Abstract 6032: Exploiting metabolic vulnerabilities of ovarian cancer with upregulated succinate dehydrogenase

Abstract

Abstract Ovarian cancer remains the deadliest of all gynecologic malignancies nationwide due to limited therapeutic options and chemotherapy resistance. The response to chemotherapy is substantially influenced by the high metabolic flexibility of ovarian cancer cells, which allows the cells to reprogram their metabolism and survive the treatment. Better understanding mechanisms regulating ovarian tumor metabolism could be exploited to develop new improved therapies. Our work demonstrated that the upregulation of mitochondrial enzyme succinate dehydrogenase (SDHA) is particularly prevalent (~20% of patients) in ovarian carcinoma and contributes to high energy tumor metabolism and cell survival. We observed that SDHA overexpressing ovarian cancer cells showed improved ability to survive and generate colonies in anchorage-independent conditions, which is an important feature of ovarian tumor cells surviving and spreading in peritoneal fluid (ascites). Proteomics data revealed that the SDHA overexpressing tumor cells showed reduced levels of proteins promoting anaerobic glycolysis (LDHA and HIF1α), and increased levels of mitochondrial pyruvate carrier (MPC) proteins. In addition, our tracer-based metabolomics data revealed that the elevated SDHA stimulates glutaminolysis by increasing mitochondrial glutamine supply fueling the TCA cycle with essential metabolites. We also demonstrated that the overexpression of SDHA is associated with a significant increase of OXPHOS and ATP production rate. Further, we reasoned that the SDHA overexpressing tumor cells could be particularly vulnerable to drugs disrupting glucose and/or glutamine metabolism. We performed a drug screening and identified an anti-metabolic compound shikonin known to disrupt glucose and amino acid metabolism. In in vitro studies, shikonin exhibited a profound anti-tumor efficacy and selectivity towards SDHA overexpressing tumor cells superior to that observed with chemotherapy. Importantly, our in vivo study validated the in vitro observations, and showed that shikonin is highly effective in suppressing SDHA overexpressing patient-derived tumor growth. In summary, the unique metabolic state of ovarian cancer associated with SDHA amplification could be successfully targetable offering a potential new treatment strategy for ovarian cancer patients. Citation Format: Lin Wang, Magdalena Bulicz, Patryk Mucha, Michael Kinter, Atul Pranay, Timothy M. Griffin, Benjamin F. Miller, Magdalena Bieniasz. Exploiting metabolic vulnerabilities of ovarian cancer with upregulated succinate dehydrogenase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6032.