TUMOR AND IMMUNO-METABOLISM BASED LACTATE TRANSPORTER INHIBITORs FOR METASTATIC MELANOMA

TUMOR AND IMMUNO METABOLISM BASED LACTATE TRANSPORTER INHIBITOR FOR METASTATIC MELANOMA Abstract Immunotherapy area for cancer is rapidly expanding with the discovery of new targets and methods to activate immune function within tumorsHoweverimmunotherapy has been successful so far only subset of metastatic patientsMetastatic melanoma is highly heterogeneous cancer and lack of response to current treatments is largely due to high heterogeneity in the tumor microenvironmentTMEof melanomaLactate rich TME has been shown as highly immunosuppressive and promotes tumor growth and progressionCancer cells transport lactate across the cell membrane to the extracellular matrix via monocarboxylate transportersMCTand MCTWe have developed dual MCTinhibitorsdMCTisto block lactate excretion to the TME thereby directly killing cancer cells and simultaneously activating local immunity in the TMEIn our preliminary studieswe have shown that dMCTis are potent compounds against multiple melanoma cell lines in vitroAlsowe have shown that in in vivo experiments with both xenograft modelMDA MBbreast cancerand syngeneic mouse models of melanomaBFBRAFWTand SMBRAFVEMCTinhibitors exert significant anti tumor efficacyAnti tumor efficacy in MDA MBimmune deficient xenograft model shows inhibitorsdirect cell killing effectIn the SMsyngeneic modelwe observed a decrease in expression of multiple immunosuppressive molecules such as Bfamily proteins in treated tumors compared to the control tumorsFurthermoreprofiling of cytokines indicated an increase in pro inflammatory IFNTNFILand decrease in tumor promoting TGFILin treated tumors compared to the control tumors confirming that the anti tumor effect of dMCTis is in part due to enhanced immune functionThis was further corroborated by the immune only efficacy of the compound in BFmodel indicating the immune component of these compoundsSupported by the preliminary datawe hypothesize that blocking the lactate shuttle with MCT inhibitor will reprogram the metabolic landscape of tumor microenvironment in melanoma by suppressing the tumor growth and enhancing the immune surveillancethereby promoting the efficacy of these inhibitors as a single agent or in combination with immune check point inhibitors in metastatic melanomaTo test our hypothesiswe propose the following specific aimsTo study in vitro effects and mechanisms of dMCTi inhibitorNGY B in representative melanoma cell linesTo investigate the efficacy and immune activation power of NGY B in immune deficient Amouse xenograft modelTo evaluate in vivo effects of NGY B as a single agent and in combination with immune checkpoint inhibitors in immune competent SMand BFmetastatic mouse modelsThe proposed work will determine the feasibility of dMCTis as novel immunotherapeutic agents to treat metastatic melanomaWe anticipate that the proposed study will enhance our understanding of the role of lactate on local TMEand its effect on the composition and function of infiltrating immune cells to develop novel immunotherapeutic combinations to treat metastatic melanoma Project Narrative Metastatic melanoma is a critically unmet medical needandyear survival rate is andlteven with current immunotherapyThere are no good therapies to treat metastatic melanomaThe current proposal aims to enhance our understanding of the role of novel lactate transporter inhibitors and tumor derived lactate in shaping the local tumor microenvironment and metabolic profile of tumor cells and immune cells in melanomaLactate transporter inhibitors will not only suppress the tumor growth but also enhances the local immune functionThe proposed study is of high relevance to the public health in advancing novel approaches to target cancer cell metabolic pathways that will impair cancer cell survival while enhancing the endogenous antitumor immunityUpon completion of the studymetastatic melanoma patients would significantly benefit from the proposed single agent or combination therapy with lactate transport inhibitors and immune check point inhibitors