I that quickly became widely available to Beckman, and was adapted to other instruments.  This was intended to replace the CK isoenzyme MB, that is highly elevated in rhabdomyolysis associated with sepsis or with anesthesia in special cases.

The troponins I and T had a tenfold scale difference, and the Receiver Operator Curve Generated cutoff was accurate for AMI, but had significant elevation with end-stage renal disease.  The industry worked in concert to develop a high sensitivity assay for each because there were some missed AMIs just below the ROC cutoff, which could be interpreted as Plaque Rupture.  However, the concept of plaque rupture had to be reconsidered, and we are left with type1 and type 2 AMI (disregarding the case of post PCI or CABG related).   This led to the current establishment of 3 standard deviations above the lowest measureable level at 10% coefficient of variation.  This has been discussed sufficiently elsewhere.  It did introduce a problem in the use of the test as a “silver bullet” once the finer distinctions aqnd the interest in using the test for prognosis as well as diagnosis.   This is where the use of another protein associated with heart failure came into play – either the B type natriuretic peptide, or its propeptide, N-terminal pro BNP.  The prognostic value of using these markers, secreted by the HEART and acting on the kidneys (sodium reabsorption) has proved useful.  But there has not been a multivariate refinement of the use of a two biomarker approach.  In the following part D, I illustrate what can be done with an algorithmic approach to multiple markers.

Software Agent for Diagnosis of AMI

Isaac E. Mayzlin, Ph.D., David Mayzlin, Larry H. Bernstein, M.D. The so called gold standard of proof of a method is considered the Receiver-Operating Characteristic Curve, developed for detecting “enemy planes or missiles”, and adopted first by radiologists in medicine.  This matches the correct “hits” to the actual calssification and it is generally taught as a plot of sensitivity vs (1 – specifity).  But what if you had no “training” variable?  Work inspired by Eugene Rypka’s bacterial classification led to Rosser Rudolph’s application of the Entropy of Shannon and Weaver to identify meaningful information, referring to what was Kullback-Liebler distance as “effective information”.  This allowed Rudolph and Bernstein to classify using disease biomarkers obtaing the same results as the ROC curve using an apl program.  The same data set was used by Bernstein, Adan et al. previously, and was again used by Izaak Mayzlin from University of Moscow with a new wrinkle.  Dr. Mayzlin created a neural network (Maynet), and then did a traditional NN with training on the data, and also clustered the data using geometric distance clustering and trained on the clusters.  It was interesting to see that the optimum cluster separation was closely related to the number of classes and the accuracy of classification.  An earlier simpler model using the slope of the MB isoenzyme increase and percent of total CK activity was perhaps related to Burton Sobel’s work on CK-MB disappearance rate for infarct size. The main process consists of three successive steps: (1)       clustering performed on training data set, (2)       neural network’s training on clusters from previous step, and (3)       classifier’s accuracy evaluation on testing data. The classifier in this research will be the ANN, created on step 2, with output in the range [0,1], that provides binary result (1 – AMI, 0 – not AMI), using decision point 0.5. Table  1.  Effect  of  selection  of  maximum  distance  on  the  number  of  classes  formed  and  on  the accuracy of recognition by ANN

Clustering Distance Factor F(D = F * R) Number ofClasses Number of Nodes in The Hidden Layers Number of Misrecognized Patterns inThe TestingSet of 43 Percent ofMisrecognized
10.90.80.7 2414135 1,  02,  03,  01,  02,  03,  0 3,  2 3,  2 121121 1 1 2.34.62.32.34.62.3 2.3 2.3

– Creatine kinase B-subunit activity in serum in cases of suspected myocardial infarction: a prediction model based on the slope of MB increase and percentage CK-MB activity. L H Bernstein, G Reynoso Clin Chem 1983; 29(3):590-592 ICID: 825549 – Diagnosis of acute myocardial infarction from two measurements of creatine kinase isoenzyme MB with use of nonparametric probability estimation. L H Bernstein, I J Good, G I Holtzman, M L Deaton, J Babb.  Clin Chem 1989; 35(3):444-447 ICID: 825570 – Information induction for predicting acute myocardial infarction. R A Rudolph, L H Bernstein, J Babb. Clin Chem 1988; 34(10):2031-2038 ICID: 825568

Related articles

Related articles published on this Open Access Online Scientific Journal, include the following:

Calcium Cycling (ATPase Pump) in Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension and Percutaneous Intra-coronary Artery Infusion for Heart Failure: Contributions by Roger J. Hajjar, MD

Aviva Lev-Ari, PhD, RN 8/1/2013

http://pharmaceuticalintelligence.com/2013/08/01/calcium-molecule-in-cardiac-gene-therapy-inhalable-gene-therapy-for-pulmonary-arterial-hypertension-and-percutaneous-intra-coronary-artery-infusion-for-heart-failure-contributions-by-roger-j-hajjar/

High-Sensitivity Cardiac Troponin Assays- Preparing the United States for High-Sensitivity Cardiac Troponin Assays

Larry Bernstein, MD, FCAP 6/13/2013

http://pharmaceuticalintelligence.com/2013/06/13/high-sensitivity-cardiac-troponin-assays/

Dealing with the Use of the High Sensitivity Troponin (hs cTn) Assays

Larry Bernstein and Aviva Lev-Ari  5/18/2013

http://pharmaceuticalintelligence.com/2013/05/18/dealing-with-the-use-of-the-hs-ctn-assays/

Acute Chest Pain/ER Admission: Three Emerging Alternatives to Angiography and PCI – Corus CAD, hs cTn, CCTA

Aviva Lev-Ari  3/10/2013

http://pharmaceuticalintelligence.com/2013/03/10/acute-chest-painer-admission-three-emerging-alternatives-to-angiography-and-pci/

  • Redberg’s conclusions are correct for the initial screening. The issue has been whether to do further testing for low or intermediate risk patients.
  • The most intriguing finding that is not at all surprising is that the CCTA added very little in the suspect group with small or moderate risk.
  • The ultra sensitive troponin threw the ROC out the window
  • The improved assay does pick up minor elevations of troponin in the absence of MI.

Critical Care | Abstract | Cardiac ischemia in patients with septic …
Aviva Lev-Ari  6/26/2013
http://pharmaceuticalintelligence.com/2013/06/26/critical-care-abstract-cardiac-ischemia-in-patients-with-septic/

  • refer to:  Cardiac ischemia in patients with septic shock randomized to vasopressin or norepinephrine

Mehta S, Granton J,  Gordon AC, Cook DJ, et al.
Critical Care 2013, 17:R117   http://dx.doi.org/10.1186/cc12789
Troponin and CK levels, and rates of ischemic ECG changes were similar in the VP and NE groups. In multivariable analysis

  • only APACHE II was associated with 28-day mortality (OR 1.07, 95% CI 1.01-1.14, p=0.033).

