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.
Dr. S. John Weroha is Assistant Professor of Medical Oncology and Medicine at the Mayo Clinic, Rochester. He graduated from the University of Kansas (KU) with distinction and completed combined-degree PhD/MD training at KU Medical Center in 2007. His Internal Medicine Residency and Medical Oncology Fellowship training was completed at Mayo Clinic in 2013. As a fellow, he was awarded funding from the Minnesota Ovarian Cancer Alliance and Mayo Clinic Ovarian Cancer SPORE. In the clinic, Dr. Weroha specializes in the medical treatment of gynecologic cancers.
Dr. Weroha’s research interest is centered on overcoming platinum resistance in ovarian cancer. Although most patients have an initial response to debulking surgery and platinum-based chemotherapy, the majority of patients will experience cancer recurrences and, eventually, chemotherapy resistance. To address this, Dr. Weroha is utilizing a large resource of patient-derived tumorgrafts (also referred to as patient Avatars) with the following goals. First, identifying predictive markers of sensitivity to platinum chemotherapy and targeted therapy may help select the most appropriate patients for a specific therapy and avoid toxicity from ineffective therapies. Secondly, targeting of aberrant gene expression or pathway activation in Avatars with acquired platinum resistance may lead to new therapies to overcome or attenuate resistance. Thirdly, since recurrent ovarian cancer is generally not considered curable, testing of novel front-line platinum-based combinations in Avatars will hopefully lead to longer recurrence-free intervals and improve the cure rate for ovarian cancer patients.