Blunting the Activity of Protein Abcc10 May Help Counter Taxane Drug Resistance In Ovarian Cancer

New findings by Fox Chase Cancer Center researchers identify one protein, Abcc10, as being intimately involved in resistance to certain drugs used to treat breast, ovarian, lung, and other cancers. The results suggest that blunting the activity of Abcc10 might help counter resistance and extend the effectiveness of these anticancer drugs.

Today’s anticancer drugs often work wonders against malignancies, but sometimes tumors become resistant to the effects of such drugs, and treatment fails. Medical researchers would like to find ways of counteracting such resistance, but first they must understand why and how it happens. New findings by Fox Chase Cancer Center researchers identify one protein, Abcc10 (ATP-binding cassette transporter 10) (also known as multidrug resistance protein 7 (Mrp7)), as being intimately involved in resistance to certain drugs used to treat breast, ovarian, lung, and other cancers. The results suggest that blunting the activity of Abcc10 might help counter resistance and extend the effectiveness of these anticancer drugs.

The findings appear in the May 15, 2011 issue of the journal Cancer Research.

Elizabeth A. Hopper-Borge, Ph.D., Assistant Professor, Fox Chase Cancer Center, Philadelphia, Pennsylvania

In earlier work, Elizabeth A. Hopper-Borge, Ph.D., an assistant professor at Fox Chase, showed that Abcc10 confers resistance to a number of anticancer agents, particularly taxanes, which include paclitaxel (Taxol) and docetaxel (Taxotere). These drugs––originally derived from the Pacific yew tree––work by disrupting cell division, thus arresting the growth and spread of tumors. The initial finding that Abcc10, a member of a ubiquitous family of proteins called ATP-binding cassette transporters, thwarts taxanes’ anti-tumor activity was something of a surprise, says Hopper-Borge, because none of the other family members seem to have that ability.

In the new research, Hopper-Borge and colleagues wanted to further explore, in both cultured cells and mice, the role of Abcc10. They developed a “knockout” mouse, in which the gene that codes for Abcc10 was missing, or knocked out. These mice appeared normal and healthy in every other respect, suggesting that Abcc10 is not essential for overall health and survival.

The researchers isolated cells from the knockout mice and tested the cells’ reactions to taxanes and two other anticancer drugs, vincristine and Ara-C. Compared to cells from normal mice that still possessed the gene for Abcc10, the knockout mouse cells were much more sensitive to the drugs.

Abcc10 and its ilk work by pumping drugs out of cells, so one might expect to see the drugs accumulating in cells that lack Abcc10, and that’s exactly what Hopper-Borge’s group saw. It had been suggested that other proteins might take over for Abcc10 if that protein were knocked out, but the researchers found no evidence suggesting that had happened.

Next, the research team studied the effects of one particular taxane, paclitaxel, on mice and found that the knockout mice were more sensitive to the drug, as reflected in body weight, white blood cell count, and ability to survive escalating doses of the drug.

“After seeing the effects on white blood cells, we decided to look at the tissue types that produce white blood cells to see if we could actually see differences there,” says Hopper-Borge. As expected, knockout mice treated with paclitaxel had smaller spleens and thymus glands and underdeveloped bone marrow, compared to normal mice treated with the same drug.

The results provide the first evidence from living organisms that Abcc10 is a cell’s built-in protection against the effects of powerful drugs, and raises the possibility of using Abcc10 inhibitors to break down that resistance and sensitize tumor cells to anticancer agents. The fact that mice lacking the protein have no obvious health problems is encouraging, suggesting that Abcc10 inhibitors could be used in human patients without causing side effects that might be expected to result from interfering with the pump’s normal functions.

Several Abcc10 inhibitors already have been identified, but they also inhibit other cellular transporters, which could have deleterious effects. For that reason, Hopper-Borge thinks the best approach may be developing inhibitors that work only in tumor cells or coming up with compounds that modulate, rather than completely inhibit the protein’s activity.

But using such treatments in patients is still far in the future, she emphasizes.

“I’d like to stress that we did this work in a mouse model,” Hopper-Borge says. “Our results so far suggest that this protein may be a clinically relevant target, but we need to do more studies to find out for sure.”

Co-authors on the study include Timothy Churchill, Chelsy Paulose, Emmanuelle Nicolas, Joely D. Jacobs, Olivia Ngo, Andres J. Klein-Szanto and Martin G. Belinsky of Fox Chase; Yehong Kuang of Central South University, Changsha, China; Alex Grinberg and Heiner Westphal of the National Institute of Child Health and Human Development; and Gary D. Kruh of the University of Illinois at Chicago.

The research was supported by the National Institutes of Health.

Sources:

• Hopper-Borge EA, Churchill T, Paulose C, et. al.  Contribution of Abcc10 (Mrp7) to In Vivo Paclitaxel Resistance as Assessed in Abcc10−/− Mice. Cancer Res (May 15, 2011) 71:3649-3657.

• New Findings Show that the Protein Abcc10 May be Effective in Counteracting Resistance and Extending the Effectiveness of Some Anticancer Drugs, Press Release, Fox Chase Cancer Center, May 16, 2011.

FDA Awards $1.6M Orphan Drug Grant for Clinical Phase II Development of EGEN-001 for Treatment of Ovarian Cancer

EGEN, Inc. announced that the Food and Drug Administration (FDA) awarded the company a four-year grant of $1.6 million to assist in the phase II clinical development of EGEN-001, the company’s lead product. EGEN-001 is under clinical development for the treatment of advanced recurrent ovarian cancer.

EGEN, Inc. announced that the Food and Drug Administration (FDA) awarded the company a four-year grant of $1.6 million to assist in the phase II clinical development of EGEN-001, the company’s lead product. EGEN-001 is under clinical development for the treatment of advanced recurrent ovarian cancer.[1]

EGEN, Inc. is developing gene-based biopharmaceuticals that rely on proprietary delivery technologies such as TheraPlas™ (illustrated above). In preclinical studies, the application of this approach produced anti-cancer activity in the treatment of disseminated abdominal cancers, solid tumors and metastatic cancers. (Photo: EGEN, Inc.)

EGEN-001 was developed as an interleukin-12 (IL‑12) gene therapy for the treatment of disseminated epithelial ovarian cancer. It is a low concentration formulation composed of a human IL-12 plasmid formulated with a proprietary PPC delivery system. EGEN-001 is designed for intraperitoneal (IP) administration. The subsequent IL-12 protein expression is associated with an increase in immune system activity, including T-lymphocyte and natural killer (NK) cell proliferation, and cytotoxic activation and secretion of interferon gamma (IFN-g), which in turn, leads to tumor inhibition. Additionally, IL-12 inhibits angiogenesis and formation of tumor vascularization.

EGEN has successfully completed two Phase I trials of EGEN-001 in ovarian cancer patients.  In the first study, EGEN-001 was administered as monotherapy in platinum-resistant ovarian cancer patients[2] and in the second study in combination with carboplatin/docetaxel chemotherapy in platinum-sensitive ovarian cancer patients.[3] In both studies, EGEN-001 treatment resulted in good safety, biological activity and encouraging efficacy.[4-5] EGEN-001 received Orphan Drug Status from the FDA in 2005, and its first $1 million FDA orphan grant in 2005.

“This is a significant milestone and accomplishment for the company,” commented Dr. Khursheed Anwer, President and Chief Science Officer of EGEN. “We are pleased to receive this FDA support, which has been very useful in the advancement of our novel EGEN-001 product in the clinic for the treatment of recurrent ovarian cancer. The product utilizes the Company’s proprietary TheraPlas® delivery technology and is composed of interleukin-12 (IL-12) gene formulation with a biocompatible delivery polymer. IL-12 is a potent cytokine which works by enhancing the body’s immune system against cancer and inhibiting tumor blood supply.”