Assessing Cardiovascular Disease with Biomarkers

Larry H Bernstein, MD, FCAP 12/25/2012

http://pharmaceuticalintelligence.com/2012/12/25/assessing-cardiovascular-disease-with-biomarkers/

Vascular Medicine and Biology: CLASSIFICATION OF FAST ACTING THERAPY FOR PATIENTS AT HIGH RISK FOR MACROVASCULAR EVENTS Macrovascular Disease – Therapeutic Potential of cEPCs

Aviva Lev-Ari, PhD, RN 8/24/2012

http://pharmaceuticalintelligence.com/2012/08/24/vascular-medicine-and-biology-classification-of-fast-acting-therapy-for-patients-at-high-risk-for-macrovascular-events-macrovascular-disease-therapeutic-potential-of-cepcs/

 PENDING Integration

  • ‘Ryanopathy’: causes and manifestations of RyR2 dysfunction in heart failureCardiovasc Res. 2013;98:240-247,
  • Up-regulation of sarcoplasmic reticulum Ca2+ uptake leads to cardiac hypertrophy, contractile dysfunction and early mortality in mice deficient in CASQ2Cardiovasc Res. 2013;98:297-306,
  • Myocardial Delivery of Stromal Cell-Derived Factor 1 in Patients With Ischemic Heart Disease: Safe and PromisingCirc. Res.. 2013;112:746-747,
  • Circulation Research Thematic Synopsis: Cardiovascular GeneticsCirc. Res.. 2013;112:e34-e50,
  • Gene and cytokine therapy for heart failure: molecular mechanisms in the improvement of cardiac functionAm. J. Physiol. Heart Circ. Physiol.. 2012;303:H501-H512,
  • Ryanodine Receptor Phosphorylation and Heart Failure: Phasing Out S2808 and “Criminalizing” S2814Circ. Res.. 2012;110:1398-1402,

http://circres.ahajournals.org/content/110/5/777.figures-only

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Dasatinib in Combination With Other Drugs for Advanced, Recurrent Ovarian Cancer

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, tagged , on December 8, 2012| 4 Comments »

Reporter: Prabodh Kandala PhD

Researchers at Moffitt Cancer Center and Duke University Medical Center have conducted a phase I trial of dasatinib, an oral SRC-family tyrosine kinase inhibitor, to determine the maximum tolerated dose when combined with paclitaxel and carboplatin to treat patients with advanced or recurrent ovarian cancer. They found that 150 mg daily in combination with the two other drugs was optimum.

The study appears in the October issue of Clinical Cancer Research, a publication of the American Association for Cancer Research.

Dasatinib has promising potential in treating advanced ovarian cancer because the SRC pathways play a role in the increased activation of cell migration, proliferation, survival, invasion and angiogenesis (tumor blood vessel growth). The SRC pathways have been found to be frequently disregulated in solid tumors and can increase chemotherapy resistance.

Previous laboratory studies have shown that SRC inhibition enhanced the cytotoxic efficacy of both paclitaxel and cisplatin in ovarian cancer cell lines. In vivo studies found that SRC inhibition resulted in decreased tumor growth.

“This is the first study to define the proper dose of dasatinib that, in combination with paclitaxel and carboplatin, can be moved forward into phase II or III studies,” said study co-author Robert M. Wenham, M.D., M.S., F.A.C.O.G., F.A.C.S., member of the Center for Women’s Oncology and Experimental Therapeutics Program at Moffitt. “Those additional trials may better help us understand not only the tolerability of the combination, but the efficacy in treating cancers.”

The study found that administration of dasatinib with paclitaxel did not alter the effects of either drug and that dasatinib may be better used in combination with chemotherapy agents for a synergistic effect.

“It may also be better to combine dasatinib with only one cytotoxic therapy to improve tolerability,” Wenham added.

The researchers concluded that finding biomarkers to direct the use of targeted therapies is of the utmost importance. Although SRC gene expression was not correlated with response, the research team found several differentially regulated genes between responders and those with stable disease.

“Unfortunately, a biomarker was unable to be identified to demonstrate which women are most likely to benefit from dasatinib,” said study contributor Johnathan M. Lancaster, M.D., Ph.D., chair of Moffitt’s Department of Women’s Oncology, member of the Experimental Therapeutics Program and president of the Moffitt Medical Group. “Further study should explore relevant biomarkers and identify a patient population most likely to benefit from the addition of dasatinib.”

 Abstract:

Purpose: We conducted a phase I study of dasatinib, an oral SRC-family tyrosine kinase inhibitor, in combination with paclitaxel and carboplatin in the treatment of advanced and recurrent epithelial ovarian cancer.

Experimental Design: The primary objective was to determine the maximum tolerated dose (MTD). Secondary objectives included defining toxicity, response rate (RR), pharmacokinetics, and pharmacodynamics. Using a “3+3” design, cohorts of three to six patients received paclitaxel (175 mg/m2) and carboplatin (AUC 6) every 3 weeks with escalating doses of dasatinib (100, 120, and 150 mg daily), followed by an eight-patient expansion cohort.

Results: Twenty patients were enrolled between June 2007 and December 2009. The median age was 61 years (range: 42–82) with a median of 2 prior regimens (range: 0–6), and 71% had platinum-sensitive disease. There were three to six patients in each cohort, and eight in the expansion cohort. Pharmacokinetics were observed over the first two cycles of therapy. One DLT was observed in the 100 mg dasatinib cohort (grade 3 myalgia). Other toxicities in all cycles included neutropenia (95% grade 3–4; 91% in the 150 mg dosing cohort), thrombocytopenia (35% grade 3–4), and fatigue (10% grade 3). The RR was 40% [three complete responses, (15%); five partial responses, (25%)],10 patients (50%) had stable disease, and two were not evaluable. The PFS6-month actuarial estimate was 86%. The median PFS and OS were 7.8 and 16.2 months, respectively.

Conclusions: Due to the high incidence of myelosuppression with subsequent cycles, the recommended phase II dose of dasatinib is 150 mg daily in combination with paclitaxel and carboplatin. The combination was safe with evidence of clinical activity

Ref:

1. Moffitt Cancer Center (2012, November 14). Researchers investigate dasatinib in combination with other drugs for advanced, recurrent ovarian cancer. ScienceDaily. Retrieved December 8, 2012, from http://www.sciencedaily.com­

2. http://clincancerres.aacrjournals.org/content/18/19/5489

 

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Squeezing Ovarian Cancer Cells to Predict Metastatic Potential: Cell Stiffness as Possible Biomarker

Posted in Biological Networks, Gene Regulation and Evolution, CANCER BIOLOGY & Innovations in Cancer Therapy, Disease Biology, Small Molecules in Development of Therapeutic Drugs, tagged , on December 8, 2012| 8 Comments »

Screen Shot 2021-07-19 at 7.15.40 PM

Word Cloud By Danielle Smolyar

Reporter/curator: Prabodh Kandala, PhD

New Georgia Tech research shows that cell stiffness could be a valuable clue for doctors as they search for and treat cancerous cells before they’re able to spread. The findings, which are published in the journal PLoS One, found that highly metastatic ovarian cancer cells are several times softer than less metastatic ovarian cancer cells.

