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.

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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.

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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.

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UCLA Researchers Significantly Inhibit Growth of Ovarian Cancer Cell Lines With FDA-Approved Leukemia Drug Dasatinib (Sprycel®)

The drug dasatinib (Sprycel®), approved for use by the U.S. Food and Drug Administration in patients with specific types of leukemia, significantly inhibited the growth and invasiveness of ovarian cancer cells and also promoted their death, say UCLA researchers in the November 10th issue of the British Journal of Cancer. The drug, when paired with a chemotherapy regimen, was even more effective in fighting ovarian cancer cell lines in which signaling of the Src family kinases — associated with approximately one-third of ovarian cancers– is activated. Clinical trials that involve the testing of dasatinib against ovarian cancer and solid tumors are currently ongoing.

Researchers affiliated with the University of California, Los Angeles (UCLA), Mayo Clinic and Harvard Medical School announced that they have established a biological rationale to support the clinical study of the U.S. Food & Drug Administration (FDA)-approved leukemia drug dasatinib (U.S. brand name: Sprycel®), either alone or in combination with chemotherapy, in patients with ovarian cancer. The study appears in the November 10th edition of the British Journal of Cancer.

Background

Dasatinib is an FDA-approved drug for the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome positive acute lymphoblastic leukemia (ALL). Dasatinib is a small-molecule inhibitor that targets several tyrosine kinases, including the Src kinase family, Ephrin type-A receptor 2 ( EphA2) , and the focal adhesion kinase (FAK).

Src is the prototypic member of a family of nine non-receptor tyrosine kinases (Src, Lyn, Fyn, Lck, Hck, Fgr, Blk, Yrk, and Yes). The Src family kinase (SFK) proteins regulate four main cellular fuctions that ultimately control the behavior of transformed cancer cells:  cell proliferation, adhesion, invasion, and motility.

Eph receptors and ephrins are integral players in cancer formation and progression, and are associated with advanced ovarian cancer and poor clinical outcome.

FAK is a non-receptor tyrosine kinase involved in the regulation of cell adhesion, survival, and migration.  Preclinical studies indicate that FAK plays a signficant role in ovarian cancer cell migration and invasion.

Dasatinib Study Methodology & Findings

slamon1

One of the dasatinib study authors is Dennis J. Slamon, M.D. Ph.D. Dr. Slamon is the Director of Clinical/Translational Research & Director of the Revlon/UCLA Women's Cancer Research Program, at the UCLA Jonsson Comprehensive Cancer Center. He is also the co-discoverer of Herceptin®, a targeted therapy that revolutionized the treatment of HER-2 positive breast cancer.

The researchers carried out the study by testing the effects of dasatinib on human ovarian cancer cells in vitro, using a panel of 34 established human ovarian cancer cell lines.  The 34 cell lines selected were representative of the major epithelial ovarian cancer subtypes:

On this basis, the researchers examined the effects of dasatinib on ovarian tumor cell proliferation, invasion, apoptosis, and cell-cycle arrest.  To more fully understand the activity of dasatinib, the researchers also studied the efficacy of chemotherapeutic drugs (i.e., carboplatin and paclitaxel) in combination with dasatinib against ovarian cancer cells that were previously determined to be dasatinib-sensitive.

The overarching goals of the study were (i) to provide a rationale to test dasatinib as a single agent or in combination with chemotherapy in patients with ovarian cancer, and (ii) to identify molecular markers that may help define subsets of ovarian cancer patients most likely to benefit from treatment with dasatinib.

Significant findings reported in the dasatinib study are summarized below.

  • Concentration-dependent, anti-proliferative effects of dasatinib were seen in all ovarian cancer cell lines tested.
  • Dasatinib significantly inhibited tumor cell invasion, and induced tumor cell death, but was less effective in causing tumor cell-cycle arrest.
  • At a wide range of clinically achievable drug concentrations, additive and synergistic interactions were observed for dasatinib plus carboplatin or paclitaxel.
  • 24 out of 34 (71%) representative ovarian cancer cell lines were highly sensitive (i.e.,  ≥ 60% growth inhibition) to dasatinib.
  • 6 cells lines were moderately sensitive (i.e., 40% – 59% growth inhibition) to dasatinib.
  • 4 cell lines were resistant (i.e., < 40% growth inhibition) to dasatinib.
  • When comparing dasatinib sensitivity between cell lines based solely upon histological subtype (i.e., serous papillary, clear cell, endometrioid, mucinous, and undifferentiated ovarian cancer cell lines), no single histological subtype was more sensitive than another.
  • Ovarian cancer cell lines with high expression of Yes, Lyn, Eph2A, caveolin-1 and 2, moesin, annexin-1 and 2 and uPA (urokinase-type Plasminogen Activator), as well as those with low expression of IGFBP2 (insulin-like growth factor binding protein 2), were particularly sensitive to dasatinib.
  • Ovarian cancer cell lines with high expression of HER-2 (Human Epidermal growth factor Receptor 2), VEGF (Vascular endothelial growth factor) and STAT3 (Signal Transducer and Activator of Transcription 3) were correlated with in vitro resistance to dasatinib.

Based upon the findings above, the researchers concluded that there is a clear biological rationale to support the clinical study of dasatinib, as a single agent or in combination with chemotherapy, in patients with ovarian cancer.