About EGEN, Inc.

EGEN, Inc. (EGEN), with laboratories and headquarters in Huntsville, Alabama, is a privately held biopharmaceutical company focused on developing therapeutics for the treatment of human diseases including cancer. The Company specializes in the delivery of therapeutic nucleic acids (DNA and RNAi) and proteins aimed at specific disease targets. The Company has a significant intellectual property position in synthetic carriers, their combination with DNA, and their therapeutic applications. EGEN’s research pipeline products are aimed at treatment of various cancer indications. In addition, the Company has its TheraSilence® delivery technology aimed at delivery of therapeutic siRNA for the treatment of human diseases. EGEN collaborates with outside investigators, biotech organizations, and universities on various projects in these areas.

References:

1/ A Phase II Evaluation of Intraperitoneal EGEN-001 (IL-12 Plasmid Formulated With PEG-PEI-Cholesterol Lipopolymer) in the Treatment of Persistent or Recurrent Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Cancer, Clinical Trial Summary, ClinicialTrials.gov (Identifier:  NCT01118052).

2/A Phase 1, Open Label, Dose Escalation Study of the Safety, Tolerability and Preliminary Efficacy of Intraperitoneal EGEN-001 in Patients With Recurrent Epithelial Ovarian Cancer, Clinical Trial Summary, ClinicialTrials.gov (Identifier: NCT00137865).

3/A Phase 1, Open-Label, Dose Escalation Study of the Safety and Preliminary Efficacy of EGEN-001 in Combination With Carboplatin and Docetaxel in Women With Recurrent, Platinum-Sensitive, Epithelial Ovarian Cancer, Clinical Trial Summary, ClinicialTrials.gov (Identifier:  NCT00473954).

4/Kendrick JE, Matthews KS, Straughn JM, et. al.  A phase I trial of intraperitoneal EGEN-001, a novel IL-12 gene therapeutic, administered alone or in combination with chemotherapy in patients with recurrent ovarian cancer.  J Clin Oncol 26: 2008 (May 20 suppl; abstr 5572).

5/Anwar K, Barnes MN, Kelly FJ, et. al. Safety and tolerability of a novel IL-12 gene therapeutic administered in combination with carboplatin/docetaxel in patients with recurrent ovarian cancer.  J Clin Oncol 28:15s, 2010 (suppl; abstr 5045).

Source: FDA Awards EGEN, Inc. Orphan -Drug Grant for Clinical Development of EGEN-001 for Treatment of Ovarian Cancer, Press Release, EGEN, Inc., February 2, 2011.

Largest Study Matching Genomes To Potential Anticancer Treatments Releases Initial Results

The largest study to correlate genetics with response to anticancer drugs released its first results on July 15. The researchers behind the study, based at Massachusetts General Hospital Cancer Center and the Wellcome Trust Sanger Institute, describe in this initial dataset the responses of 350 cancer samples (including ovarian cancer) to 18 anticancer therapeutics.

U.K.–U.S. Collaboration Builds a Database For “Personalized” Cancer Treatment

The Genomics of Drug Sensitivity in Cancer project released its first results on July 15th. Researchers released a first dataset from a study that will expose 1,000 cancer cell lines (including ovarian) to 400 anticancer treatments.

The largest study to correlate genetics with response to anticancer drugs released its first results on July 15. The researchers behind the study, based at Massachusetts General Hospital Cancer Center and the Wellcome Trust Sanger Institute, describe in this initial dataset the responses of 350 cancer samples (including ovarian cancer) to 18 anticancer therapeutics.

These first results, made freely available on the Genomics of Drug Sensitivity in Cancer website, will help cancer researchers around the world to obtain a better understanding of cancer genetics and could help to improve treatment regimens.

Dr. Andy Futreal, co-leader of the Cancer Genome Project at the Wellcome Trust Sanger Institute, said:

Today is our first glimpse of this complex interface, where genomes meet cancer medicine. We will, over the course of this work, add to this picture, identifying genetic changes that can inform clinical decisions, with the hope of improving treatment.  By producing a carefully curated set of data to serve the cancer research community, we hope to produce a database for improving patient response during cancer treatment.

How a patient responds to anticancer treatment is determined in large part by the combination of gene mutations in her or his cancer cells. The better this relationship is understood, the better treatment can be targeted to the particular tumor.

The aim of the five-year, international drug-sensitivity study is to find the best combinations of treatments for a wide range of cancer types: roughly 1000 cancer cell lines will be exposed to 400 anticancer treatments, alone or in combination, to determine the most effective drug or combination of drugs in the lab.

The therapies include known anticancer drugs as well as others in preclinical development.

To make the study as comprehensive as possible, the researchers have selected 1000 genetically characterized cell lines that include common cancers such as breast, colorectal and lung. Each cell line has been genetically fingerprinted and this data will also be publicly available on the website. Importantly, the researchers will take promising leads from the cancer samples in the lab to be verified in clinical specimens: the findings will be used to design clinical studies in which treatment will be selected based on a patient’s cancer mutation spectrum.

The new data released today draws on large-scale analyses of cancer genomes to identify genomic markers of sensitivity to anticancer drugs.

The first data release confirms several genes that predict therapeutic response in different cancer types. These include sensitivity of melanoma, a deadly form of skin cancer, with activating mutations in the gene BRAF to molecular therapeutics targeting this protein, a therapeutic strategy that is currently being exploited in the clinical setting. These first results provide a striking example of the power of this approach to identify genetic factors that determine drug response.

Dr. Ultan McDermott, Faculty Investigator at the Wellcome Trust Sanger Institute, said:

It is very encouraging that we are able to clearly identify drug–gene interactions that are known to have clinical impact at an early stage in the study. It suggests that we will discover many novel interactions even before we have the full complement of cancer cell lines and drugs screened. We have already studied more gene mutation-drug interactions than any previous work but, more importantly, we are putting in place a mechanism to ensure rapid dissemination of our results to enable worldwide collaborative research. By ensuring that all the drug sensitivity data and correlative analysis is freely available in an easy-to-use website, we hope to enable and support the important work of the wider community of cancer researchers.

Further results from this study should, over its five-year term, identify interactions between mutations and drug sensitivities most likely to translate into benefit for patients: at the moment we do not have sufficient understanding of the complexity of cancer drug response to optimize treatment based on a person’s genome.

Professor Daniel Haber, Director of the Cancer Center at Massachusetts General Hospital and Harvard Medical School, said:

We need better information linking tumor genotypes to drug sensitivities across the broad spectrum of cancer heterogeneity, and then we need to be in position to apply that research foundation to improve patient care.  The effectiveness of novel targeted cancer agents could be substantially improved by directing treatment towards those patients that genetic study suggests are most likely to benefit, thus “personalizing” cancer treatment.

The comprehensive results include correlating drug sensitivity with measurements of mutations in key cancer genes, structural changes in the cancer cells (copy number information) and differences in gene activity, making this the largest project of its type and a unique resource for cancer researchers around the world.

Professor Michael Stratton, co-leader of the Cancer Genome Project and Director of the Wellcome Trust Sanger Institute, said:

“This is one of the Sanger Institute’s first large-scale explorations into the therapeutics of human disease.  I am delighted to see the early results from our partnership with the team at Massachusetts General Hospital. Collaboration is essential in cancer research: this important project is part of wider efforts to bring international expertise to bear on cancer.”