This study used atomic force microscopy (AFM) to study the mechanical properties of various ovarian cell lines. A soft mechanical probe “tapped” healthy, malignant and metastatic ovarian cells to measure their stiffness. In order to spread, metastatic cells must push themselves into the bloodstream. As a result, they must be highly deformable and softer. This study results indicate that cell stiffness may be a useful biomarker to evaluate the relative metastatic potential of ovarian and perhaps other types of cancer cells.

ust as previous studies on other types of epithelial cancers have indicated, Sulchek also found that cancerous ovarian cells are generally softer and display lower intrinsic variability in cell stiffnesss than non-malignant cells.

Sulchek’s lab partnered with the molecular cancer lab of Biology Professor John McDonald, who is also director of Georgia Tech’s newly established Integrated Cancer Research Center.

“This is a good example of the kinds of discoveries that only come about by integrating skills and knowledge from traditionally diverse fields such as molecular biology and bioengineering,” said McDonald. “Although there are a number of developing methodologies to identify circulating cancer cells in the blood and other body fluids, this technology offers the added potential to rapidly determine if these cells are highly metastatic or relatively benign.”

Sulchek and McDonald believe that, when further developed, this technology could offer a huge advantage to clinicians in the design of optimal chemotherapies, not only for ovarian cancer patients but also for patients of other types of cancer.

Abstract of the study:

The metastatic potential of cells is an important parameter in the design of optimal strategies for the personalized treatment of cancer. Using atomic force microscopy (AFM), we show, consistent with previous studies conducted in other types of epithelial cancer, that ovarian cancer cells are generally softer and display lower intrinsic variability in cell stiffness than non-malignant ovarian epithelial cells. A detailed examination of highly invasive ovarian cancer cells (HEY A8) relative to their less invasive parental cells (HEY), demonstrates that deformability is also an accurate biomarker of metastatic potential. Comparative gene expression analyses indicate that the reduced stiffness of highly metastatic HEY A8 cells is associated with actin cytoskeleton remodeling and microscopic examination of actin fiber structure in these cell lines is consistent with this prediction. Our results indicate that cell stiffness may be a useful biomarker to evaluate the relative metastatic potential of ovarian and perhaps other types of cancer cells.

Ref:

1. Georgia Institute of Technology (2012, October 10). Squeezing ovarian cancer cells to predict metastatic potential: Cell stiffness as possible biomarker. ScienceDaily. Retrieved December 8, 2012, from http://www.sciencedaily.com­/releases/2012/10/121010131556.htm

2. http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0046609

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BRCA1 a tumour suppressor in breast and ovarian cancer – functions in transcription, ubiquitination and DNA repair

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Molecular Genetics & Pharmaceutical, tagged , , , , , , , on December 4, 2012| 4 Comments »

BRCA1 a tumour suppressor in breast and ovarian cancer – functions in transcription, ubiquitination and DNA repair

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

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Word Cloud By Danielle Smolyar

Interest in BRCA1 stems from its role as a tumour suppressor in breast and ovarian cancer. Intensive research in BRCA1 has revealed little about its specific role in cancer; rather, this protein has been implicated in a multitude of important cellular processes.

The diverse biochemical activities of BRCA1 combine to protect the genome from damage.

New data reveal that BRCA1

BRCA1 functions in several processes, but it is unclear how these relate to the BRCA1 requirement in all cell types. Similar to the p53 tumour suppressor, BRCA1 activates genes encoding the DNA-repair response. Unlike p53, BRCA1 also has a direct role in the repair process.

According to the earlier suggested model, BRCA1–BARD1 functions in genome surveillance by scanning active genes in association with the holo-pol, and when the elongating transcription complex encounters DNA lesions, BRCA1 initiates a repair response. It is interesting to note that a BRCA1-binding cofactor, COBRA1, which regulates BRCA1 function in a chromatin decompression assay, has been found to be a required subunit of a complex that regulates transcription elongation.

When damage is encountered on the DNA template, the lesion could be corrected by transcription-coupled repair (step 1), a known BRCA1 function. Alternatively, some types of damage might require that the polymerase be removed to effect repair. Since the polymerase synthesizing mRNA on a DNA template is quite stably bound, it has been hypothesized that BRCA1 would then ubiquitinate the polymerase signaling its degradation (step 2).

Although current evidence does not implicate BRCA1 in this process, the polymerase is ubiquitinated and degraded following DNA damage. The residual BRCA1 complex might remain bound to the DNA lesion.

BRCA1 has been found to bind DNA cruciforms and three-way junctions, such as might occur at damage sites (step 3). This bound BRCA1 would then recruit repair factors, such as the RAD50-containing complex, which would then mend the lesion (steps 4 and 5).

One might infer from the recruitment of the H2AX kinase to sites in which BRCA1 is bound to DNA that this surveillance of the template by transcription results in BRCA1-dependent degradation of the transcription apparatus and recruitment of the H2AX kinase to nucleate the assembly of a repair focus.

Although there is no yeast homolog for BRCA1, perhaps a analogous pathway is conserved in this organism, mediated by a transcription elongation factor that is genetically linked in this pathway to holo-pol components.

The key cellular functions assigned to BRCA1 are numerous. BRCA1 can interact with many cellular proteins and pathways, but how these many interactions address the key questions of required ubiquitous function and tumour suppressing breast and ovarian cell function are unclear. These diverse activities of BRCA1 may be linked in a single pathway, or BRCA1 might function in multiple nuclear processes.

Source References:

http://www.ncbi.nlm.nih.gov/pubmed?term=The%20multiple%20nuclear%20functions%20of%20BRCA1%3A%20transcription%2C%20ubiquitination%20and%20DNA%20repair

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Warning signs may lead to better early detection of ovarian cancer

Posted in Biological Networks, Gene Regulation and Evolution, CANCER BIOLOGY & Innovations in Cancer Therapy, tagged , on September 23, 2012| 5 Comments »

Warning signs may lead to better early detection of ovarian cancer

Curator: Prabodh Kandala, PhD.

Article 9.5.Warning signs may lead to better early detection of ovarian cancer

Ovarian cancer is one of the leading gynecological malignancies. Although rare, it is deadly and affects more than 35,000 female population every year in U.S alone. It was referred to as silent killer in the past and affects one in 70 women. The most difficult part of the ovarian cancer is its detection. There are no sufficiently accurate screening tests that can diagnose this malignancy. Although several tests were proposed and tested, none of them confirmed the accurate detection. Two recent reports suggested that early detection is key in the fight against ovarian cancer.

 

Northwestern Memorial Hospital (2011, September 19). Early detection is key in the fight against ovarian cancer. ScienceDaily. Retrieved September 23, 2012, from http://www.sciencedaily.com­/releases/2011/09/110915163957.htm

 

Catching ovarian cancer early increases five-year survival odds from 30 percent to more than 90 percent. But the symptoms of ovarian cancer often mimic other less dangerous conditions making it difficult to recognize. Women should be aware of possible early warning signs which include

 

1. Bloating

2. pelvic of abdominal pain

3. Difficulty eating or feeling full quickly

4. Urinary symptoms (urgency or frequency)

5. Increased abdominal size

 

Women who frequently (almost daily for two to three weeks) experience one or more than one symptoms listed above should see the doctor.