Konecny

Gottfried E. Konecny, M.D., UCLA Assistant Professor of Hematology/Oncology, UCLA Jonsson Comprehensive Cancer Center Researcher & First Author of the Dasatinib Study

Ovarian cancer, which will strike 21,600 women this year and kill 15,500, causes more deaths than any other cancer of the female reproductive system. Few effective therapies for ovarian cancer exist, so it would be advantageous for patients if a new drug could be found that fights the cancer, said Gottfried E. Konecny, M.D., a UCLA assistant professor of hematology/oncology, a Jonsson Comprehensive Cancer Center researcher, and first author of the study.

“I think Sprycel® could be a potential additional drug for treating patients with Src dependent ovarian cancer,” Konecny said. “It is important to remember that this work is only on cancer cell lines, but it is significant enough that it should be used to justify clinical trials to confirm that women with this type of ovarian cancer could benefit.”

Recent gene expression studies have shown that approximately one-third of women have ovarian cancers with activated Src pathways, so the drug could potentially help 7,000 ovarian cancer patients every year. Notably, a gene expression study published in 2007 reported Src activation in approximately 50% of the ovarian cancer tumors examined.

In the dasatinib study, the UCLA team tested the drug against 34 ovarian cancer cell lines and conducted genetic analysis of those lines. Through these actions, the researchers were able to identify genes that predict response to dasatinib. If the work is confirmed in human studies, it may be possible to test patients for Src activation and select those who would respond prior to treatment, thereby personalizing their care.

“We were able to identify markers in the pre-clinical setting that would allow us to predict response to Sprycel®,” Konecny said. “These may help us in future clinical trials in selecting patients for studies of the drug.”

Dasatinib is referred to as a “dirty” kinase inhibitor, meaning it inhibits more than one cellular pathway. Konecny said it also inhibits the focal adhesion kinase (FAK) and ephrin receptor, also associated with ovarian cancer, in addition to the Src cellular pathway.

The next step, Konecny said, would be to test the drug on women with ovarian cancer in a clinical trial. The tissue of responders would then be analyzed to determine if the Src and other pathways were activated. If that is confirmed, it would further prove that dasatinib could be used to fight ovarian cancer. In studies, women would be screened before entering a trial and only those with Src dependent cancers could be enrolled to provide further evidence, Konecny said, much like the studies of the molecularly targeted breast cancer drug Herceptin® enrolled only women who had HER-2 positive disease.

“Herceptin® is different because we knew in advance that it only worked in women with HER-2 [gene] amplification,” he said. “In this case, we don’t clearly know that yet. The data reassures us that the drug works where the targets are over-expressed but we need more testing to confirm this.”

The tests combining the drug with chemotherapy are significant because chemotherapy, namely carboplatin and paclitaxel, is considered the standard first line treatment for ovarian cancer patients following surgery. Because dasatinib proved to have a synergistic effect when combined with chemotherapy, it may be possible to add this targeted therapy as a first line treatment if its efficacy is confirmed in future studies.

Dasatinib Study Significance

The dasatinib study is potentially significant to the area of ovarian cancer treatment for several reasons.

First, although this study only tested dasatinib in vitro against ovarian cancer cell lines, the drug is already FDA-approved.  Accordingly, the general safety of the drug has already been established by the FDA.

Second, 71% of the ovarian cancer lines were highly sensitive to dasatinib.

Third, dasatinib was additive to, or synergistic with, the standard of care chemotherapy drugs used in first line ovarian cancer treatment, i.e., carboplatin and paclitaxel.

Fourth, the study established molecular markers that may be predictive of dasatinib effectiveness in particular patients.  In theory, a patient’s tumor biopsy could be tested for the presence of those molecular markers to determine whether a patient will benefit from dasatinib.

Fifth, one of the dasatinib study authors is Dennis J. Slamon, M.D. Ph.D. Dr. Slamon is the director of Clinical/Translational Research, and director of the Revlon/UCLA Women’s Cancer Research Program, at the UCLA Jonsson Comprehensive Cancer Center. Dr. Slamon is also the co-discoverer of Herceptin®, a targeted therapy that revolutionized the treatment of HER-2 positive breast cancer.  Herceptin® is a targeted therapy that kills HER-2 positive breast cancer cells while leaving normal cells unaffected.  The potential use of dasatinib to treat select ovarian cancer patients who test “positive” for specific molecular markers (e.g., Src cellular pathway activation) is similar to the extremely successful drug development approach used for Herceptin®.

Open Clinical Trials Testing Dasatinib (Sprycel®) Against Ovarian Cancer & Solid Tumors

As of this writing, there are several open (i.e., recruiting) clinical trials that involve testing dasatinib against ovarian cancer and solid tumors.

For a list of open clinical trials that involve testing dasatinib against ovarian cancer, CLICK HERE.

For a list of open clinical trials that involve testing dasatinib against solid tumors, CLICK HERE.

All potential volunteers must satisfy the clinical trial entrance criteria prior to enrollment.  Depending on the drug combination being tested, one or more of the solid tumor clinical trials may not be appropriate for an ovarian cancer patient.

About the UCLA Jonsson Comprehensive Cancer Center

UCLA’s Jonsson Comprehensive Cancer Center (JCCC) has more than 240 researchers and clinicians engaged in disease research, prevention, detection, control, treatment and education. One of the nation’s largest comprehensive cancer centers, JCCC is dedicated to promoting research and translating basic science into leading-edge clinical studies. In July 2009, JCCC was named among the top 12 cancer centers nationwide by U.S. News & World Report, a ranking it has held for 10 consecutive years. For more information on JCCC, visit the website at http://www.cancer.ucla.edu.

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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.

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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:

  • 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).
  • 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].

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.

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, platinumresistant 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.

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