Ovarian Cancer Sample Gene Mutation Prevalence

As part of the Cancer Genome Project, researchers identified gene mutations found in 20 ovarian cancer cell lines and the associated prevalence of such mutations within the sample population tested. For purposes of this project, a mutation — referred to by researchers as a “genetic event” in the project analyses description — is defined as (i) a coding sequence variant in a cancer gene, or (ii) a gene copy number equal to zero (i.e., a gene deletion) or greater than or equal to 8 (i.e., gene amplification).  The ovarian cancer sample analysis thus far, indicates the presence of mutations in twelve genes. The genes that are mutated and the accompanying mutation prevalence percentage are as follows:  APC (5%), CDKN2A (24%), CTNNB1 (5%), ERBB2/HER-2 (5%), KRAS (10% ), MAP2K4 (5%), MSH2 (5%), NRAS (10%), PIK3CA (10%), PTEN (14%), STK11 (5%), and TP53 (62%). Accordingly, as of date, the top five ovarian cancer gene mutations occurred in TP53, CDKN2A, CDKN2a(p14)(see below), PTEN, and KRAS.

Click here to view the Ovary Tissue Overview.  Click here to download a Microsoft Excel spreadsheet listing the mutations in 52 cancer genes across tissue types. Based upon the Ovary Tissue Overview chart, the Microsoft Excel Chart has not been updated to include the following additional ovarian cancer sample mutations and associated prevalence percentages: CDKN2a(p14)(24%), FAM123B (5%), FBXW7 (5%), MLH1 (10%), MSH6 (5%).

18 AntiCancer Therapies Tested; Next 9 Therapies To Be Tested Identified

As presented in the initial study results, 18 drugs/preclinical compounds were tested against various cancer cell lines, including ovarian. The list of drugs/preclinical compounds that were tested for sensitivity are as follows:  imatinib (brand name: Gleevec),  AZ628 (C-Raf inhibitor), MG132 (proteasome inhibitor), TAE684 (ALK inhibitor), MK-0457 (Aurora kinase inhibitor), sorafenib (C-Raf kinase & angiogenesis inhibitor) (brand name: Nexavar), Go 6976 (protein kinase C (PKC) inhibitor), paclitaxel (brand name: Taxol), rapamycin (mTOR inhibitor)(brand name: Rapamune), erlotinib (EGFR inhibitor)(brand name: Tarceva), HKI-272 (a/k/a neratinib) (HER-2 inhibitor), Geldanamycin (Heat Shock Protein 90 inhibitor), cyclopamine (Hedgehog pathway inhibitor), AZD-0530 (Src and Abl inhibitor), sunitinib (angiogenesis & c-kit inhibitor)(brand name:  Sutent), PHA665752 (c-Met inhibitor), PF-2341066 (c-Met inhibitor), and PD173074 (FGFR1 & angiogenesis inhibitor).

Click here to view the project drug/preclinical compound sensitivity data chart.

The additional drugs/compounds that will be screened by researchers in the near future are metformin (insulin)(brand name:  Glucophage), AICAR (AMP inhibitor), docetaxel (platinum drug)(brand name: Taxotere), cisplatin (platinum drug)(brand name: Platinol), gefitinib (EGFR inhibitor)(brand name:  Iressa), BIBW 2992 (EGFR/HER-2 inhibitor)(brand name:  Tovok), PLX4720 (B-Raf [V600E] inhibitor), axitinib (angiogenesis inhibitor)(a/k/a AG-013736), and CI-1040 (PD184352)(MEK inhibitor).

Ovarian cancer cells dividing. (Source: ecancermedia)

Ovarian Cancer Therapy Sensitivity

Targeted molecular therapies that disrupt specific intracellular signaling pathways are increasingly used for the treatment of cancer. The rational for this approach is based on our ever increasing understanding of the genes that are causally implicated in cancer and the clinical observation that the genetic features of a cancer can be predictive of a patient’s response to targeted therapies. As noted above, the goal of the Cancer Genome Project is to discover new cancer biomarkers that define subsets of drug-sensitive patients. Towards this aim, the researchers are (i) screening a wide range of anti-cancer therapeutics against a large number of genetically characterized human cancer cell lines (including ovarian), and (ii) correlating drug sensitivity with extensive genetic data. This information can be used to determine the optimal clinical application of cancer drugs as well as the design of clinical trials involving investigational compounds being developed for the clinic.

When the researchers tested the 18 anticancer therapies against the 20 ovarian cancer cell lines, they determined that the samples were sensitive to many of the drugs/compounds. The initial results of this testing indicate that there are at least six ovarian cancer gene mutations that were sensitive to eight of the anticancer therapies, with such results rising to the level of statistical significance.  We should note that although most (but not all) of the ovarian cancer gene mutations were sensitive to several anticancer therapies, we listed below only those which were sensitive enough to be assigned a green (i.e., sensitive) heatmap code by the researchers.

Click here to download a Microsoft Excel spreadsheet showing the effect of each of the 51 genes on the 18 drugs tested. Statistically significant effects are highlighted in bold and the corresponding p values for each gene/drug interaction are displayed in an adjacent table.  A heatmap overlay for the effect of the gene on drug sensitivity was created, with the color red indicating drug resistance and the color green indicating drug sensitivity.

The mutated genes present within the 20 ovarian cancer cell line sample that were sensitive to anticancer therapies are listed below.  Again, only statistically significant sensitivities are provided.

• CDKN2A gene mutation was sensitive to TAE684, MK-0457, paclitaxel, and PHA665752.

• CTNNB1 gene mutation was sensitive to MK-0457.

• ERBB2/HER-2 gene mutation was sensitive to HKI-272.

• KRAS gene mutation was sensitive to AZ628.

• MSH2 gene mutation was sensitive to AZD0530.

• NRAS gene mutation was sensitive to AZ628.

We will provide you with future updates regarding additional ovarian cancer gene mutation findings, and new anticancer therapies tested, pursuant to the ongoing Cancer Genome Project.

Sources:

• Largest study of genomes and cancer treatments releases first results, Press Release, The Wellcome Trust Sanger Institute, July 15, 2010.

• Cancer Genome Project website, The Wellcome Trust Sanger Institute.

• Genomics of Drug Sensitivity in Cancer website, The Wellcome Trust Sanger Institute.

_____________________________________________________________

About The Genomics of Drug Sensitivity In Cancer Project

The Genomics of Drug Sensitivity In Cancer Project was launched in December 2008 with funding from a five-year Wellcome Trust strategic award. The U.K.–U.S. collaboration harnesses the experience in experimental molecular therapeutics at Massachusetts General Hospital Cancer Center and the expertise in large scale genomics, sequencing and informatics at the Wellcome Trust Sanger Institute. The scientists will use their skills in high-throughput research to test the sensitivity of 1000 cancer cell samples to hundreds of known and novel molecular anticancer treatments and correlate these responses to the genes known to be driving the cancers. The study makes use of a very large collection of genetically defined cancer cell lines to identify genetic events that predict response to cancer drugs. The results will give a catalogue of the most promising treatments or combinations of treatments for each of the cancer types based on the specific genetic alterations in these cancers. This information will then be used to empower more informative clinical trials thus aiding the use of targeted agents in the clinic and ultimately improvements in patient care.

Project leadership includes Professor Daniel Haber and Dr. Cyril Benes at Massachusetts General Hospital Cancer Center and Professor Mike Stratton and Drs. Andy Futreal and Ultan McDermott at the Wellcome Trust Sanger Institute.

About Massachusetts General Hospital

Massachusetts General Hospital (MGH), established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $600 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, systems biology, transplantation biology and photomedicine.