 

Doctors say it is not clear what causes ovarian cancer but there are factors that increase the odds of developing the disease including carrying a mutation of the BRCA gene, having a personal history of breast cancer or a family history of ovarian cancer, being over the age of 45 or if a woman is obese. If a woman is high-risk, doctors recommend screening begin at age 20 to 25, or five to 10 years earlier than the youngest age of diagnosis in the family. In addition, there are genetic tests available that can identify women who are at a substantially increased risk.

 

Studies have shown there are ways to reduce the risk of developing the disease. Women who use birth control pills for at least five years are three-times less likely to develop ovarian cancer. In addition, permanent forms of birth control such as tubal ligation have been found to reduce the risk of ovarian cancer by 50 percent. In cases where women have an extensive family history of breast or ovarian cancer, or who carry altered versions of the BRCA genes, may receive a recommendation to remove the ovaries and fallopian tubes which lowers the risk of ovarian cancer by more than 95 percent.

 

Eating a diet rich in fruits and vegetables, getting regular exercise, maintaining a normal body weight and managing stresses are all ways women can help decrease their risk of ovarian cancer

 

The best scenario would be to prevent this cancer entirely but until that day comes women need to focus on good health behaviors, listen to their bodies and know their family history

Ovarian Cancer Screening: Simple Two-Minute Questionnaire That Checks for Six Warning Signs May Lead to Better Early Detection

 

M. Robyn Andersen, Barbara A. Goff, Kimberly A. Lowe.Development of an instrument to identify symptoms potentially indicative of ovarian cancer in a primary care clinic setting. Open Journal of Obstetrics and Gynecology, 2012; 02 (03): 183 DOI:

 

Researchers at Fred-Hutchison cancer center came up with a simple three question paper and pencil survey that effectively identify those who are experiencing symptoms that may indicate ovarian cancer. This study represents the first evaluation of an ovarian cancer symptom-screening tool in a primary care setting among normal-risk women as part of their routine medical-history assessment. The survey asked about the frequency and duration of above mentioned symptoms: how many days a month and for how long?

 

This study also strengthens the above report from Northwestern memorial hospital.

 

“Symptoms such as pelvic pain and abdominal bloating may be a sign of ovarian cancer but they also can be caused by other conditions. What’s important is to determine whether they are current, of recent onset and occur frequently,” said lead author M. Robyn Andersen, Ph.D., a member of the Hutchinson Center’s Public Health Sciences Division. Previous research by Andersen and colleagues has found that about 60 percent of women with early-stage ovarian cancer and 80 percent of women with advanced disease report symptoms that follow this distinctive pattern at the time of diagnosis.

“Women with symptoms that are frequent, continual and new to them in the past year should talk to their doctor, as they may be candidates for further evaluation with ultrasound and blood tests that measure markers of ovarian cancer such as CA-125,” she said. “Recent research indicates that approximately one in 140 women with symptoms may have ovarian cancer. Aggressive follow-up of these symptoms can lead to diagnosis when ovarian cancer can be caught earlier and more effectively treated.”

The study involved 1,200 women, age 40 to 87, who were seen in a Seattle women’s health clinic. More than half of the study participants reported being postmenopausal and approximately 90 percent were white. About half of the clinic visits were for a current health concern or for follow-up of a health problem reported at an earlier visit. The other half were for routine appointments such as mammography screening.

Of those surveyed, 5 percent had a positive symptom score that indicated the need for further testing. Of this group of about 60 women, one was diagnosed with ovarian cancer shortly thereafter. Of the 95 percent of women who tested negative on the symptom survey, none developed ovarian cancer during a 12-month follow-up period, which attests to the accuracy of the screening tool.

Those who reported current symptoms on the questionnaire or reported other medical concerns scored higher than those who did not. Non-white women were also about twice as likely to receive a positive symptom score as compared to white women.

“If ovarian cancer screening using symptoms is widely adopted, maximizing the specificity of screening programs will be important,” the authors wrote. “Until better biomarkers are identified and tested, collecting information about symptoms appears to have promise.” The bottom line, Andersen said, is that the screening tool can be used easily in a primary-care setting, is acceptable to patients and providers, and identifies women with symptoms that are worthy of concern with minimal false-positive results.

The study questionnaire that was tested in the clinic was based on a symptom-screening index developed in 2006 by Andersen and co-author Barbara Goff, M.D., professor and director of Gynecologic Oncology at the University of Washington School of Medicine.


Ref:

http://www.sciencedaily.com/releases/2012/09/120921161638.htm

http://www.sciencedaily.com/releases/2011/09/110915163957.htm

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Targeted Tumor-Penetrating siRNA Nanocomplexes for Credentialing the Ovarian Cancer Oncogene ID4

Posted in Biological Networks, Gene Regulation and Evolution, CANCER BIOLOGY & Innovations in Cancer Therapy, Chemical Genetics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Genome Biology, Population Health Management, Genetics & Pharmaceutical, tagged , , , , on September 10, 2012| 5 Comments »

Targeted Tumor-Penetrating siRNA Nanocomplexes for Credentialing the Ovarian Cancer Oncogene ID4

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

Article-7.4.3. Targeted Tumor Penetrating siRNA Nanocomplexes for Credentialing the Ovarian Cancer Oncogene ID4

Genome-scale studies of cancer samples have begun to provide a global depiction of genetic alterations in human cancers, but the complexity and volume of data that emerge from these efforts have made dissecting the underlying biology of cancer difficult, and little is known about the functions of most of the candidates that emerge. For example, in studies of 489 primary high-grade serous ovarian cancer genomes, 1825 genes were identified as targeted by recurrent amplification events. Systematic approaches to study the function of genes in cancer cell lines, such as genome-scale pooled short hairpin RNA (shRNA) screens, offer a means to assess the consequences of the genetic alterations found in such genome characterization efforts. The comprehensive characterization of a large number of cancer genomes will eventually lead to a compendium of genetic alterations in specific cancers. Unfortunately, the number and complexity of identified alterations complicate endeavors to identify biologically relevant mutations critical for tumor maintenance because many of these targets are not amenable to manipulation by small molecules or antibodies. RNA interference provides a direct way to study putative cancer targets; however, specific delivery of therapeutics to the tumor parenchyma remains an intractable problem.

