Clinical implementation of precision systems oncology in the treatment of ovarian cancer based on ex-vivo drug testing and molecular profiling

Ovarian cancer (OC) is difficult to treat and has a high mortality rate. There is a strong need for new therapies, but OC is often not the main indication for drug development activities. Hence, here we explored systematic drug repurposing based on clues from ex-vivo testing of human OC patient cells. We established patient-derived cancer cell (PDCs) cultures using ascites or tumor tissue from serous OC patients and applied them to ex vivo Drug Sensitivity and Resistance Testing (DSRT) with a panel of 528 approved and investigational oncology drugs. The representativity of the PDCs was confirmed by genomic and phenotypic profiling in comparison to the original tumor sample. Both 2D and 3D culture conditions were applied and compared for their drug responses. 9 PDCs and 11 high-grade serous OC cell lines were examined. High grade serous OC (HGSOC, 6 cases) with TP53 mutation and CCNE1, CCNE1/KRAS or MYC/KRAS amplifications showed highly resistant drug response profiles, which reflects the clinical challenges in treating this OC subtype. Some HGSOC PDCs showed vulnerability to SMAC mimetics, inhibitors of Apoptosis Protein Antagonists, (e.g. birinapant) and to prexasertib, a checkpoint kinase 1 and 2 inhibitor. In contrast, low-grade serous OC (LGSOC, 3 cases) showed subtype-specific sensitivity to several kinase inhibitors, including EGFR/Her2, MEK, mTOR and PI3K inhibitors. In a metastatic LGSOC patient, RNA-sequencing revealed a CLU-NRG1 fusion gene, which creates an autocrine activation loop of the ErbB family of receptor kinases. DSRT assay confirmed a strong sensitivity of the PDCs ex-vivo to dual-kinase inhibitors, including afatinib. Based on these data, the patient has received approved kinase inhibitors, including afatinib monotherapy followed by a combination of herceptin and pertuzumab. This strategy has managed to keep the disease in control for over 3 years as measured by clinical criteria, including imaging and serum CA125 antigen levels. In conclusion, systems precision cancer medicine with PDCs could provide a valuable approach to reveal patient-specific drug efficacies that can be translated to the clinic in real-time. Citation Format: Astrid Murumagi, Daniela Ungureanu, Suleiman Khan, Akira Hirasawa, Mariliina Arjama, Katja Valimaki, Piia Mikkonen, Wilhelmiina Niininen, Ashwini Kumar, Samuli Eldfors, Teijo Pellinen, Vilja Pietiainen, Andrus Magi, Riitta Koivisto-Korander, Johanna Tapper, Mikko Loukovaara, Tero Aittokallio, Ralf Butzow, Olli Kallioniemi. Clinical implementation of precision systems oncology in the treatment of ovarian cancer based on ex-vivo drug testing and molecular profiling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2945.