Targeting PARP Inhibitor Resistance
Abstract
Various inhibitors of poly(ADP-ribose) (PAR) polymerase (PARPi) have recently entered the clinic for the treatment of patients with ovarian cancers defective in homology-directed DNA repair, e.g. due to the loss of BRCA1/2 function. Despite the success of this approved novel therapy, drug resistance is a major clinical hurdle. The overall goal of this project is to target PARPi resistance in BRCA1/2-mutated high-grade serous ovarian cancer (HGS-OvCa), in order to optimize the use of PARPi and to develop new therapeutic approaches to overcome drug resistance. To achieve this goal, we have addressed the following two specific aims in the first year of this project: 1. Targeting primary resistance by combining RNA-SCS-based tumor cell deconvolution with computational pathology and patient-derived organoids.2. Targeting secondary resistance using LCM-guided whole exome sequencing and RNAseq of tumor samples collected from PARPi-resistant BRCA1/2-mutated HGS-OvCa samples. In this technical report, we show that we have addressed all major tasks according to our initial plan. There are no major deviations, and we plan to publish our first data from this project in the coming reporting period. Importantly, with the loss of H2AX we present a novel mechanism that may indeed contribute to PARPi resistance in human ovarian cancer.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2023
- Accession Number
- AD1218509
Entities
People
- Intidhar Labidi-Galy
- Sven Rottenberg
Organizations
- University of Geneva