Recently an shRNA-based approach was used to find genes that are both overexpressed in human primary tumors and essential for the proliferation of ovarian cancer cells. This approach identified 54 overexpressed and essential genes in ovarian cancer and 16 genes in non–small cell lung cancer that required further validation in vivo. Furthermore, many of these candidates represent targets that are not amenable to antibody-based therapeutics or traditional small molecule approaches. Thus, if one envisions a discovery pipeline that begins with cancer genomes and ends with novel therapeutics, there is a bottleneck at the point of in vivo validation of novel targets. Achieving silencing in the epithelial cells in the tumor parenchyma is especially critical to study the genetic alterations of interest. RNA interference (RNAi) is a potentially attractive means to silence the expression of candidate genes in vivo, particularly for undruggable gene products. However, systemic delivery of small interfering RNA (siRNA) to tumors has been challenging, owing to rapid clearance, susceptibility to serum nucleases, and endosomal entrapment of small RNAs, in addition to their inherent inadequate tumor penetration. Tumor penetration is also a problem for the delivery of siRNA and shRNA, among other cargos, and is characterized by limited transport into the extravascular tumor tissue beyond the perivascular region. This low penetration is thought to arise from the combination of dysfunctional blood vessels that are poorly perfused and a high interstitial pressure, especially in solid tumors, in part due to dysfunctional lymphatics. The leakiness of tumor vessels partially counteracts the poor penetration [the so-called enhanced permeability and retention (EPR) effect], but the size dependence and variability of this property can limit its usefulness. Desmoplastic stromal barriers can further impede transport of therapeutics through tumors. A new class of tumor-penetrating peptides has been described recently, which home to several types of tumors and leverage a consensus R/KXXR/K C-terminal peptide motif [the C-end rule (CendR)] to stimulate transvascular transport and rapidly deliver therapeutic cargo deep into the tumor parenchyma. These peptides are tumorspecific, unlike canonical cell-penetrating peptides (CPPs) that do not display cell- or tissue-type specificity, and are able to improve the delivery of small molecules, antibodies, and nanoparticles. Despite their promise, this class of peptides has not been successfully co-opted for siRNA delivery, in part owing to the additional challenges of delivering oligonucleotides across cell membranes, out of endosomes, and into the cytosol to achieve gene silencing. Here, an siRNA delivery vehicle has been designed that was tumorpenetrating and modular, so it could be easily assembled in a single step to accommodate different payloads to various genes of interest. It can be envisaged that such a technology would enable a platform wherein novel targets can be identified by structural and functional genomics and subsequently rapidly credentialed both in vitro and in vivo. Followup studies could then identify the mechanism of action underlying the observations and establish (and ultimately prioritize) novel oncogenes as therapeutic targets. To achieve this goal, a systematic effort was combined to identify genes that are both essential and genetically altered in human cancer cell lines and tumors with the development and deployment of a novel tumor-specific and tissue-penetrating siRNA delivery platform.

Current genome characterization efforts will eventually provide insight into the genetic alterations that occur in most cancers and may define new therapeutic targets. However, most epithelial cancers harbor hundreds of genetic alterations as a consequence of genomic instability. For example, whereas recurrent somatic alterations occur in a small number of genes in high-grade ovarian cancers, ovarian cancer genomes are characterized by multiple regions of copy number gain and loss involving at least 1825 genes. This genomic chaos complicates efforts to identify biologically relevant mutations critical for tumor maintenance.

To isolate which recurrent genetic alterations are involved in cancer initiation, tumor maintenance, and/or metastasis, functional assays can be performed after systematic manipulation of the candidate oncogenes. Results from Project Achilles was combined, a large scale screening effort to identify genes essential for proliferation and survival in human cancer cell lines with genome characterization of high-grade ovarian cancers. Using this approach, an oncogene candidate  was identified, ID4, which was amplified in 32% of high-grade serous ovarian cancers. ID4 is overexpressed in a large fraction of high-grade serous ovarian cancers, and ovarian cancer cell lines that overexpress ID4 are highly dependent on ID4 for survival and tumorigenicity. Expression of ID4 at levels corresponding to those observed in patient-derived samples induced transformation of immortalized ovarian and FT epithelial cells.

In summary, a targeted TPN was developed capable of precisely delivering siRNA into the tumor parenchyma, and have combined this technology with large-scale methods to credential ID4 as an oncogene target in ovarian cancer. Because large-scale efforts to characterize all cancer genomes accelerate, this capability illustrates a path to identify genes that are altered in tumors, validate those that are critical to cancer initiation and maintenance, and rapidly evaluate in vivo the subset of such genes amenable to RNAi therapies and clinical translation. These observations not only credential ID4 as an oncogene in 32% of high-grade ovarian cancers but also provide a framework for the identification, validation, and understanding of potential therapeutic cancer targets.

Source References:

http://www.ncbi.nlm.nih.gov/pubmed/22896676

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enough is enough: Treat ‘Each Patient as an Individual’

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, Computational Biology/Systems and Bioinformatics, Genome Biology, Personalized and Precision Medicine & Genomic Research, Pharmaceutical R&D Investment, Proteomics, tagged , , , , , , , on June 26, 2012| 2 Comments »

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

An interesting Interview by Dr. Miller with renowned OncoMeds on ASCO 2012 annual meeting:

American Society of Clinical Oncology

Kathy D. Miller, MD: Hello. I am Kathy Miller, Associate Professor of Medicine at the Indiana University School of Medicine in Indianapolis. I would like to welcome you to Medscape Oncology Insights, our annual wrap-up of the 2012 meeting of the American Society of Clinical Oncology (ASCO®). I am joined today by several of my colleagues: Dr. David Kerr, Professor of Cancer Medicine from the University of Oxford and former President of the European Society of Medical Oncology; Dr. Bruce Cheson, Deputy Chief of Hematology and Oncology, and Head of Hematology at the Georgetown University Hospital and Lombardi Comprehensive Cancer Center in Washington, DC; and last but not least, Dr. Maurie Markman, Vice President, Patient Oncology Services, and National Director for Medical Oncology, Cancer Treatment Centers of America, based in Philadelphia. Thank you all for joining us today.

Maurie, let’s start with you. When you think about highlights of this year’s ASCO® meeting for genitourinary (GU) and ovarian cancers, what are you taking home?

Ovarian Cancer: Clear Benefit With Bevacizumab

Maurie Markman, MD: There was a very interesting session, because of what was seen and what was not seen. The surprise for me was the randomized phase 3 trial[1] that looked at the question of bevacizumab plus chemotherapy vs chemotherapy alone in platinum-resistant ovarian cancer. Everyone would have predicted, on the basis of 30-plus years of research in this area, that it would be a negative trial, as all past trials have been. In fact, I was convinced it would be a negative trial because there were no press releases ahead of time. That usually tells you the story.

It turns out that the combination of bevacizumab and chemotherapy substantially improved progression-free survival in this setting — the first time this has ever been seen. I would suspect, however, that what most people take away from it is the fact that there was a tripling of the objective response rate, and clear evidence of patient benefit. This was very much a surprise; I don’t think anyone expected this.

The next question is going to be, what happens next? Is this drug going to receive regulatory approval on this basis? This is clearly an unmet need. That was a real positive.

On the other hand, one could argue that in contrast to other things that we will hear about, there is still no target of therapy in any of the gynecologic cancers. We haven’t found anything that would suggest an epidermal growth factor receptor (EGFR) mutation, or anything to suggest a KRAS mutation or anything that could point to where we need to go in this area. On the one hand, that is a very interesting finding, from the perspective of biology. But it is quite discouraging from the perspective of drug development.

Dr. Miller: The Cancer Genome Atlas (TCGA) data had to be discouraging. Essentially, every ovarian tumor is a different ovarian tumor.

Dr. Markman: Absolutely.