About The Wellcome Trust Sanger Institute

The Wellcome Trust Sanger Institute, which receives the majority of its funding from the Wellcome Trust, was founded in 1992 as the focus for U.K. gene sequencing efforts. The Institute is responsible for the completion of the sequence of approximately one-third of the human genome as well as genomes of model organisms such as mouse and zebrafish, and more than 90 pathogen genomes. In October 2005, new funding was awarded by the Wellcome Trust to enable the Institute to build on its world-class scientific achievements and exploit the wealth of genome data now available to answer important questions about health and disease. These programs are built around a Faculty of more than 30 senior researchers. The Wellcome Trust Sanger Institute is based in Hinxton, Cambridge, U.K.

About The Wellcome Trust

The Wellcome Trust is a global charity dedicated to achieving extraordinary improvements in human and animal health. It supports the brightest minds in biomedical research and the medical humanities. The Trust’s breadth of support includes public engagement, education, and the application of research to improve health. It is independent of both political and commercial interests.

Required Cancer Genome Project Disclaimer:

The data above was obtained from the Wellcome Trust Sanger Institute Cancer Genome Project web site, http://www.sanger.ac.uk/genetics/CGP. The data is made available before scientific publication with the understanding that the Wellcom Trust Sanger Institute intends to publish the initial large-scale analysis of the dataset. This publication will include a summary detailing the curated data and its key features.  Any redistribution of the original data should carry this notice: Please ensure that you use the latest available version of the data as it is being continually updated.  If you have any questions regarding the sequence or mutation data or their use in publications, please contact cosmic@sanger.ac.uk so as to obtain any updated or additional data.  The Wellcome Trust Sanger Institute provides this data in good faith, but makes no warranty, express or implied, nor assumes any legal liability or responsibility for any purpose for which the data are used.

Identifying & Overcoming Taxane Drug Resistance

Proteomics study reveals a protein that, when suppressed, makes cancers more susceptible to chemotherapy involving taxane drugs.

Taxanes, a group of cancer drugs that includes paclitaxel (Taxol®) and docetaxel (Taxotere®), have become front-line therapy for a variety of metastatic cancers. But as with many chemotherapy agents, resistance can develop, a frequent problem in breast, ovarian, prostate and other cancers. Now, cancer researchers at Children’s Hospital Boston report a protein previously unknown to be involved in taxane resistance and could potentially be targeted with drugs, making a cancer more susceptible to chemotherapy.

The researchers believe that this protein, prohibitin1, could also serve as a biomarker, allowing doctors to predict a patient’s response to chemotherapy with a simple blood test. The study was published online by the Proceedings of the National Academy of Sciences in its online early edition during the week of January 25.

Bruce Zetter, Ph.D., Charles Nowiszewski Professor of Cancer Biology, Vascular Biology Program, Department of General Surgery, Children's Hospital Boston

The study, led by Bruce Zetter, PhD, of Children’s Vascular Biology Program, used proteomics techniques to compare the proteins present in Taxol-susceptible versus Taxol-resistant human tumor cell lines. The researchers found that the resistant cell lines, but not the susceptible cell lines, had prohibitin1 on their surface. When they suppressed prohibitin1 with RNA interference techniques, the tumor cells became more susceptible to Taxol, both in cell culture and in live mice with implanted Taxol-resistant tumors.

Zetter’s lab is still investigating why having prohibitin1 on the cell surface makes a tumor cell resistant to taxanes. But in the meantime, he believes that not only could prohibitin1 be suppressed to overcome taxane resistance, but that it could also be exploited as a means of targeting chemotherapy selectively to resistant cancer cells.

“We are working to target various cancer drugs to taxane-resistant cells by attaching them to compounds that bind to prohibitin,” Zetter explains. One such compound is already known, and works well in animals to target other prohibitin-rich cells, but has yet to be tested in humans.

Suppressing prohibitin1 alone probably isn’t enough to make a cancer fully Taxol-susceptible, but could be combined with other strategies aimed at increasing taxane susceptibility, such as targeting another protein called GST Pi, the researchers say. Other mechanisms of resistance are known, but they so far haven’t been shown to present effective targets for therapy.

Zetter’s lab is also trying to develop prohibitin1 as a biomarker for taxane resistance that physicians could use in the clinic. Since it’s on the surface of the cell, Zetter believes prohibitin1 may circulate in the blood where it could easily be detected. His lab is in talks with several cancer centers to obtain serum samples from patients who did and didn’t respond to Taxol, so that prohibitin1 levels could be measured and compared.

Zetter notes that prohibitin1 could easily have been overlooked, and was found only because the team happened to look specifically at proteins in the cell membrane, rather than simply doing a whole-cell proteomic analysis.

“The interesting finding was that prohibitin was not just another over-expressed protein,” Zetter says. “It was up-regulated primarily on the cell surface. When we looked at the whole cell, the absolute amount of prohibitin wasn’t changed. Instead, prohibitin was moving from the inside of the cell to the cell surface. It had shifted from one location to another, and when it did, the tumor cells became resistant to taxanes. The fact that it moves to the cell surface also makes it easier to direct drugs to it.”

Children’s Hospital Boston has pending and issued international patents on this technology.  Nish Patel, PhD, was the study’s first author. The study was funded by a grant from the National Institutes of Health.

About Children’s Hospital Boston

Founded in 1869 as a 20-bed hospital for children, Children’s Hospital Boston today is one of the nation’s leading pediatric medical centers, the primary pediatric teaching hospital of Harvard Medical School, and the largest provider of health care to Massachusetts children. In addition to 396 pediatric and adolescent inpatient beds and more than 100 outpatient programs, Children’s houses the world’s largest research enterprise based at a pediatric medical center, where its discoveries benefit both children and adults. More than 500 scientists, including eight members of the National Academy of Sciences, 11 members of the Institute of Medicine and 13 members of the Howard Hughes Medical Institute comprise Children’s research community. For more information about the hospital visit: www.childrenshospital.org/newsroom.

Sources:

• Overcoming Taxane Resistance in Cancer – Proteomics study reveals a protein that, when suppressed, makes cancers more susceptible to chemotherapy, News Release, Children’s Hospital of Boston, January 25, 2010.

• Patel N, Chatterjee SK, Vrbanac V, et. al. Rescue of paclitaxel sensitivity by repression of Prohibitin1 in drug-resistant cancer cells. Proc Natl Acad Sci U S A. 2010 Jan 25. [Epub ahead of print, PMID: 20133800].

2009 ASCO Annual Meeting Highlights: Ovarian Cancer & Select General Issues

The 2009 American Society of Clinical Oncology (ASCO) Annual Meeting was held in Orlando, Florida from May 29 through June 2, 2009.  We provide below select highlights from the 2009 ASCO Annual Meeting that relate to ovarian cancer and other general issues.

The 2009 American Society of Clinical Oncology (ASCO) Annual Meeting was held in Orlando, Florida from May 29 through June 2, 2009.  We provide below select highlights from the 2009 ASCO Annual Meeting that relate to ovarian cancer and other general issues. Learn more about How to Read a Medical Abstract in a Research Study.

Development Time of Cancer Clinical Trials Linked to Accrual Goals.

• Abstract #CRA6509.
• ASCO 2009: Development Time of Cancer Clinical Trials Linked to Accrual Goals, by Roxanne Nelson, Medscape Conference Coverage – American Society of Clinical Oncology (ASCO) 45th Annual Meeting, MedscapeToday, June 4, 2009 (free registration required to view article).

Physicians Need to Address Prescription Costs With Patients Who Participate In Clinical Trials.

• Abstract #9503.
• ASCO 2009: Physicians Need to Address Cost of Cancer Care With Patients, by Roxanne Nelson, Medscape Conference Coverage – American Society of Clinical Oncology (ASCO) 45th Annual Meeting, MedscapeToday, May 18, 2009 (free registration required to view article).

Availability of Experimental Therapy Outside of Randomized Clinical Trials In Oncology.

