Rational design of drug combinations to target chemotherapy resistance in high-grade serous ovarian cancer via metabolomic profiling of patient-derived organoids

项目

Project Summary/Abstract This resistant disease rates women, metabolomics resistance, of algorithm To regulatory of organoids. identified therapies project aims to develop a novel, interdisciplinary framework for the designed reprogramming of drug- tumors towards a responsive state. This pilot will focus on high-grade serous ovarian cancer, a with up to 20% o patients being refractory to primary treatment with carboplatin, and 80% relapse of initially responsive patients. We will obtain primary tumor tissue rom 12 refractory and 12 responsive grow patient-derived organoids as a personalized in vitro model of the patients' tumors, and perform profiling on both tissue samples and organoids. This will allow us to identify metabolic states of which will pinpoint the molecular escape mechanisms resistant tumors employ to evade the action the chemotherapeutic agent. In the second phase of the project, we wil l develop a novel computational that predicts which other drug is most likely to reprogram the tumor into a carboplatin-sensitive state. this end, we will map the metabolic profiles of resistance onto an integrated metabolic, signaling and pathway map to then identify drugs whose targets are upstream of the desired effect. In the last part the project, we will choose the highest-scoring predictions and validate them experimentally on the Specifically, we expect to render resistant organoids responsive by pretreating them with the drugs. If successful, this project will establish a new paradigm for the rational design of combination in refractory tumors. f f