Dr. Miller: You have 10,000 rare diseases.

Dr. Markman: Other than p53, and we have known of that mutation for decades. It is universal, certainly in the high-grade cancers. But we don’t know how to deal with it. Other than that, the number of mutations found per tumor is enormous, and there are no patterns. So we have to do a lot of thinking. That is, the smart biologists have to do a lot of thinking.

Lymphoma: Chemotherapy? Enough Is Enough

Dr. Miller: Bruce, you spend a lot of your time focusing on the hematology side of malignancies. With the American Society of Hematology (ASH) and a whole separate meeting, sometimes it seems as though hematology doesn’t get as much attention at ASCO®. Was there any big news in the hematologic malignancies that people need to know about?

Bruce D. Cheson, MD: There were not. However, this has the potential to be an historic meeting, because we are going to finally learn that “enough is enough” with chemotherapy, and we are at that point.

We saw some very historic presentations. We saw rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), vs rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP), vs rituximab, fludarabine, and mitoxantrone (RFM) — where basically the only difference is in toxicity.[2]

Dr. Miller: “Pick your poison” — toxicity, but you will get to the same place.

Dr. Cheson: Yes. We also saw that R-bendamustine was better than R-CHOP,[3] but there are questions about the R-CHOP arm looking kind of lame. We were thinking, where are we going in follicular lymphoma?

Where we are going is what John Leonard and colleagues[4] presented in the relapse setting, and that’s biological agents. We have lots of those. We have lots of targeted agents. I predict that in the next year, instead of hearing more about R-CHOP and R-bendamustine, we are going to be hearing more about the GS-1101s; the PI3-kinase inhibitors; ibrutinib, the Bruton tyrosine kinase (BTK) inhibitor; and those drugs which we in the Cancer and Leukemia Group B (CLGB) (now Alliance) have been planning on combining with biological strategies. We are going to be trying to get rid of chemotherapy. This may be, hopefully, the last meeting we hear about regimen A vs regimen B. It’s kind of sickening.

We have the same situation in Hodgkin lymphoma — where we cure, depending on the stage, up to 90% of people, and at this meeting we see adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) vs bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) again for about the fourth iteration. Lo and behold, there is no survival difference.

We saw lots of that, but now we have other drugs. We have brentuximab vedotin, which is an antibody/drug conjugate. It is anti-CD30, linked to auristatin, a tubulin poison, which in transplant-refractory patients had a 75% response rate. There weren’t any data at this meeting. The data on that drug were presented at ASH. But there are now trials incorporating brentuximab/vedotin, not only in second-line treatment, but we are now moving it up into front-line.

So, we have the tools; it’s just a question of being smart enough, and figuring out how to put them together in a coherent fashion, on the basis of scientific rationale. The most important thing I took away from this meeting is, enough is enough. You can pick your poison, as you put it. But don’t hold on to it for dear life, because there are new, very exciting drugs coming along that are being combined in a biological fashion.

Breast Cancer: Targeted Therapies Are Clear Winners

Dr. Miller: You might have snuck into a breast cancer session, because that is how I would summarize the breast cancer world this year as well. We saw adjuvant trials, metastatic trials, comparing one chemotherapy regimen with another. To summarize a lot of data, pick your third-generation adjuvant chemotherapy regimen and the toxicity will differ, depending on the drugs, but the efficacy doesn’t differ at all. In the metastatic setting, newer wasn’t better. It brought more toxicity, which then led to more dose reductions, which hampered efficacy.

So when we thought we were getting newer and better drugs, they didn’t actually do better for our patients. It sounded a little bit like ABVD vs BEACOPP in Hodgkin disease.

Dr. Cheson: We have to get rid of chemotherapy.

Dr. Miller: Targeted therapies, either with direct molecular targets or antibody/ drug conjugates, were the clear winners, with major improvements in efficacy and substantially less toxicity. I would be quite happy if I didn’t have to look at another basic chemotherapy study in breast cancer again. Was that the case in the gastrointestinal (GI) studies as well, David?

GI Phenotypes and 5 Daughters of Eve

David J. Kerr, MD: It was. We are seeing mildly disappointing and moderately good results. The big, well-designed study, REAL 3,[5] looking at the role of panitumumab with combination chemotherapy, had negative findings. Panitumumab seemed to do a bit worse, which was somewhat disappointing.

Some positives are coming out in colorectal cancer. The antiangiogenic therapies look as if they are here to stay. A nice randomized trial[6] looking at discontinuation or continuation of bevacizumab following progression in first-line chemotherapy shows that the bevacizumab follow-through has significant advantages, in terms of progression-free survival.

An interesting, clever, genetically designed drug, aflibercept, which is a vascular endothelial growth factor (VGEF) trap, showed very promising activity in second- line therapy.[7] So something is holding true there. We have a new drug, regorafenib, which is one of these oral multitargeted kinase inhibitors, that seems to have an important clinically useful role to play in third-line chemotherapy.

For me, the take-home message, in contradistinction to Maurie, is that we are starting to get a feel for the different molecular phenotypes for colorectal cancer. It looks as though there may be 5 daughters of Eve, and it needs to be confirmed. We need to internationalize what we are doing. It looks as though some patterns are starting to emerge that will allow us to make prognostic inferences, possibly treatment-wise, and so on. Things are starting to stack up for us, in terms of driver mutations, therapeutics, and providing the patient with better information, so this is somewhat luckier than the situation with ovarian just now.

How Do We Eliminate Chemotherapy?

Dr. Miller: When we look ahead, we would all love to get rid of chemotherapy. How do we do that? By understanding the biology, which is the easy answer. Bruce, you mentioned that we do tend to cling to our chemotherapy regimens. We have been having discussions about how to do this in breast cancer, and there is a great reluctance to give up the regimens that have gotten us to where we are.

Dr. Cheson: Reluctance from the doctor, but not from the patient.

Dr. Miller: So how do we move forward?

Dr. Cheson: There are a couple of ways. First is a better understanding of tumor biology. We have been sitting around doing what we do for so long. Now we have some tools, but we need to know how to apply them. At every clinical trial in CLGB (now Alliance), we have correlative science. We are doing natural killer (NK) cell numbers and functions. We are doing microarrays so that we can understand which regimen works in which patient. It may not be like your field (gynecologic cancer), where every patient has their own disease, which is what I get accused of saying in lymphoma all the time. I am glad someone else has that problem.

We have the drugs. We need to know how to put them together, but which patients should we target? Then, we need to figure out how to move them up front — such drugs as brentuximab, the Hodgkin drug, and anti-CD30, which in anaplastic large cell lymphoma has an 86% response rate in relapsed patients. In a good clinical trial, we need to take a risk and just do it. If a drug is 86% effective in the refractory setting, it is not going to be worse up front.

There are those who will say, “Well, the response may not last as long.” But there are several ways you can introduce these drugs in an up-front setting, such as window-of-opportunity studies, Or, you can first tack them on to some chemotherapy and then try and wean off the chemotherapy.

There are a number of ways to do it. You just have to do it. You have to take a risk and view it as a challenge. You have to say, “We have had enough of this; let’s move on.” We have the tools; let’s do it.

