Abstract AP10: A NOVEL PAN–ALDH1A INHIBITOR INDUCES NECROPTOSIS IN OVARIAN CANCER STEM–LIKE CELLS AND SYNERGIZES WITH CHEMOTHERAPY TO IMPROVE OUTCOMES

Abstract

Abstract BACKGROUND: We recently demonstrated that Aldehyde dehydrogenase (ALDH) activity and the stem cell marker CD133 can be used to define an ovarian cancer cell differentiation hierarchy. We demonstrated that even small increases in multipotent ALDHbrightCD133+ cancer stem–like cells (CSC) significantly increase chemotherapy resistance and tumor initiation capacity. ALDH1A family members (ALDH1A1, 1A2, and 1A3) have been implicated as the primary enzymes identifying CSC and have been strongly linked with chemotherapy resistance. Given the expression of ALDH1A family members in CSC and their role in chemotherapy resistance we hypothesized they could be important therapeutic targets. METHODS AND RESULTS: We developed a panel of novel ALDH inhibitors (ALDHi). We identified a DEAB analog 673540 (673A) which inhibits all three ALDH1A1 enzymes (IC50 ~220nM). Pan–ALDH1A inhibition, induced necroptotic cell death specifically in ALDHbright and CD133+ ovarian CSC. 673A induced necroptosis was driven by the induction of the mitochondrial uncoupling proteins, UCP1 and UCP3, and reduction in OXPHOS capacity. Necroptosis was caspase and RIP1 independent, but is associated with MLKL translocation to membrane, and DRP1 activation and translocation to mitochondria. 673A therapy was highly synergistic with chemotherapy, reducing tumor initiation capacity, and resulting in a 60% tumor cure rate in multiple tumor models in–vivo. CONCLUSIONS: ALDHi are highly active in experimental models of ovarian cancer. As ALDHi induce metabolic necroptosis, ALDHi are active in apoptosis resistant ovarian cancer cell lines. These studies support the development of ALDHi as novel therapeutics for ovarian cancer. Citation Format: Ilana Chefetz, Linda Hong, Kun Yang, Brandt Huddle, Charles Landen, Thomas Hurley, Scott D. Larsen, and Ronald J. Buckanovich. A NOVEL PAN–ALDH1A INHIBITOR INDUCES NECROPTOSIS IN OVARIAN CANCER STEM–LIKE CELLS AND SYNERGIZES WITH CHEMOTHERAPY TO IMPROVE OUTCOMES [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr AP10.