DF/HCC Announces 2013 Menís Collaborative to Cure Womenís Cancers Award Recipients
December 16, 2013
The DF/HCC Menís Collaborative to Cure Womenís Cancers is an unprecedented partnership providing a vehicle for men to come together as a unified force to support cutting edge research in breast and gynecologic cancers across the Harvard medical community. The Breast and Gynecologic Cancer Pilot Project Awards support investigators conducting innovative translational research and are designed to test the relevance of a biological or clinical discovery in womenís cancers risk, prevention, diagnosis, prognosis, or treatment and/or to determine the biological and molecular basis of disease.
The Menís Collaborative enables the most promising collaborative research projects and supports the next generation of physician-scientists with the goal of discovering powerful new treatments in the fight against womenís cancers. Award amount includes $55,000 per year for up to two years (total costs).
Principal Investigator: Geoffrey Shapiro, MD, PhD (DFCI)
Project Title: Evaluation of the nucleoside analog sapacitabine as monotherapy and in combination in BRCA-deficient and proficient triple negative breast cancer
Abstract: Sapacitabine is a novel chemotherapy drug that causes breaks in tumor cell DNA. These breaks require repair for cancer cells to survive. Cells deficient in DNA repair, such as those that lack BRCA proteins, are expected to be highly sensitive to sapacitabine. In addition, the activity of sapacitabine may be augmented in both BRCA-deficient and BRCA-proficient cancer cells by other new classes of drugs that compromise DNA repair, including CDK inhibitors and PARP inhibitors. Recently, several BRCA mutation carriers with advanced breast or ovarian cancer experienced tumor responses in a trial combining sapacitabine and a CDK inhibitor. To better understand this result, this proposal will evaluate sapacitabine as monotherapy and in combination in triple-negative breast cancer (TNBC) models. TNBC remains the most difficult breast cancer subset to treat, with new approaches needed. In the first specific aim, sapacitabine alone and in combination with a CDK inhibitor, a PARP inhibitor or cisplatin will be evaluated in BRCA-deficient TNBC cell lines and mouse models. The activity of sapacitabine monotherapy will be defined in BRCA-deficient breast cancer cells and synergism of drugs used in combination will be evaluated, along with assessment of biomarkers of drug activity. In the second specific aim, similar experiments will be performed in BRCA-proficient TNBC models to determine whether these strategies can be extended to the larger group of TNBC patients who do not carry a BRCA germline mutation. The data generated are expected to inform the next set of sapacitabine-based clinical trials in both BRCA-deficient and BRCA-proficient TNBC.
Principal Investigator: Daniel Silver, MD, PhD (DFCI)
Project Title: Personalized Targeted Epigenetic Therapy for Ovarian Cancer
Abstract: The lab has recently discovered a novel oncogene, MECP2, which appears to be important for tumor formation across a large number of human cancers. This new oncogene is particularly important in ovarian cancer, where almost 40% of tumors show extra DNA copies of this gene. The research has yielded evidence in an experimental system and in cell lines derived from human breast and lung cancers that inhibition of the expression of this gene causes very significant growth inhibition. Further, these experiments aimed at understanding how this gene contributes to tumorigenesis suggest that two classes of drugs, DNA methylation inhibitors and HDAC inhibitors, may obstruct the action of MECP2. This proposal, we will test ovarian cancer cell lines and human primary tumors growing in immunosuppressed mice (avatars) for addiction to the oncogene MECP2. The team will also investigate the response of the cell lines and avatars to DNA methylation inhibitors and HDAC inhibitors. In addition, the team will develop an antibody that will be useful to determine the level of MECP2 expression in clinical samples, use that antibody to investigate the percentage of ovarian cancers that overexpress MECP2 and explore the possibility that those tumors have distinct clinical characteristics. Because the two classes of drugs that inhibit MECP2 action are readily available and have been successfully combined in a lung cancer clinical trial for other reasons, these experiments can be rapidly translated into the clinic, and the proposed work will lay the groundwork necessary for swift clinical translation in ovarian cancer.