Abstract 2652: Efficacy of a small molecule MCT1 and MCT4 transporter inhibitor in cancer

Abstract

Abstract Targeting metabolic pathways has been a major clinical interest to effectively treat cancer patients. FDA approval of TIVSOVO(R) (IDH1 inhibitor) has validated the clinical importance of targeting tumor metabolism in cancer. Although MCT1-targeting small molecule inhibitor is currently under investigation for lymphoid cancers, the therapeutic efficacy of this compound is compromised by compensatory overexpression of MCT4 by tumor cells. Therefore, there is a need for a dual MCT1/4 inhibitor to target cancer. We have developed a first-in-class orally bioavailable small molecule inhibitor that targets lactate transport through MCT1 and MCT4 transporters. In 4T1 syngeneic model, we observed a significant dose-dependent reduction of tumor growth by NGY-B treatment that also correlated with serum lactate levels. Immunoprofiling of tumors revealed that NGY-B promoted anti-tumor immune response in 4T1 tumor bearing mice indicating simultaneous immune activation. Also, the combination of NGY-B with a checkpoint inhibitor led to greater efficacy and overall survival in this model suggesting a potential combination therapy in the clinic. Furthermore, we demonstrated the direct tumor cell killing effect of NGY-B in multiple human CDX and PDX models. Therefore, NGY-B intervenes two key hallmarks of cancer - tumor metabolism and anti-tumor immunity, and provides a novel modality to therapeutically target cancer. Citation Format: Sambad Sharma, Gregory Goreczny, Nicole Bowman, Jennifer Duffy, Daliya Banerjee, Sanath Wijerathna, John Dzuris, Kerui Wu, Shih-Ying Wu, Abhishek Tyagi, Kounosuke Watabe, Jaime Escobedo, Vincent Sandanayaka. Efficacy of a small molecule MCT1 and MCT4 transporter inhibitor in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2652.