Abstract 2856: Targeting OXPHOS with IACS-010759 to eliminate standard of care resistant tumor cells
Authors: Marszalek Joseph R. , Seth Sahil , Corti Denise , Zhang Qi , Echeverria Gloria V. , Han Lina , Sun Yuting , Molina Jennifer , Gera Sonal , Chang Edward , Khor Tin O. , Mahendra Mikhila , Feng Ningping , Gay Jason P. , McAfoos Timothy , Giuliani Virginia , Shi Xi , Jeter-Jones Sabrina , Loponte Sarah , Li Chieh-Yuan , Bristow Christopher A. , Francesco Maria Emilia Di , Piwnica-Worms Helen , Konopleva Marina , Carugo Alessandro , Viale Andrea , Jones Philip , Heffernan Timothy P. , Draetta Giulio F. 
Published: August 2018

Tumors are comprised of heterogenous populations of tumor cells that rely on both glycolysis and oxidative phosphorylation (OXPHOS) for bioenergy and synthetic processes in support of cell proliferation. Over the past few years, we and others have reported that there is a subpopulation of tumors cells that are resistant to standard of care treatment or targeted therapies, and that these so-called persistent tumor cells possess stem cell like properties. Of note, these cells have elevated levels of mitochondria and are dependent on OXPHOS for survival. We have previously disclosed the discovery of IACS-010759, a potent, selective inhibitor of complex I of the electron transport chain, which is orally bioavailable and has excellent PK and physicochemical properties in preclinical species. IACS-010759 is currently in phase I clinical trials in relapsed/refractory AML and solid tumors where initial safety, pharmacokinetics, efficacy and pharmacodynamic impacts on tumor cell biology are being evaluated. As part of the development of IACS-010759, we were interested to explore the impact of the compound to target the persistent tumor cells, in particular by treating AML, TNBC and PDAC PDX models post-chemotherapy with IACS-010759. For all three contexts, IACS-010759 extended progression free survival, consistent with IACS-010759 targeting the recently described metabolically adapted residual tumor cells. For solid tumor indications, we have utilized innovative barcoding and clonal tracking strategies to confirm dependency of a specific subpopulation of tumor cells on OXPHOS. We show that OXPHOS inhibition extends survival and limits AML growth in secondary transplantation by stimulating terminal differentiation of putative stem cells. Taken together, these data provide rationale for multiple Phase II/III clinical trials where IACS-010759 will be used to target persistent tumor cell population and extend survival.

Citation Format: Joseph R. Marszalek, Sahil Seth, Denise Corti, Qi Zhang, Gloria V. Echeverria, Lina Han, Yuting Sun, Jennifer Molina, Sonal Gera, Edward Chang, Tin O. Khor, Mikhila Mahendra, Ningping Feng, Jason P. Gay, Timothy McAfoos, Virginia Giuliani, Xi Shi, Sabrina Jeter-Jones, Sarah Loponte, Chieh-Yuan Li, Christopher A. Bristow, Maria Emilia Di Francesco, Helen Piwnica-Worms, Marina Konopleva, Alessandro Carugo, Andrea Viale, Philip Jones, Timothy P. Heffernan, Giulio F. Draetta. Targeting OXPHOS with IACS-010759 to eliminate standard of care resistant tumor cells [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 2856.