2014 Program Project Development Grant Recipient – Ursula Matulonis, MD
Ursula Anne Matulonis, MD
Dana-Farber Cancer Institute
Rational Combinations of Novel Biologic Agents for Ovarian Cancer Therapy
Gerburg Wulf, MD, PhD
Panagiotis Konstantinopoulos, MD, PhD
Anthony George Letai, MD, PhD
Joyce Liu, MD, MPH
William Thomas Barry, PhD
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.
Ursula A. Matulonis, MD, is Medical Director and Disease Center Leader of the Medical Gynecologic Oncology Program at Dana-Farber Cancer Institute and Associate Professor of Medicine at Harvard Medical School. Her research focuses on developing new targeted therapies for gynecologic malignancies, with a specific interest in the genetic changes in ovarian cancer and how that can lead to rationale drug selection.
Dr. Matulonis is Principal Investigator (PI) of several clinical trials and translational studies for ovarian cancer. She is the PI of a Department of Defense grant on ovarian cancer entitled “Prediction of Response to Therapy and Clinical Outcome Through a Pilot Study of Complete Genetic Assessment of Ovarian Cancer” and a Co-PI on the project “Genetic similarities between serous ovarian cancer and triple negative breast cancer” funded by the Breast Cancer Research Foundation. Dr. Matulonis serves on the National Comprehensive Cancer Network Recommendation and Guideline committee for both ovarian cancer and for the treatment of anemia, the Gynecologic Oncology Group ovarian committee and quality of life committee, the National Cancer Institute Ovarian Cancer Task Force, and is Medical Director and Board Member for the non-profit organization Ovations for the Cure. She is a recipient of the Dennis Thompson Compassionate Care Scholar award, the Lee M. Nadler “Extra Mile” Award, the Zakim Award for patient advocacy and has been named one of Boston’s Best Physicians in Medical Oncology by Boston Magazine.
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 Dana-Farber.
This grant was made possible in part thanks to the generous support of Ovarian Cycle Newport.