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

项目总结 肺癌是世界上与癌症相关的死亡人数最多的疾病。非小细胞肺 非小细胞肺癌(NSCLC)是肺癌的主要类型。这些肿瘤通常在晚期被发现。 当选择有限，生存困难的时候。迫切需要有效的战略来改善结果 从这种毁灭性的癌症中。 非小细胞肺癌普遍表现出较高的糖酵解率以支持其快速生长和扩散。一个关键的速率限制 糖酵解途径中的步骤是由6-磷酸果糖-1-激酶(PFK1)催化的。激活了PFK1 由6-phosphofructo-2-kinase/fructose-2，6-bisphosphatase生产的果糖-2，6-二磷酸(F26BP) 酶家族(PFKFB1-4)。在以前的研究中，我们发现PFKFB4酶在 NSCLCs，并确定了其在调节这些肿瘤中的葡萄糖代谢和生长方面的要求。 我们开发了一种有效的新型PFKFB4小分子抑制剂MPN-22，它可以选择性地抑制 PFKFB4，并抑制非小细胞肺癌体内糖酵解、增殖和肿瘤生长。在最近的研究中，我们已经 发现免疫抑制的Th17和γδT17细胞表达F26BP和PFKFB4，而MPN-22 在带肺肿瘤的小鼠身上给药会降低这些细胞的频率和活性。我们假设 PfKFB4是Th17/γδT17活性所必需的，而MPN-22会降低它们的活性，导致 活化的CD4+和CD8+T细胞增多。我们进一步推测MPN-22将增强其抗肿瘤作用。 免疫检查点抑制物(ICIS)的活性可有效抑制非小细胞肺癌的生长。我们建议研究 MPN-22抑制pFKFB4对Th17/γδT17细胞体外生长及活性的影响 另外，确定MPN-22对免疫细胞和肿瘤进展的影响及其在 联合ICIS在相关癌基因驱动的肺癌模型中的应用。我们预计MPN-22将 显著降低免疫抑制T细胞亚群的活性，提高ICIS的疗效 非小细胞肺癌。我们研究的最终目标是开发一种有效的治疗策略，以成功 治疗和改善晚期非小细胞肺癌的预后。

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.