Investigating the Role of PFKFB4 in the Immune Regulation of Lung Cancer

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PROJECT SUMMARY Lung cancer is responsible for the highest number of cancer-related deaths in the world. Non-small cell lung cancers (NSCLC) form the majority of lung tumors. These tumors are often discovered at an advanced stage when options are limited and survival is poor. Effective strategies are desperately needed to improve outcomes from this devastating cancer. NSCLCs universally exhibit a high rate of glycolysis to support their rapid growth and spread. A key rate-limiting step in the glycolytic pathway is catalyzed by the enzyme 6-phosphofructo-1-kinase (PFK1). PFK1 is activated by fructose-2,6-bisphosphate (F26BP) - produced by the 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase family of enzymes (PFKFB1-4). In previous studies, we found that the PFKFB4 enzyme is highly expressed in NSCLCs and established its requirement in the regulation of glucose metabolism and growth in these tumors. We have developed a potent novel small molecule inhibitor of PFKFB4, MPN-22, that selectively inhibits PFKFB4, and decreases NSCLC glycolysis and proliferation and tumor growth in vivo. In recent studies, we have found that immunosuppressive Th17 and γδT17 cells express F26BP and PFKFB4 and that MPN-22 administration in lung tumor-bearing mice decreases the frequency and activity of these cells. We hypothesize that PFKFB4 is required for Th17/γδT17 activity and that MPN-22 will decrease their activity resulting in an increase in activated CD4+ and CD8+ T cells. We further postulate that MPN-22 will potentiate the antitumor activity of immune checkpoint inhibitors (ICIs) to effectively decrease NSCLC growth. We propose to examine the effects of PFKFB4 inhibition with MPN-22 on Th17/γδT17 cell development and activity in vitro and additionally determine the effects of MPN-22 on immune cells and tumor progression and its efficacy in combination with ICIs in relevant oncogene-driven models of lung cancer. We anticipate that MPN-22 will significantly decrease the activity of immunosuppressive T cell subsets and increase the efficacy of ICIs in NSCLC. The ultimate goal of our studies is to develop an effective therapeutic strategy to successfully treat and improve outcomes in advanced NSCLC.