I-SPY: New Paradigm for Clinical Trials?

Dr. Miller: Maurie, you know I can’t resist, because this issue of clinical trials came up last year when we were talking about melanoma data, with striking activity reported by the BRAF investigators. Are you going to do those trials? Are you willing to take that risk?

Dr. Markman: Obviously, you have to look at the individual cancers. Consider the report that said breast cancer had 10 different cancers, maybe more. It is going to be harder and harder to do randomized trials in 10 subsets, even in a disease that is as common as breast cancer.

Dr. Miller: We are actually closer to your problem, where each patient is an individual disease, than to Bruce’s situation.

Dr. Markman: We do have to come up with a different clinical trial paradigm as we get to smaller subsets. Of course, the tsunami that many have predicted is here. It wasn’t part of the meeting directly, but a half-dozen or dozen companies are now offering whole-genome sequencing. We have to figure out how to use all these things. It may not be as simple as a particular molecular abnormality, but it may be, as many people are saying, particular systems.

For example, in the ovarian cancer area, there are BRCA1 and BRCA2, and there are some drugs that affect those mutations. But a very important study from last year looked at maintenance therapy in the second-line setting with olaparib[8] in tumors that were said to have a BRCA-ness profile. In other words, there is a molecular profile that is similar to that of BRCA1 and BRCA2, and in fact, it was a very positive trial, at least from the perspective of progression-free survival. You may not be able to find a particular molecular abnormality, but there may be patterns. And that may be (in our area, where you can’t find an abnormality) much more complicated than just finding a mutation. That may be the way forward in such diseases as ovarian cancer.

Dr. Cheson: Maybe I did wander into the breast meeting, but we need to reconsider how many phase 3 trials we want to do. The I-SPY concept is where we need to be going. You take a regimen that should work in a subset of patients, and you test that and see if it does. Then you can figure out who responded and who didn’t, doing various molecular techniques, and then you take the patients who responded and put them in one pile, and enrich that pile. You take the patients who didn’t respond, figure out why they didn’t respond, and retarget them. After a while, you have high response rates in this one, and you start to improve the outcome in the other one. We need to do this. There is no way around it. It’s coming.

I hate to say this, but I think maintenance is for losers, because if you are going to do right, you have to do it up front. Progression-free survival doesn’t necessarily correlate with overall survival. It is nice. You don’t see the doctor as often. But we need to do this right the first time. I thoroughly agree with you, Maurie — it is going to be a conglomerate of things, and that is why we have new, exciting drugs coming down the pipeline, such as these PI3-kinase mammalian target of rapamycin (mTOR) hybrid inhibitors. We need to block multiple pathways, because the tumors are damn smart. If you block one, it has all these other ways of getting around you.

More Fun With Something vs Nothing Trials

Dr. Kerr: Indeed, and that comes back to Maurie’s point about thinking in systems and programmatically. The answer to Kathy’s question — can we get rid of chemotherapy? — is no. But can we do better? Think about the huge focus that we have in trying to map biomarkers to the new drugs, often mechanistic. We are not doing enough with the conventional cytotoxic drugs that we have.

We could do a lot more. Genome-wide association studies, looking at patterns of toxicity, so that we can use polymorphisms to say “you get full dose of the drug, you get the reduced dose.” We could be using the tools of trade that we have much better. With the new platform technologies, we should be able select patients who do better with 5-fluorouracil (5-FU), with taxane, and so on.

Dr. Cheson: So, how do you study that in randomized trials?

Dr. Kerr: We are lucky in that we have been collecting material from the old days. Makes us something like Dickensian characters. We have hoarded a lot of material from something vs nothing-type trials, and that gives us the opportunity, in that large randomized setting, to develop some of these predictive markers for “yes or no 5-FU, yes or no taxane.” So, it is going back to our youths, when we did all that stuff.

Dr. Miller: That is how we made advances in breast cancer. The predecessors in my field collected tumors long before the technology that we now use to interrogate them was even a glint in someone’s eye. That may actually have a bigger global impact.

Dr. Kerr: I think so.

Dr. Miller: Although this is the American Society of Clinical Oncology, one third of our members are from outside the United States, one half of the attendees are from outside the United States, and most of the fabulous molecular things we have been talking about are not within reach of most patients globally. But some of our old things are cheap. Perhaps using them in a more intelligent way may actually have more benefit on a global scale.

A Question of Value

Dr. Kerr: Exactly. So you have segued into the concept of value. I was delighted to see the brief stance that ASCO® has taken toward value, and saying that there are some things that we do that don’t add value to the care of the patients that we look after. I am a huge fan of US medicine at its the very best, but there’s a lot of waste in what we do. The fact that ASCO® is trying to identify this — 17.5% of the gross domestic product (GDP) is being spent in health now — I thought that was fantastic. Yes, there is value out there, and we should seek it. We should mine old databases, fiddle with new drugs and old drugs, teach old drugs new tricks, and so on.

Dr. Cheson: Five years from now, you are going to look at this video, and you had a whole list of “mabs and mibs” that you are going to figure out and put together, and all of a sudden, FOLFOX, FOLFIRI will be “pffft.” You are going to be combining those biologic agents intelligently, and you are going to get rid of those chemotherapy drugs, I predict.

Dr. Miller: We are out of time for this year, but I am going to book you both for 5 years from now to see whose prediction of the future comes true, where the value lies, and where we can make improvements, because I’m not so sure that they are mutually exclusive. But that’s all from this year’s Medscape Oncology wrap-up of the Annual Oncology Society Meeting. Thank you again for joining me.

