2013 Ann Schreiber Grant Recipient – David Pepin
David Pepin, PhD
Massachusetts General Hospital
Mechanisms and Markers to Target a Stem Enriched Population of Primary Ovarian Cancer Ascites with the Müllerian Inhibiting Substance
We have shown that a specific subpopulation of cells, the ovarian cancer stem cells, may respond deferentially to treatment, being paradoxically stimulated by chemotherapeutics such as Doxorubicin and Cisplatin, while exhibiting an exquisite sensitivity to inhibition by the Müllerian Inhibiting Substance (MIS). The cancer stem cell is thought to be responsible for metastasis, chemoresistance and disease recurrence, underscoring the importance of targeting this subpopulation in future treatments for ovarian cancer. Recombinant MIS is currently in pre-clinical evaluation as a novel therapeutic for ovarian cancer for which our laboratory is currently pursuing a scale up of production. To assist in the design of a clinical trial we need to estimate the percentage of ovarian cancer patients who may respond to MIS, identify biomarkers that are predictive of response, and determine how we can recruit the immune system to enhance our treatment. To address these questions we will use primary cancer cells derived from patient ascites. This allows us to use a system that closely resembles advanced disease as it presents itself in patients while retaining the diversity contained in the patient population in a minimally invasive way. Preliminary evidence suggests that MIS both inhibits the ovarian cancer stem cells and stimulate the immune system by influencing the secretion of immune modulators by the these cells. Studying this response using patient-derived cancer cells will allow us to tailor MIS adjuvant therapy together with chemotherapeutic agents in future clinical trials in ovarian cancer. Furthermore, by focusing on the mechanism behind these properties of the cancer stem cell we hope to uncover additional therapeutic avenues for the treatment of ovarian cancer.
David Pepin was trained as a molecular and developmental biologist at the University of Ottawa, Canada, where he completed a Ph.D. elucidating the role of chromatin remodeling during ovarian development and in ovarian cancers. During his training he has also worked, in collaboration with industry, on pre-clinical testing of novel therapies for ovarian cancer. In 2011, Dr. Pepin joined the Pediatric Surgical Research Laboratories as a Research Fellow at the Massachusetts General Hospital, in Boston to continue his training in ovarian cancer research. The laboratory of Dr. Donahoe is evaluating the use of a recombinant reproductive hormone, Mullerian Inhibiting Substance (MIS), as a potential therapy for ovarian cancer. Building on his expertise Dr. Pepin is doing pre-clinical testing of MIS as an adjuvant therapy and working on identifying patients who could benefit most from this treatment.
This grant was made possible in part through a generous donation from Jennifer Clark, and from Karl Margolis and family in memory of Kate Margolis.