Abstract 4838: Exploiting mitochondrial metabolism to enhance the response to standard of care treatments in ovarian cancer

Abstract

Abstract Ovarian cancer best practice consists of debulking surgery followed by platinum/taxane based chemotherapy combined with the angiogenesis inhibitor bevacizumab, and the PARP inhibitor olaparib for HRD positive tumors. However, despite significant improvements in its treatment, the 5-year survival rate remains low due to disease recurrence and resistance to therapy. Emerging evidence suggests that the metabolic requirements of cancer cells change after exposure to chemotherapy or targeted therapies, generating a potential Achilles’ heel. Here, we focused on exploiting the intrinsic or therapy-induced metabolic vulnerabilities of ovarian cancer to improve its response to the standard medical care. To this aim, ovarian cancer patient-derived xenografts (OC-PDX), injected orthotopically in nude mice, were used to assess i) the association between the metabolic profile of OC-PDXs and their responsiveness to treatments (i.e. cisplatin, bevacizumab, olaparib), ii) the metabolic changes induced by the treatments and iii) the therapeutic benefit of combining an OXPHOS inhibitor with the above-stated therapies. The effect on tumor progression was evaluated as increase of survival of OC-PDX bearing mice. First, we characterized the metabolic profile of OC-PDXs and divided them into high- and low-OXPHOS according to their dependence on mitochondrial metabolism. Then, we evaluated their response to the standard of care treatments and found that 75% of high-OXPHOS OC-PDXs were sensitive to cisplatin and olaparib, while 100% of low-OXPHOS OC-PDXs were poorly responsive. Response to bevacizumab varied in the two OC-PDX subsets. Further, we demonstrated that cisplatin or bevacizumab treatment induced the emergence of a sub-population of cells from malignant ascites with higher mitochondrial content and tricarboxylic acid cycle (TCA) intermediates and reduced expression of glycolysis-related genes, thus suggesting a shift toward oxidative metabolism in the residual cancer cells after treatment. Targeting these OXPHOS-dependent cells with the respiratory chain complex I inhibitor IACS-010759 improved the survival of mice. These results indicate that the metabolic profile of ovarian cancer cells is associated with the response to cisplatin and olaparib and lay the ground for the rational combination with OXPHOS inhibition to prolong therapies efficacy and eventually delay the development of recurrent disease. Supported by AIRC IG2019 ID 23520 to RG. Citation Format: Laura Formenti, Alessandra Decio, Valentina Dematteis, Giulia Dellavedova, Maria Rosa Bani, Raffaella Giavazzi, Carmen Ghilardi. Exploiting mitochondrial metabolism to enhance the response to standard of care treatments in ovarian cancer. [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 4838.