• Abstract #6539.
• ASCO 2009: Should Experimental Cancer Therapies Be Available Outside Clinical Trials?, by Roxanne Nelson, Medscape Conference Coverage -American Society of Clinical Oncology (ASCO) 45th Annual Meeting, MedscapeToday, June 18, 2009 (free registration required to view article).

ASCO Fertility Preservation Guidelines For Cancer Patients Not Widely Followed By Oncologists.

• Abstract #9509, Abstract #CRA9508.
• ASCO 2009: Fertility Preservation Guidelines Not Widely Followed, by Roxanne Nelson, Medscape Conference Coverage – American Society of Clinical Oncology (ASCO) 45th Annual Meeting, Medscape Today, June 1, 2009 (free registration required to view article).

Ginger (Zindol®) Quells Cancer Patients’ Chemotherapy-Related Nausea.

• Abstract #9511.
• Libby’s H*O*P*E*™ Coverage.
• ASCO 2009: Ginger Helps Relieve Chemotherapy-Associated Nausea, by Roxanne Nelson, Medscape Conference Coverage – American Society of Clinical Oncology (ASCO) 45th Annual Meeting, Medscape Today, May 15, 2009 (free registration required to view article).
• Aphios Announces Presentation of Phase II/III Clinical Trial Data on Zindol® for Cancer Chemotherapy Induced Nausea, Press Release, Aphios Corporation, May 26, 2009.

Early Treatment of Recurrent Ovarian Cancer Based Upon Rising CA-125 Levels Does Not Increase Survival.

• Abstract #e16546.
• Libby’s H*O*P*E*™ Coverage.
• Doubts on Ovarian Cancer Relapse Test, by Andrew Pollack, Health Section, Research, The New York Times (online), May 31, 2009.
• Early treatment based on rising CA125 did not improve survival in recurrent ovarian cancer, 2009 ASCO Annual Meeting, HemOncToday, May 31, 2009.

Body Mass Index (BMI) Should Be Taken Into Account When Assessing A Cancer Patient’s Vitamin D Status.

• Abstract #6625.
• Researchers Say More Aggressive Vitamin D Supplementation Needed in Obese Cancer Patients, News & Information, PR Newswire, June 15, 2009.

Extreme Drug Resistance (EDR) Assay Results Do Not Independently Predict Or Alter The Outcomes of Patients With Epithelial Ovarian Cancer Who Are Treated With Optimal Cytoreductive Surgery Followed By Platinum & Taxane Combination Chemotherapy in Either a Primary or Recurrent Setting.

• Abstract #5504.

Systematic Review Of Past Study Results For Use of Cytoreductive Surgery Combined With Hyperthermic Intraperitoneal Chemotherapy (HIPEC).

• Abstract #5524.

Preliminary Results From Phase II Study of Oxaliplatin+Docetaxel+Bevacizumab As First Line Treatment of Advanced Ovarian Cancer Show 62% Overall Response Rate & 70% One-Year Progression Free Survival.

• Abstract #5546.

Combined Weekly Docetaxel + Gemcitabine In Relapsed Ovarian Cancer & Peritoneal Cancer Produces 59% Overall Response Rate.

• Abstract #5565.

A Phase II Trial of Irinotecan & Oral Etoposide Chemotherapy in Recurrent Ovarian Cancer Patients Produces 47% Overall Response Rate & 81% Clinical Benefit Rate.

• Abstract #5558.

Weekly Bevacizumab & Pegylated Liposomal Doxorubicin Produce 55% Clinical Benefit Rate In Progressing/Recurrent Ovarian Cancer Patients.

• Abstract #5547.

Phase II Study of Belotecan (CKD-602)+ Carboplatin Demonstrates 53% Overall Response Rate in Recurrent Ovarian Cancer Patients.

• Abstract #5554.

Single Agent Voreloxin Produces 11% Overall Response Rate & 52% Disease Control Rate in Phase II Study Involving Women with Platinum-Resistant Ovarian Cancer.

• Abstract #5559.
• Sunesis Pharmaceuticals Presents Voreloxin Clinical Data at the American Society of Clinical Oncology 2009 Annual Meeting, Press Release, Sunesis Pharmaceuticals, Inc., June 1, 2009.

A Phase II Study of Patupilone In Patients With Platinum Refractory/Resistant Ovarian, Primary Fallopian, or Peritoneal Cancer Produces 48% Clinical Benefit Rate.

• Abstract #5563.

Trabectedin (Yondelis®) + Pegylated Liposomal Doxorubicin (PLD) Produces Better Response Than PLD Alone.

• Abstract #5550, Abstract #5526.

M.D. Anderson Cancer Center Finds Anti-VEGF Therapy Is Highly Effective In Patients With Ovarian Granulosa Cell Tumors.

• Abstract #5574.

M.D. Anderson Cancer Center Finds That Increased Angiogenesis Is A Significant Predictor Of Poor Clinical Outcome In Patients With Sex-Cord Stromal Tumors; Suggests Anti-Angiogenesis Therapy is Warranted For This Subtype of Ovarian Cancer.

• Abstract #5575.

ZYBRESTAT™ (Combretastatin A-4 phosphate) Produces 32% Confirmed Partial Response Rate (RR) in Evaluable Patients With Platinum Resistant Ovarian Cancer (25% RR if total enrolled patients used as denominator).

• Abstract #5502.
• OXiGENE Reports Positive Data From Phase 2 Trial of ZYBRESTAT in Platinum Resistant Ovarian Cancer At the 2009 ASCO Annual Meeting – Final Data Presentation Shows 25% Confirmed Response Rate in Relapsed Patient Population, Press Release, OXiGENE, Inc., June 1, 2009.

ASSIST-5 Trial of TELCYTA® + Pegylated Liposomal Doxorubicin Produces 12% Response Rate (With One Complete Response) in Patients With Platinum Refractory and Resistant Ovarian Cancer.

• Abstract #5552.
• Telik Presents Results At ASCO From ASSIST-5 Trial of TELCYTA in Platinum Refractory And Resistant Ovarian Cancer, News & Events, Telik, Inc., May 31, 2009.

Two Studies Provide Contradictory Data for Use of Carboplatin + Pegylated Liposomal Doxorubicin in Ovarian Cancer

• Abstract #LBA5508. Carboplatin + Pegylated Liposomal Doxorubicin As First Line Treatment of Advanced Ovarian Cancer Produce Similar Results to Carboplatin + Paclitaxel But With Greater Toxicity.
• Studies offer contradictory data for carboplatin plus liposomal doxorubicin in ovarian cancer, 2009 ASCO Annual Meeting, HemOncToday, June 18, 2009.
• Abstract #LBA5509.  Carboplatin + Pegylated Liposomal Doxorubicin Better Than Carboplatin + Paclitaxel In Terms of Progression Free Survival & General Toxicity With Respect to Platinum Sensitive Ovarian Cancer Patients Enrolled In The CALYPSO Study of the Gynecologic Cancer Intergroup (GCIG).
• Schering’s Caelyx superior in ovarian cancer trial, News Article, Reuters Online, May 30, 2009.

OGX-427 Treatment Demonstrates Safety, Evidence of Declines in Circulating Tumor Cells and Reductions in Tumor Markers in a Phase I Cancer Trial, Including 60% Response Rate (Based Upon Declining CA125) For Ovarian Cancer Patients.

• Abstract #3506.
• OncoGenex Pharmaceuticals Announces OGX-427 Treatment Demonstrates Safety, Evidence of Declines in Circulating Tumor Cells and Reductions in Tumor Markers in a Phase 1 Cancer Trial, Press Release, OncoGenex Pharmaceuticals, Inc., May 30, 2009.
• A Phase 1 Study Evaluating a Second Generation Antisense Oligonucleotide (OGX-427) That Inhibits Heat Shock Protein 27 (Hsp27), Microsoft Powerpoint Presentations, OncoGenex Pharmaceuticals, Inc. [PDF Adobe Reader Doc.]

