283 Ascites-derived organoids as suitable preclinical models to depict platinum resistance in ovarian cancer

Introduction/Background High-grade serous ovarian carcinomas (HGSOC) are characterized by late-stage diagnosis and a high rate of recurrent disease after surgical treatment, associated with massive peritoneal carcinomatosis and a very poor prognosis. Crucial throughout this disease evolution, the systematic acquisition of resistance to first-line chemotherapy based on platinum determines the unfavorable outcome of HGSOC patients. To explore the molecular mechanisms associated with platinum-resistance, we have generated patient-derived organoids (PDOs) from HGSOC patients. PDOs are three-dimensional dynamic tumor models that are emerging as a relevant preclinical model system to assist in clinical decision-making, particularly for personalized therapeutic options. Methodology Proficient PDOs were generated from the ascitic fluid of HGSOC patients at the platinum-sensitive clinical setting. These PDOs accurately recapitulated the original carcinoma in terms of morphology, immunohistochemistry, genetics, and functional behavior. We further created matched platinum-resistant PDOs by in vitro sequential exposure to IC20 carboplatin. Results Immunehistology and confocal microscopy demonstrate that the ascites-derived PDO models reliably reproduced their corresponding tumors of origin. High-throughput accurate NGS for RNA-sequencing of matched platinum-sensitive and platinum-resistant PDOs, combined with LC-MSMS deep proteome and phospho-proteomics, revealed gene expression profiles and signaling pathways associated with the acquisition of resistance to platinum-based therapy in HGSOC. Ascites-derived organoids are also suitable models to address the clonal evolution of HGSOC in response to chemotherapy, or the identification of platinum-eligible patients upon relapse. Conclusion We describe the generation of efficient and clinically relevant PDO preclinical models from the ascitic fluid of HGSOC patients. We comprehensively characterized these PDOs, and validated their suitability to explore clinically relevant questions in the context of HGSOC, as the molecular determinants of platinum resistance acquisition. Disclosures No disclosures.