Disease models

Patient-derived high-grade serous cancer (HGSC) organoids could be used to help predict individual patient responses to DNA repair inhibitors in ovarian cancer. The organoids are generated by culturing solid tumor cells extracted from primary, metastatic or recurrent tumor sites in growth factor-enriched culture media and matrigel, and recapitulate the histological features, gene expression profiles and sensitivity and/or resistance to DNA repair inhibitors of the original tumor. In 33 organoids derived from 22 HGSC ovarian cancer patients, functional defects in homologous recombination or replication fork protection were associated with the corresponding patient’s sensitivity to the PARP inhibitor Lynparza olaparib, carboplatin, inhibitors of checkpoint kinase 1 (Chk1; CHEK1), and inhibitors of ataxia telangiectasia and Rad3 related (ATR; FRP1). Also in the organoids, the patients’ sensitivity to PARP inhibitors was associated with a mutational signature, identified by whole-exome sequencing, that was indicative of defects in homologous recombination. Next steps include developing a CLIA-certified program based on the organoids...