Maintenance BIBF 1120 Could Delay Disease Progression in Recurrent Ovarian Cancer.

• Abstract #5501.
• Boehringer Ingelheim to present new phase II clinical data on two lead oncology compounds at ASCO 2009, Press Release, Boehringer Ingelheim GmbH, May 15, 2009.

Oral PARP Inhibitor Olaparib (AZD2281) Effective Against BRCA-Deficient Advanced Ovarian Cancer.

• Abstract #5500.

Carfilzomib (PX-171-007) Produces Stable Disease For 4+ Months In One Ovarian Cancer Patient Who Failed Under Four Previous Treatment Lines – Phase II Solid Tumor Trial.

• Abstract #3515.
• Proteolix Presents Phase 1b/2 Clinical Data for Carfilzomib in Advanced Solid Tumor Patients at the 2009 ASCO Annual Meeting, News & Information, PR Newswire, May 30, 2009.

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About The American Society of Clinical Oncology

The American Society of Clinical Oncology is a non-profit organization founded in 1964 with the overarching goals of improving cancer care and prevention. More than 27,000 oncology practitioners belong to ASCO, representing all oncology disciplines and subspecialties. Members include physicians and health-care professionals in all levels of the practice of oncology. To view 2009 ASCO Annual Meeting presentation abstracts, click here.  To view 2009 ASCO Annual Meeting presentation abstracts regarding ovarian cancer, click here.  To view ASCO ovarian cancer information, click here.

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Cancer.Net, formerly People Living With Cancer (PLWC), brings the expertise and resources of the American Society of Clinical Oncology (ASCO), the voice of the world’s cancer physicians, to people living with cancer and those who care for and care about them. ASCO is composed of more than 27,000 oncologists globally who are the leaders in advancing cancer care. All the information and content on Cancer.Net was developed and approved by the cancer doctors who are members of ASCO, making Cancer.Net the most up-to-date and trusted resource for cancer information on the Internet. Cancer.Net is made possible by The ASCO Cancer Foundation, which provides support for cutting-edge cancer research, professional education, and patient information.

Cancer.Net provides timely, oncologist-approved information to help patients and families make informed health-care decisions. All content is subject to a formal peer-review process by the Cancer.Net Editorial Board, composed of more than 150 medical, surgical, radiation, and pediatric oncologists, oncology nurses, social workers, and patient advocates. In addition, ASCO editorial staff reviews the content for easy readability. Cancer.Net content is reviewed on an annual basis or as needed.

To view Cancer.Net ovarian cancer information, click here.

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A Weekly Combination of Topotecan & Docetaxel Produces Clinical Benefit In Heavily Pretreated Ovarian Cancer Patients

Recurrent and metastatic endometrial and ovarian cancers can be notoriously difficult to treat. … Physicians at the Albert Einstein College of Medicine of Yeshiva University showed that a combination of two chemotherapy drugs not only produced clinical benefit for such patients but were also well tolerated.  The results of this phase II study were published online in Gynecologic Oncology on March 21st. …[T]he researchers concluded that the combination of weekly topotecan and docetaxel has clinical benefit and is well tolerated in this heavily treated epithelial ovarian and uterine cancer patient population.  The researchers also noted that patients with platinum-resistant tumors had clinical benefit and should be considered for further study with this regimen. …

Recurrent and metastatic endometrial and ovarian cancers can be notoriously difficult to treat.  Both diseases are capable of  spreading to other organs and developing resistance to chemotherapy.  Typically, under this scenario, the patients have been heavily treated with chemotherapy and may not be able to endure additional treatment. Physicians at the Albert Einstein College of Medicine of Yeshiva University showed that a combination of two chemotherapy drugs not only produced clinical benefit for such patients but were also well tolerated.  The results of this phase II clinical study were published online in Gynecologic Oncology on March 21st.

Mark H. Einstein, M.D., M.S., Associate Professor of Obstetrics & Gynecology and Women's Health, Albert Einstein College of Medicine of Yeshiva University

“Women with recurrent gynecologic cancers have often had multiple rounds of chemotherapy, which can cause tumor cells to develop resistance to these drugs,” says Mark H. Einstein, M.D., M.S., Associate Professor of Obstetrics & Gynecology and Women’s Health at Einstein, who headed the study. “This resistance can make it difficult for doctors to devise a treatment protocol that will impact the cancers while avoiding the often-severe side effects that certain chemotherapy drugs can cause, particularly when patients have already been heavily pretreated with other anti-cancer drugs.”Under the trial protocol, eligible patients with recurrent epithelial ovarian or uterine cancers were treated with weekly topotecan 3.5 mg/m(2) and docetaxel 30 mg/m(2) for 3 consecutive weeks. Cycles were repeated every 4 weeks for 6 cycles or until evidence of disease progression or unacceptable toxicity. Patient response was assessed under Response Evaluation Criteria In Solid Tumors (RECIST) or, when appropriate, Rustin’s Criteria.  The majority of patients had received 2 prior chemotherapy regimens (9 pts had received 1 previous regimen, 16 pts. had received 2, 1 pt. had received 3, and 1 pt. had received 4).  Of the twenty-seven patients registered, 24 were evaluable for response.  The results of the trial are set forth below.

• 86 cycles of chemotherapy were administered.
• There were three grade 4 (all neutropenia) and ten grade 3 toxicities.Six of the grade 3 toxicities were unrelated to treatment.
• There were 8 dose delays and 4 dose reductions.
• The overall response rate was 25%  (8% CR, 17% PR).
• The clinical benefit rate was 38% (8% CR+17% PR+13% SD).
• The median duration of response was 8.5 months (range 3-19 months).
• The median overall survival was 18.5 months (range 1.8-50.7 months.

Based upon the foregoing results, the researchers concluded that the combination of weekly topotecan and docetaxel has clinical benefit and is well tolerated in this heavily treated epithelial ovarian and uterine cancer patient population.  The researchers also noted that patients with platinum–resistant tumors had clinical benefit and should be considered for further study with this regimen.Compared with previous clinical trials, an unusually high proportion of these women had been heavily pretreated with chemotherapy─yet nearly 40 percent of them experienced clinical benefit. In addition, the overall survival with the drug combination (median survival of 18.5 months) was higher than in previous phase II studies that evaluated the drugs on an individual basis.  Finally, there were few and relatively mild side effects from the drug combination compared with toxicities observed in similar studies.

The effectiveness and safety outcomes of the trial are “promising enough to justify a larger clinical study of this drug combination for women with recurrent gynecologic cancers,” Dr. Einstein said.

Other researchers at Einstein involved in the trial were Divya Gupta, M.D., Ricky L. Owers, M.D., Mimi Kim, Sc.D., Dennis Yi-Shin Kuo, M.D., Gloria S. Huang, M.D., Shohreh Shahabi, M.D., and Gary L. Goldberg, M.D. Dr. Einstein’s research was funded, in part, by investigator-initiated grants from Sanofi-Aventis and GlaxoSmithKline Oncology for research-related trial costs.

Sources:

• Gupta D, Owers RL, Kim M, et. al. A phase II study of weekly topotecan and docetaxel in heavily treated patients with recurrent uterine and ovarian cancers. Gynecol Oncol. 2009 Mar 21. [Epub ahead of print].  PMID: 19307014.

• New Treatment Shows Promise Against Recurrent Gynecologic Cancers, Einstein News, Albert Einstein College of Medicine of Yeshiva University, April 21, 2009.

