Targeting PARP Inhibitor Resistance
Abstract
Rationale and Objective: Although various effective treatments have become available for ovarian cancer patients over the last years, anti-cancer therapy resistance remains the major cause of death of women with metastasized tumors. Striking examples are patients with tumors that are defective in DNA repair, e.g., due to the presence of mutations in the BRCA1 or BRCA2 genes. To target this defect, a novel type of therapy has recently entered the clinic: drugs like olaparib (Lynparza), inhibitors of the protein PARP, called PARPi, specifically kill the tumor cells while causing only moderate side effects compared to standard of care platinum-based chemotherapy. In recent years, three different PARPi have been approved by the FDA to treat ovarian cancer patients, and PARPi in ovarian cancer is a prime example of individualized medicine in oncology. Previous research of the initiating principal investigator (Prof. Sven Rottenberg) using mouse models for BRCA-mutated cancers was instrumental in the current use of PARPi as a maintenance therapy in ovarian cancer patients who carry these mutations. The partnering principal investigator (Dr. Intidhar Labidi-Galy) is a clinician scientist and has made seminal findings on the pathogenesis of ovarian cancer. Moreover, she has established important correlations between the type of BRCA1/BRCA2 mutations and response to PARPi. Unfortunately, PARPi resistance of primary or metastasized tumors eventually emerges, which minimizes therapeutic options and greatly reduces survival. It is therefore crucial to identify novel approaches to target drug resistance in order to decrease the current annual ovarian cancer mortality of more than 14,000 women in the USA. The Central Problem and How It Will Advance the Field of Ovarian Cancer Research: Using genetically engineered mouse models, we have identified various mechanisms of PARPi resistance, and we think that these mechanisms are relevant in ovarian cancer patients. In this project, we will confirm which of these drug resistance mechanisms is also present in ovarian cancer patients. Then, we will search for new vulnerabilities of PARPi-resistant tumors that can be exploited therapeutically. The hope is to yield novel targets for drug development or provide new rationales to use already existing drugs for this purpose. At an early stage, this would greatly increase the chances of choosing successful targets that provide a real benefit for women with drug-resistant ovarian cancer. Unfortunately, the field is also lacking useful markers to predict which individual patients have a great benefit of PARPi therapy and which do not. By leveraging recent technical advances of single cell RNA sequencing in combination with artificial intelligence-based image analysis of the pathological ovarian cancer tissue, we expect to move the field forward. This research will specifically help patients with PARPi-resistant ovarian cancers for whom there is currently no other targeted therapy available and chemotherapy had limited efficacy. Regarding potential short-term outcomes, mapping BRCA1/2 mutations that are more likely to respond to PARPi will have an immediate benefit for ovarian patients. Moreover, if we understand which mechanisms of resistance are relevant in patients, we can search for novel vulnerabilities and drug targets. If inhibited, these might re-sensitize these tumors to treatment. Potential long-term outcomes are therefore the development of new personalized anti- cancer drugs that can be offered to patients suffering from PARPi-resistant tumors. The overall goal of our research is to provide novel therapeutic strategies to improve the health and well-being of Service Members, Veterans, retirees, their family members, and all women impacted by PARPi-resistant ovarian cancer. We have close interactions with oncologists who are experts in clinical research in ovarian cancer at leading comprehensive cancer centers
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210557
Entities
People
- Sven Rottenberg
Organizations
- United States Army
- University of Bern