A Gene Expression Profile of BRCAness That Predicts for Responsiveness to Platinum and PARP Inhibitors

Institution Receiving Award: DANA-FARBER CANCER INSTITUTE
Program: OCRP
Proposal Number: OC093426
Award Number: W81XWH-10-1-0585
Funding Mechanism: Ovarian Cancer Academy┬┐Early-Career Investigator/Designated Mentor
Partnering Awards:
Award Amount: $1,260,737.00


More than 20,000 American women are diagnosed with ovarian cancer each year. Approximately 5-10 percent of these patients will be born with genetic changes, called mutations, in certain genes called BRCA-1 and BRCA-2, that make them more prone to developing ovarian cancer. Patients who develop ovarian cancer because of mutations in BRCA-1 or -2 tend to live longer and respond better to chemotherapy than patients who do not have this genetic form of ovarian cancer. One of the reasons for this is because cancer cells that contain a BRCA-1 or -2 mutation cannot repair the damage caused by chemotherapy, and are thus killed more effectively by chemotherapy. In particular, patients with the genetic form of ovarian cancer are particularly sensitive to a medicine called carboplatin, which is the most commonly used chemotherapy drug in ovarian cancer. Furthermore, patients with the genetic form of the disease are particularly sensitive to a new type of chemotherapy drug called PARP inhibitors. These drugs, which are often taken in pill form, have resulted in promising tumor shrinkage in patients with the genetic form of the disease, even if they have already developed resistance to other agents. Because the genetic form of ovarian cancer is relatively rare (5-10 percent of all patients), we have tried to figure out how to identify other patients with ovarian cancer that still might benefit from PARP inhibitors, even if they do not have a BRCA-1 or -2 mutation (these patients are referred to as having the more common, "sporadic" form of the disease). We are excited by a recent discovery in our laboratory in which we have identified a set of genes in ovarian cancer cells that appears to predict which patients with sporadic disease might benefit from PARP inhibitors. These genes can be detected in the patient's own tumor, using a chip the size of a microscope slide, and provides potentially powerful information that can tell us which patients may, or may not, benefit from this exciting class of new drugs. We propose a series of experiments to evaluate how well this test works in selecting for sporadic patients that might respond well to chemotherapy agents such as PARP inhibitors. We also propose to study the underlying molecular basis for why a cancer cell develops resistance to PARP inhibitors. In addition, we have identified certain drugs that may help patients who have developed resistance to PARP inhibitors, because it appears that these drugs may be able to reverse that resistance, and make PARP inhibitors work better. We will formally test this idea in the laboratory as part of this proposal. Finally, we propose to check how well this test works when we apply it the typical kinds of tumor samples that are stored in the pathology department after an operation or tumor biopsy is performed in order to make our test applicable to everyday clinical practice. We feel that this is a very exciting research plan that might enable a much larger number of patients with ovarian cancer to benefit from PARP inhibitors than was originally thought possible. We expect to answer most of these questions within the next few years, which will hopefully translate into significant benefit for ovarian cancer patients quickly. As an Early-Career investigator, I am looking forward to participating in the Ovarian Cancer Research Program Ovarian Cancer Academy and to collaborating with other investigators in the ovarian cancer field. This will help my goal to eventually become an independent investigator in ovarian cancer, dedicated to developing new tests that predict for response to therapy and that provide a better understanding of chemotherapy resistance. With the help of my Designated Mentor, who is an accomplished ovarian cancer investigator, the support of my institution that has hired me specifically to perform this kind of research, and my participation in the Academy, I am very hopeful that I will be able to reach my goals.