2009 Society of Gynecologic Oncologists Annual Meeting Ovarian Cancer Highlights

From February 5th through 8th, 2009, the Society of Gynecologic Oncologists’ (SGO) held its 40th Annual Meeting on Women’s Cancer in San Antonio, Texas. The meeting, viewed as the preeminent scientific and educational conference for women’s cancer care specialists, featured more than 350 scientific oral and poster presentations as well as educational sessions dealing with advances in the care and treatment of women’s cancers.

From February 5th through 8th, 2009, the Society of Gynecologic Oncologists‘ (SGO)  held its 40th Annual Meeting on Women’s Cancer in San Antonio, Texas.  The meeting, viewed as the preeminent scientific and educational conference for women’s cancer care specialists, featured more than 350 scientific oral and poster presentations as well as educational sessions dealing with advances in the care and treatment of women’s cancers.  Several important presentations relating to ovarian cancer were made during the meeting and are highlighted below:

• Combined Bevacizumab and Topotecan Associated With Complications, Limited Activity in Platinum-Resistant Ovarian Cancer:  Presented at SGO, by Gabe Waggoner, DocGuide.com, DGDispatch dated Feb. 6, 2009 [Presentation title: Bevacizumab and Weekly Topotecan as Salvage Chemotherapy for Ovarian Cancer. Abstract 112].

• SGO: IVF Confers Slight Long-Term Risk of Ovarian Cancer, by Charles Bankhead, Medical News from SGO: Society of Gynecologic Oncologists Meeting, February 6, 2009 [Presentation Source:  Burger C, et al; The risk of borderline and invasive ovarian tumors after ovarian stimulation for in vitro fertilization in a large Dutch cohort after 15 years of follow-up, SGO 2009; 112(Suppl 1): Abstract 6].

• SGO: Optimal Surgery Holds Benefits in Ovarian Cancer with Upper Abdominal Disease, by Charles Bankhead, Medical News from SGO: Society of Gynecologic Oncologists Meeting, February 6, 2009 [Presentation Source:  Zivanovic O, et al; Upper abdominal disease cephalad to the greater omentum and the impact on progression-free survival in patients with stage IIIC ovarian cancer;  SGO 2009; 112(Suppl 1): Abstract 1].

• SGO: Rectovaginal Nodules Predict Bowel Perforation Risk with Bevacizumab, by Charles Bankhead, Medical News from SGO: Society of Gynecologic Oncologists Meeting, February 9, 2009 [Presentation Source:  Richardson DL, et al; Which factors predict bowel complications in patients with recurrent epithelial ovarian cancer being treated with bevacizumab? SGO 2009; 112(Suppl 1): Abstract 41].

• Low Completion Rates for GOG 172 Intraperitoneal Chemotherapy Regimen: See Aletti G, et al Intraperitoneal chemotherapy for ovarian cancer: Exploring the “dark side” of the moon” SGO 2009; 112(Suppl 1): Abstract 40 (Source:  SGO: Few Ovarian Cancer Patients Tolerate Intraperitoneal Regimen, by Charles Bankhead, Medical News from SGO: Society of Gynecologic Oncologists Meeting, February 11, 2009).

• Six Chemotherapy Cycles More Beneficial Than Three in Treating Stage I Ovarian Cancer: Presented at SGO, by Gabe Waggoner, DocGuide.com, DGDispatch dated Feb. 9, 2009 [Presentation title: Is There a High-Risk Subgroup With Stage I Ovarian Cancer Most Likely to Benefit From Six Versus Three Cycles of Adjuvant Chemotherapy? Abstract 43 ].

• No Differences in Tumour-Biomarker Response Between Women Receiving Intravenous Versus Intraperitoneal Chemotherapy for Ovarian Cancer: Presented at SGO, by Gabe Waggoner, DocGuide.com, DGDispatch dated Feb. 9, 2009 [Presentation title:  CA-125 Regression in Ovarian Cancer Patients Treated With Intravenous Versus Intraperitoneal Platinum-Based Chemotherapy: A Gynecologic Oncology Group Study. Abstract 46].

• Oxaliplatin (Eloxatin®), Docetaxel (Taxotere®) & Bevacizumab (Avastin®) Combination Shows Promise for Women With Advanced Ovarian, Peritoneal, and Fallopian Tube Cancer: See Herzog TJ, et al; Preliminary safety results of TEACO, a phase 2 trial of oxaliplatin, docetaxel, and bevacizumab as first-line therapy for advanced cancer of the ovary, peritoneum,and fallopian tube SGO 2009; 112(Suppl 1): Abstract 48 (Source:  SGO: Novel Drug Combination Shows Promise in Advanced Ovarian Cancer, by Charles Bankhead, Medical News from SGO: Society of Gynecologic Oncologists Meeting, February 10, 2009).

• Vermillion Presents Critical Data From Its OVA1 Clinical Trial, Vermillion Inc. News Release, February 10, 2009 [Presentation based upon a study entitled, A biomarker panel for distinguishing between malignant and benign ovarian tumors, which was co-authored by Fred Ueland, MD, Associate Professor of Gynecologic Oncology at the University of Kentucky and Principal Investigator of the OVA1 clinical trial, and Zhen Zhang, PhD, Associate Professor of Pathology at the Johns Hopkins University School of Medicine as well as Vermillion scientists].

• Angiogenesis Linked to Poor Survival in Patients With Rare Type of Ovarian Cancer – Drugs that block new blood vessel formation may improve outcomes of patients with sex cord-stromal tumors, M.D. Anderson Cancer Center News Release, Feb. 5, 2009 (Researchers from The University of Texas M. D. Anderson Cancer Center found that increased angiogenesis, or blood vessel formation, and vascular endothelial growth factor expression are associated with poor survival in women with sex cord-stromal ovarian tumors. This data was presented in a poster session).

About the Society of Gynecologic Oncologists

The SGO is a national medical specialty organization of physicians who are trained in the comprehensive management of women with malignancies of the reproductive tract. Its purpose is to improve the care of women with gynecologic cancer by encouraging research, disseminating knowledge which will raise the standards of practice in the prevention and treatment of gynecologic malignancies, and cooperating with other organizations interested in women’s health care, oncology and related fields. The Society’s membership, totaling more than 1280, is primarily comprised of gynecologic oncologists, as well as other related medical specialists including medical oncologists, radiation oncologists and pathologists. SGO members provide multidisciplinary cancer treatment including chemotherapy, radiation therapy, surgery and supportive care. More information on the SGO can be found at http://www.sgo.org.

MK-0457 Alone and in Combination With Docetaxel Inhibits Ovarian Cancer Growth In Vivo

…[T]he [M.D. Anderson Cancer Center & Baylor College of Medicine] researchers concluded that [Aurora kinase] AK inhibition [produced by MK-0457] significantly reduces ovarian cancer tumor burden and cell proliferation, and increases tumor cell apoptosis in preclinical ovarian cancer mouse models. The researchers noted that the role of Aurora kinase inhibition in ovarian cancer merits further investigation in clinical trials.

Chemotherapeutic drugs that interfere with the normal progression of cell division are used regularly for anti-cancer treatment. These so-called “antimitotic” drugs work by halting the cell cycle in mitosis, thereby inducing cell death (apoptosis) in tumor cells. Unfortunately, these compounds act not only on proliferating tumor cells, but exhibit significant side effects on non-proliferating or normal cells.

Aurora kinases (AKs), a specific family of protein kinases, are essential for various steps in human cell division. The cell division process is one of the hallmarks of every living organism. Within the complete cell-cycle process, mitosis constitutes one of the most critical steps. The main purpose of mitosis is to segregate sister chromatids into two daughter cells. This process is tightly regulated by several proteins, some of them acting as check points that ultimately ensure the correct coordination of this critical biologic process.

