Improvement in the treatment ovarian cancer has reached a plateau using our current treatment arsenal. Newer agents that target ovarian cancer genetic abnormalities have shown some efficacy as single agents, but cancer cells eventually figure out ways to grow despite the drug. One strategy to improve ovarian cancer treatment is to target several abnormal biologic pathways at once. Accomplishment of this requires testing of drug combinations first in cell culture and then in mice that have been injected with ovarian cancer cells from ascites from women with ovarian cancer. Only promising combinations would thus move to phase I trials.
The goals of this project are to 1) test novel combinations of biologic agents in the laboratory, and, if of interest, in mice who have human ovarian cancer cells growing in their abdomen and 2) screen for ways to predict if the cancer will respond to the treatment and when the cancer grows, figure out why the cancer is growing. The ultimate goal of this project is to quickly bring laboratory-tested and verified novel combinations into ovarian cancer clinical trials.
Our team is comprised of basic and clinical/translational scientists experienced in ovarian cancer research and who work together currently. Project 1: This project will study the effects on the PI3-kinase pathway in ovarian cancer cells when both PI3-kinase pathway and PARP are inhibited. This will be done in Dr. Wulf’s laboratory using tissue samples obtained from an ongoing clinical trial NCT01623349 (PI is Dr. Matulonis) that combines a PARP inhibitor (olaparib) and a drug that blocks the PI3kinase pathway (BKM120), an important signaling pathway in cancer cells. The rationale for this clinical trial came from Dr. Wulf’s lab showing that this combination led to cancer regression in a mouse model. Project 2: Dr. Konstantinopoulos has developed a test to predict if a patient’s cancer displays “BRCAness” meaning the cancer responds to drugs like platinum and PARP inhibitors. This test showed that a combination of a drug called a Heat Shock Protein (HSP) inhibitor worked in synergy (i.e. combination works better than either alone) with a PARP inhibitor. This project will test the effect of HSP90 inhibitors on DNA repair in ovarian cancer cells given this observed synergy and will figure out how and why this synergy occurs. Project 3: Dr. Letai has developed a technique called BH3 profiling that provides a measure of “priming” which determines how close a cancer cell is undergoing self-programmed death. This project proposes to test combinations of ABT263 which is a drug that can push cells into self-programmed death and PI3kinase inhibitors as well as PARP inhibitors in human ovarian cancer cells. Cell culture experiments show that these combinations have anti-ovarian cancer effects. BH3 profiling may be a novel and useful tool in guiding us to successful drug combinations.
This grant was made possible in part thanks to the generous support of Ovarian Cycle Newport.
Medical Director, Medical Gynecologic Oncology Disease Center Leader, Medical Gynecologic Oncology Program Dana-Farber Cancer Institute Associate Professor, Medicine Harvard Medical SchoolUrsula A. Matulonis, MD, is Chief and Director of the Division of Gynecologic Oncology at the Dana-Farber Cancer Institute and Professor of Medicine at Harvard Medical School. She is the first recipient of the Brock-Wilson Family Chair at the Dana-Farber Cancer Institute. She also co-leads the Ovarian Cancer Program within the Dana-Farber/Harvard Cancer Center. Her research focuses on developing new targeted therapies for gynecologic malignancies, with a specific interest in ovarian cancer and endometrial cancer. Dr. Matulonis has led several PARP inhibitor, anti-angiogenic agent, immunotherapy, and combination trials for ovarian cancer in the United States and internationally. Dr. Matulonis serves on the Massachusetts Ovarian Cancer Task Force, the NRG ovarian committee, and the Scientific Advisory Board for the Ovarian Cancer Research Alliance and the Clearity Foundation. She received the Dana-Farber Dennis Thompson Compassionate Care Scholar award, the Lee M. Nadler “Extra Mile” Award, the Clearity Foundation award, and the Zakim Award at Dana-Farber for patient advocacy. After receiving her MD from Albany Medical College, she completed an internship and residency at the University of Pittsburgh, followed by a medical oncology fellowship at the Dana-Farber Cancer Institute in Boston, MA.