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

探讨 PFKFB4 在肺癌免疫调节中的作用

• 批准号: 10512933
• 负责人: Sucheta Telang
• 金额: $ 18.29万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10512933
• 关键词: 6-Phosphofructo-2-kinase; 6-Phosphofructokinase; Attenuated; CD8-Positive T-Lymphocytes; CD8B1 gene; Cancer Etiology; Cells; Cessation of life; Data; Deoxyglucose; Development; Diagnosis; Disease; Enzymes; Evaluation; Exhibits; Family; Frequencies; Fructose; Fructose-2,6-bisphosphatase; Genetic Transcription; Glucose; Glycolysis; Goals; Growth; Hypoxia; IL17 gene; Immune; Immune checkpoint inhibitor; Immunosuppression; In Vitro; Interleukin-17; KRASG12D; Knock-out; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Modeling; Mus; Myeloid-derived suppressor cells; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Oncogenes; Oral; Outcome; Pathway interactions; Patients; Play; Positron-Emission Tomography; Production; Pyruvate; Regulation; Role; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; TP53 gene; Therapeutic; United States; advanced disease; analog; anti-PD-1; anti-PD1 antibodies; base; blood glucose regulation; cell growth; clinically relevant; directed differentiation; effective therapy; effector T cell; fluorodeoxyglucose positron emission tomography; glucose metabolism; growth promoting activity; immunoregulation; improved outcome; in vivo; inhibitor; lung cancer cell; mortality; neoplastic cell; normoxia; novel; novel therapeutic intervention; phase I trial; rapid growth; response; small molecule; small molecule inhibitor; systemic toxicity; therapeutically effective; tumor; tumor growth; tumor progression

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.

项目摘要 肺癌是世界上癌症相关死亡人数最多的原因。非小细胞肺 非小细胞肺癌（NSCLC）构成了大多数肺肿瘤。这些肿瘤通常在晚期被发现 当选择有限，生存率很低的时候迫切需要有效的战略来改善结果 从这场毁灭性的癌症中解脱出来 NSCLC普遍表现出高的糖酵解速率，以支持其快速生长和扩散。关键限速 糖酵解途径中的一个步骤由酶6-磷酸果糖-1-激酶（PFK 1）催化。PFK 1被激活 果糖-2，6-二磷酸（F2, 6 BP）-由6-磷酸果糖-2-激酶/果糖-2，6-二磷酸酶产生 酶家族（PFKFB 1 -4）。在以前的研究中，我们发现PFKFB 4酶在大肠杆菌中高度表达。 非小细胞肺癌并确定了其在调节这些肿瘤的葡萄糖代谢和生长方面的需求。 我们已经开发了一种有效的新型PFKFB 4小分子抑制剂MPN-22， PFKFB 4，并降低NSCLC糖酵解和增殖以及体内肿瘤生长。在最近的研究中， 发现免疫抑制性Th 17和γδT17细胞表达F26 BP和PFKFB 4，而MPN-22表达F26 BP和PFKFB 4。 在携带肺肿瘤的小鼠中给药降低了这些细胞的频率和活性。我们假设 PFKFB 4是Th 17/γδT17活性所必需的，而MPN-22将降低它们的活性，从而导致 活化的CD 4+和CD 8 + T细胞增加。我们进一步假设MPN-22将增强抗肿瘤活性。 免疫检查点抑制剂（ICI）的活性，以有效降低NSCLC生长。我们建议研究 用MPN-22抑制PFKFB 4对Th 17/γδT17细胞体外发育和活性的影响， 另外确定MPN-22对免疫细胞和肿瘤进展的作用以及其在免疫治疗中的功效。 在相关的癌基因驱动的肺癌模型中与ICI组合。我们预计MPN-22将 显著降低免疫抑制性T细胞亚群的活性，并增加ICIs在 NSCLC。我们研究的最终目标是开发一种有效的治疗策略， 治疗和改善晚期NSCLC的结局。