There is evidence linking AK overexpression with various types of malignant human cancer cells. Given the potential selectivity to target tumor cells while leaving normal cells unaffected, several “AK inhibitors” have been developed by various drug companies. Researchers at the University of Texas M.D. Anderson Cancer Center (Departments of Gynecologic Oncology, Surgical Oncology, and Cancer Biology) and the Baylor College of Medicine (Departments of Molecular and Cellular Biology and Obstetrics and Gynecology) tested MK-0457, a small molecule AK inhibitor, alone and in combination with docetaxel against ovarian cancer growth in vitro and in vivo. MK0457, initially developed by Vertex Pharmaceuticals Inc. (Vertex), is now being developed clinically by Merck & Co., Inc (Merck) for use against treatment-resistant forms of advanced leukemias.

The in vitro testing conducted by M.D. Anderson and Baylor researchers compared the use of docetaxel alone with the combination use of docetaxel and MK-0457, against two lines of chemosensitive ovarian cancer cells. Notably, the M.D. Anderson and Baylor researchers determined that the docetaxel and MK-0457 combination produced cytotoxicity that was 10 times greater than that produced by docetaxel alone. The in vivo testing, conducted in mouse models, compared the use of MK-0457 monotherapy against lines of chemosensitive and chemoresistant ovarian cancer cells. The AK inhibitor MK-0457, when used alone, significantly reduced ovarian cancer cell tumor burden. Combination treatment with docetaxel and MK-0457 resulted in significantly improved reduction in tumor growth, as well as a threefold increase in cell death, as compared to docetaxel monotherapy.

Based upon the foregoing results, the researchers concluded that AK inhibition significantly reduces ovarian cancer tumor burden and cell proliferation, and increases tumor cell apoptosis in preclinical ovarian cancer mouse models. The researchers noted that the role of Aurora kinase inhibition in ovarian cancer merits further investigation in clinical trials.

Note: In November 2007, Merck suspended new patient enrollment in two leukemia trials which involve the use of MK-0457. The suspension of new enrollees was attributable to preliminary safety data that indicated a potential cardiovascular effect in one patient. The safety findings from that patient indicated “QTc prolongation” (or “Long QT Syndrome“), a condition that can precede sudden cardiac arrest. Patients already enrolled in the two leukemia trials were permitted to continue treatment with MK-0457, provided that they were monitored for QTc prolongation. To our knowledge, based upon publicly available information, there have been no further reports of QTc prolongation within those two clinical trials.

Primary Reference: Targeting Aurora Kinase with MK-0457 Inhibits Ovarian Cancer Growth; Lin, YG et. al., Clin Cancer Res. 2008 Sep 1;14(17):5437-5446

Secondary References:

• Aurora kinase family: a new target for anticancer drug; Macarulla T et. al., Recent Patents Anticancer Drug Discov. 2008 Jun;3(2):114-22.

• Overexpression of the centrosomal protein Aurora-A kinase is associated with poor prognosis in epithelial ovarian cancer patients; Landen CN Jr et. al., Clin Cancer Res. 2007 Jul 15;13(14):4098-104.

• Predictive value of Aurora-A/STK15 expression for late stage epithelial ovarian cancer patients treated by adjuvant chemotherapy; Lassmann S et. al., Clin Cancer Res. 2007 Jul 15;13(14):4083-91.

• Activation and overexpression of centrosome kinase BTAK/Aurora-A in human ovarian cancer; Gritsko TM et. al., Clin Cancer Res. 2003 Apr;9(4):1420-6

Imatinib & Docetaxel Produce Modest Response Against Recurrent Platinum Resistant/Refractory Ovarian Cancer

A combination of imatinib mesylate (Gleevec®) and docetaxel (Taxotere®) produced only a modest response in patients with recurrent, platinum-resistant or refractory ovarian cancer, according to the results of a Phase II clinical trial conducted by the Hoosier Oncology Group at Indiana University Cancer Center.

Background

A combination of imatinib mesylate (Gleevec®) and docetaxel (Taxotere®) produced only a modest response in patients with recurrent, platinum–resistant or refractory ovarian cancer, according to the results of a Phase II clinical trial conducted by the Hoosier Oncology Group at Indiana University Cancer Center.

Imatinib mesylate (Imatinib) is an inhibitor of the (i) receptor tyrosine kinases (RTKs) for platelet-derived growth factor (PDGF) and stem cell factor (SCF), and (ii) c-Kit. RTKs are key regulators of normal cellular processes, and may play a critical role in the development and progression of many types of cancer. PDGF is one of the numerous growth factors, or proteins, that regulate cell growth and division. In particular, it plays a significant role in new blood vessel formation (angiogenesis) from existing blood vessels. SCF is a growth factor, or protein, important for the survival, proliferation, and differentiation of hematopoietic stem cells that give rise to all types of blood cells. C-kit is a protein that is expressed on the surface of hematopoietic stem cells as well as other cell types, and binds to stem cell factor (a substance that causes certain types of cells to grow). Docetaxel, a chemotherapy drug, promotes cell growth arrest.

Based upon the foregoing, the trial investigators hypothesized that use of imatinib (in tandem with docetaxel) would inhibit or block the RTKs for PDGF & SCF and the c-kit receptor, and cause tumor disruption by enhancing the effect of chemotherapy while controlling tumor angiogenesis. Also, the combination of imatinib and docetaxel previously produced synergistic effects in-vitro (in the laboratory) and in-vivo (in mice). As a monotherapy, and prior to this trial, docetaxel produced single agent activity in ovarian cancer with response rates of 30% to 40% in the platinum refractory setting.

The Imatinib/Docetaxel Phase II Clinical Trial

Pursuant to trial eligibility criteria, all patients had recurrent, platinum-resistant, or refractory epithelial ovarian cancer that expressed PDGFR or c-kit, as determined by immunohistochemistry. This screening resulted in the enrollment of 23 patients with the following tumor characteristics: 4 patients had c-kit-positive/PDGFR-negative tumors, 11 patients had PDGFR-positive/c-kit-negative tumors, and 8 patients had c-kit-positive/PDGFR-positive tumors. The median patient age was 56 years (ranging from 33 to 76 years). Enrolled patients had received a median of 3 prior lines of treatment.

The overall response rate was 21.7%, which included 1 complete response (CR) and 4 partial responses (PR). An additional 3 patients had stable disease for more than 4 months. The trial investigators determined that the expression of PDGFR and/or c-kit, did not predict response to this combination therapy. The most common adverse events encountered were fatigue (83%), nausea (74%), diarrhea (61%), anorexia (52%), and edema (65%), and the majority of those events were grade 1 or 2 events.

Based upon the foregoing, the trial investigators concluded that the combination treatment of imatinib and docetaxel was tolerated in patients with heavily pretreated epithelial ovarian cancer that expressed c-kit or PDGF, but found that few patients had sustained responses or stable disease, when compared with the 30% to 40% response rate of docetaxel used as a monotherapy in a platinum refractory setting.

Sources:

• Imatinib mesylate in combination with docetaxel for the treatment of patients with advanced, platinum-resistant ovarian cancer and primary peritoneal carcinomatosis : a Hoosier Oncology Group trial, Matei D et. al; Cancer. 2008 Aug 15;113(4):723-32.

• Imatinib mesylate and docetaxel: minimal response in platinum-resistant ovarian cancer — Few patients had sustained response or stable disease, by HemOnctoday, August 14, 2008.

• Clinical Trial Protocol: Imatinib Mesylate (Gleevec®, STI571) in Combination With Docetaxel (Taxotere) for the Treatment of Advanced, Platinum-Refractory Ovarian Cancer and Primary Peritoneal Carcinomatosis: Hoosier Oncology Group GYN03-62.