Abstract 875: Chemical biology approach to phenotypic intra-tumor heterogeneity in high-grade serous ovarian cancer

Abstract

Abstract Objective: High-grade serous ovarian cancer (HGSOC) remains the most lethal gynecologic malignancy. More than 50% of high-grade serous ovarian cancer (HGSOC) patients die due to recurrent disease within 5 years. Recurrent tumor clones are selected by chemotherapy treatment from heterogeneous subpopulations of cancer cells, and differ phenotypically. The objective of current study is to develop a high-throughput chemical biology approach to analyze phenotypic heterogeneity in HGSOC following progression of the disease. Methods: We utilize the Drug Sensitivity and Resistance Testing (DSRT) platform to assess the effects of 528 approved and investigational anti-cancer agents on primary HGSOC isolates. Samples are collected from ascites and/or solid high-grade ovarian tumors from the patients at different disease stages. DSRT profiling of the samples integrates viability and toxicity readouts with high-content imaging in order to assess the drug responses of phenotypically different cell subpopulations of epithelial cancer cells and stromal component. Results: Drug sensitivity profiling of ten primary and six relapse patient samples revealed heterogeneous drug sensitivity profiles characterized by common responsiveness to HDAC inhibitors, CDK inhibitors, and PI3K/mTOR inhibitors (mean drug sensitivity score (DSS) > 10). Relapse HGSOC samples demonstrated general trend towards resistance to a broad spectrum of chemotherapeutics and targeted drugs. Imaging-based DSRT profiling revealed that in both primary and relapse ascites-derived cancer cells the response to platinum drugs and DNA damaging agents associated with upregulation of transcriptional regulators of stemness, including BMI1, SOX2 and NANOG. The ascites-derived CK18-expressing epithelial cells collected from the same patient a) before chemotherapy, b) after 6 cycles of Carboplatin treatment and c) at the relapse demonstrated an increasing sensitivity to aldehyde dehydrogenase inhibitor disulfiram. These preliminary findings suggest that increase in a subpopulation of cancer cells with stem-like characteristics may accompany recurrence in HGSOC. Conclusions: Compound sensitivity testing combined with high-content imaging appears an informative tool to explore therapeutic vulnerabilities in chemoresistant subpopulations of ovarian cancer cells, and improves the accuracy of drug sensitivity profiling. Chemical biology screening of prospectively collected primary HGSOC samples can also help identifying phenotypic changes associated with chemoresistance development. Citation Format: Daria R. Bulanova, Katja Kaipio, Tarja Lamminen, Aleksandr Ianevski, Tero Aittokallio, Olli Carpen, Krister Wennerberg. Chemical biology approach to phenotypic intra-tumor heterogeneity in high-grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 875.