Abstract P3-07-21: Therapeutic efficacy of NGY-091 against triple negative breast cancer is mediated by direct cell killing and activation of antitumor immunity

Abstract

Abstract Aberrant metabolic reprogramming is known to drive triple negative breast cancer progression and metastasis. The increase in glycolytic flux in cancer cells creates a lactate-rich tumor microenvironment (TME) that is exploited by tumors to their advantage by activating immunosuppressive cell populations, such as Tregs and MDSCs, that thrive on lactate as a fuel source. Therefore, blockade of lactate export from glycolytic cancer cells while inhibiting lactate entry into suppressive immune cells is a novel therapeutic strategy to treat cancer. Lactate transport in cells is predominantly mediated by MCT1 and MCT4 transporters. We have developed a compound, NGY-091, that is a first-in-class small molecule dual inhibitor of the MCT1 and MCT4 lactate transporters. NGY-091 treatment exhibited a potent in vitro cytotoxicity against breast cancer cells with various levels of MCT1 and MCT4 expressions. The on-target activity of NGY-091 was validated by measuring intracellular and extracellular lactate levels. NGY-091 strongly blocked MCT1 mediated lactate import and lactate export through MCT4 in vitro. Furthermore, a direct in vivo tumor cell killing was evident in human TNBC CDX (MDA MB 231) and PDX models with the treatment of NGY-091. In a syngeneic model of 4T1, we observed a significant reduction in tumor growth and synergistic tumor regression when combined with immune checkpoint blockade therapy. Profiling of lymphoid and myeloid cells in NGY-091 treated tumors by flow cytometry revealed a significant alteration in immune architecture suggesting activation of antitumor immunity. NGY-091 treated tumors induced a profound increase in effector T cell populations, CD8/Treg ratio and tumor-suppressive M1 macrophages while significantly downregulating M2 macrophages. To further investigate if NGY-091 directly alters immune cell activation and functionality in vitro, we treated CD4 T, CD8 T, Tregs and MDSCs in a lactate-rich culture condition mimicking lactate level in the TME. NGY-091 treatment strongly increased effector CD4 and CD8 T cells while significantly reducing suppressive function of Treg and MDSCs in vitro. These findings indicate the direct effect of NGY-091 on immune cell and validate the in vivo observations in 4T1 tumors. Therefore, NGY-091 intervenes two key hallmarks of cancer – metabolism and immunity and provides a novel avenue to therapeutically target aggressive breast cancer. Citation Format: Sambad Sharma, Sanath Wijerathna, Kerui Wu, Abhishek Tyagi, Shih-Ying Wu, Kounosuke Watabe, Nelly Kuklin, Jaime Escobedo, Vincent Sandanayaka. Therapeutic efficacy of NGY-091 against triple negative breast cancer is mediated by direct cell killing and activation of antitumor immunity [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-07-21.