Although most patients with ovarian cancer respond well to optimal surgical debulking and platinum-based chemotherapy, the majority of them will relapse and in this setting, cure is uncommon. In order to improve the survival rates for our patients, a better understanding of chemotherapy resistance is needed. To achieve this goal, researchers need surrogates of ovarian cancer (or Avatars) that accurately reproduce the biology of those tumors in the laboratory so new drugs can be tested for efficacy. The Avatars presented in this proposal are such surrogates. They will be used to better understand the role of DNA repair as it relates to chemotherapy resistance.
Platinum based chemotherapy is the cornerstone of ovarian cancer treatment and it kills cancer cells by causing DNA damage. When cells are proficient at repair, they may be more resistant to chemotherapy, and when they are DNA repair-deficient, they may be more sensitive to chemotherapy. Moreover, recent advances in treatment have revealed a concept known as synthetic lethality, a process by which a cell with inherent DNA repair deficiencies (such as those with BRCA mutations) can be forced to undergo cell-death if other DNA repair mechanisms (such as base excision repair) are blocked with drugs like PARP inhibitors and the amount of DNA damage is overwhelming. However, reliable and reproducible tests to predict whether or not a patient will respond to either chemotherapy or PARP inhibitor are not available. Such a test would allow clinicians to use the most effective therapies up-front and try to improve the cure rate for ovarian cancer.
The first Aim of this proposal will define a test that may someday be used to accomplish this task, predicting response to treatment using a test to measure the functionality of the tumor’s DNA repair capabilities. The second Aim will address the common scenario of cancer recurrence and platinum resistance by trying to identify specific genes (using sequencing technology) which are “turned on” or “turned off” in recurrent/resistant cancer. To test whether these genes are important for resistance, they will either be forced to turn off or artificially tuned on. The third aim will address gaps in our knowledge regarding the best combinations to use with PARP inhibitors by testing Avatars for their response when combined with chemotherapy. The second part of Aim three will use Avatars to employ a clinically-available test by Foundation Medicine to guide targeted therapy. Although this is already being done clinically, each patient can only be treated with one drug at a time and efficacy is not guaranteed. A single Avatar model on the other hand, can be treated with multiple therapies simultaneously to determine which is most effective. This approach will help us understand which intracellular signals are most important for chemotherapy resistance.
This grant was made possible in part by a generous donation from Ms. Susan Rudolph.