References

  1. Pujade-Lauraine E, Hilpert F, Weber B, et al. AURELIA: a randomized phase III trial evaluating bevacizumab (BEV) plus chemotherapy (CT) for platinum (PT)-resistant recurrent ovarian cancer (OC). Program and abstracts of the American Society of Clinical Oncology Annual Meeting and Exposition; June 1-5, 2012; Chicago, Illinois. Abstract LBA5002.
  2. Federico M, Luminari S, Dondi A, et al. R-CVP versus R-CHOP versus R-FM as first-line therapy for advanced-stage follicular lymphoma: Final results of FOLL05 trial from the Fondazione Italiana Linfomi (FIL). Program and abstracts of the American Society of Clinical Oncology Annual Meeting and Exposition; June 1-5, 2012; Chicago, Illinois. Abstract 8006.
  3. Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab (B-R) versus CHOP plus rituximab (CHOP-R) as first-line treatment in patients with indolent and mantle cell lymphomas (MCL): updated results from the StiL NHL1 study. Program and abstracts of the American Society of Clinical Oncology Annual Meeting and Exposition; June 1-5, 2012; Chicago, Illinois. Abstract 3.
  4. Leonard J, Jung SH, Johnson JL, et al. CALGB 50401: a randomized trial of lenalidomide alone versus lenalidomide plus rituximab in patients with recurrent follicular lymphoma. Program and abstracts of the American Society of Clinical Oncology Annual Meeting and Exposition; June 1-5, 2012; Chicago, Illinois. Abstract 8000.
  5. Waddell TS, Chau I, Barbachano Y, et al. A randomized, multicenter trial of epirubicin, oxaliplatin, and capecitabine (EOC) plus panitumumab in advanced esophagogastric cancer (REAL3). Program and abstracts of the American Society of Clinical Oncology Annual Meeting and Exposition; June 1-5, 2012; Chicago, Illinois. Abstract LBA4000.
  6. Arnold D, Andre T, Bennouna J, et al. Bevacizumab (BEV) plus chemotherapy (CT) continued beyond first progression in patients with metastatic colorectal cancer (mCRC) previously treated with BEV plus CT: results of a randomized phase III intergroup study (TML study). Program and abstracts of the American Society of Clinical Oncology Annual Meeting and Exposition; June 1-5, 2012; Chicago, Illinois. Abstract CRA3503.
  7. Allegra CJ, Lakomy R, Tabernero J, et al. Effects of prior bevacizumab (B) use on outcomes from the VELOUR study: a phase III study of aflibercept (Afl) and FOLFIRI in patients (pts) with metastatic colorectal cancer (mCRC) after failure of an oxaliplatin regimen. Program and abstracts of the American Society of Clinical Oncology Annual Meeting and Exposition; June 1-5, 2012; Chicago, Illinois. Abstract 3505.
  8. Ledermann JA, Harter P, Gourley C, et al. Phase II randomized placebo-controlled study of olaparib (AZD2281) in patients with platinum-sensitive relapsed serous ovarian cancer (PSR SOC). Program and abstracts of the American Society of Clinical Oncology; June 3-7, 2011; Chicago, Illinois. Abstract 5003.

Source

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Cancer and Bone: low magnitude vibrations help mitigate bone loss

Posted in Bone Disease and Musculoskeletal Disease, CANCER BIOLOGY & Innovations in Cancer Therapy, Disease Biology, Small Molecules in Development of Therapeutic Drugs, tagged , , , , , , , , , , , , , on June 19, 2012| Leave a Comment »

Cancer and Bone: low magnitude vibrations help mitigate bone loss

Curator and Reporter: Ritu Saxena, Ph.D.

Article-7.4.4. Cancer and Bone low magnitude vibrations help mitigate bone loss

Recently, an article published in the journal Bone described that the low magnitude vibrations might be helpful in mitigating osteopenia in spontaneous granulosa cell ovarian cancer.

Osteopenia is defined as the bone mineral density (BMD) that is lower than normal peak BMD but not low enough to be classified as the diseased condition called osteoporosis. Bone mineral density is a measurement of the level of minerals in the bones, that shows how dense and strong they are. Having osteopenia means there is a greater risk that, as time passes, you may develop BMD that is very low compared to normal, known as osteoporosis

Cancer progression is often paralleled by a decline in bone mass, raising risk of fracture. Loss in bone mass can be therapeutically treated by using bone anabolic agents that increase the process of bone formation compared to bone resorption thus leading to an overall increase in bone mass. However, use of anabolic agents for preventing cancer associated bone loss presents a lot of concern as they may exacerbate cancer tissue expansion.

Bone is a mechanosensitive organ. Osteoblastogenesis, or the process of differentiation of precursor cells to bone forming cells (osteoblasts) is encouraged by low intensity vibration (LIV) via a mechanical signal. Rubin et al explored the possibility of slow cancer-associated bone loss, but this goal must be achieved without fostering disease progression. The hypothesis was tested in the murine model.

Seventy female F1-SWRxSWXJ-9 mice, a strain prone to developing granulosa cell tumors, were divided into three groups – baseline control (BC: n=10), age-matched control (AC: n=30), and LIV (n=30), which received mechanical signals (90Hz @ 0.3g) for 15m/day, 5day/w over the course of 1year. Survival curves observed in the three groups indicated that longevity was unperturbed by LIV. Rubin et al stated that “1year, bone volume of proximal tibiae in LIV mice was 25% greater than AC while bone volume of L5 vertebrae was 16% higher in LIV over AC (p<0.02). Primary lesions and peripheral metastases were apparent in both LIV and AC; however, overall tumor incidence was approximately 30% less in LIV (p=0.27) and, when disease was evident, involved fewer organ systems (p=0.09).”

These experiments indicate that LIV helps protect bone mass in mice inherently susceptible to cancer without compromising life expectancy, perhaps through mechanical control of stem cell fate. Further, these data reflect the numerous system-level benefits of exercise in general, and mechanical signals in particular, in the preservation of bone density and the suppression of cancer progression.

Source: Journal article- http://www.thebonejournal.com/article/S8756-3282(12)00867-8/abstract, http://www.webmd.com/osteoporosis/tc/osteopenia-overview

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Dimming ovarian cancer growth

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Disease Biology, Small Molecules in Development of Therapeutic Drugs, tagged , , , , , , on May 11, 2012| 1 Comment »

Reporter: Prabodh Kandala, PhD

You know that vegetables are good for you. And cruciferous vegetables – broccoli, cabbage, cauliflower, brusselsprouts – are especially healthful. New studies are demonstrating the anti-cancer effects of an ingredient in these green goddesses.

Diindolylmethane (DIM) is the wonder ingredient found in cruciferousvegetables. DIM is also sold over-the-counter as a supplement.

Researchers have found that DIM kills ovarian cancer cells in the laboratory and also improves the effectiveness of a commonly used chemotherapy agent.

Prabodh K. Kandala and Sanjay K. Srivastava, researchers in the Department of Biomedical Sciences and Cancer Biology Center at Texas Tech University Health Sciences Center, made the discoveries.

Researchers already knew that DIM slows the growth of ovarian cancer cells. In a detailed look at how the chemical behaves, they learned that DIM works by blocking the gene STAT3, which is seen in 90 percent of ovarian cancers.

In addition to causing cell death, DIM also prevented the cancer cells from invading or developing blood vessel structures which are key processes in cancer growth.

A platinum-based chemotherapy drug – cisplatin – is used to treat women with ovarian cancer. The drug doesn’t always work, though, and some patients become resistant to it.

For this study, researchers found that when DIM was combined withcisplatin, tumor growth in mice was slowed 50 percent more than when the chemo was used alone.

“DIM increases the effect of cisplatin, without being toxic to normal ovarian cells, by targeting STAT3 signaling and increasing apoptosis,” the authors explained.

“Cisplatin is very toxic and has severe side effects. If co-treatment with DIM means that a low dose of cisplatin can be given to patients without the loss of therapeutic effect, but with reduced side effects, it would represent a significant breakthrough in clinical practice,” Kandala andSrivastava concluded.

For the experiments, the supplement BioResponse DMI was used.

A number of clinical trials are currently under way to study the impact of DIM on a variety of malignancies including cancers of the breast, prostate, pancreas, kidney and others.

This new research was published in BioMed Central‘s open access journalBMC Medicine.

http://www.dailyrx.com/news-article/ovarian-cancer-cells-killed-dim-17180.html

http://www.ncbi.nlm.nih.gov/pubmed/22280969

 

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