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

基本信息

批准号：
10665075
负责人：
Sucheta Telang
金额：
$ 21.51万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
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/10665075
关键词：
6-Phosphofructo-2-kinase 6-Phosphofructokinase Attenuated Biological Availability 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 Genes Genetic Transcription Glucose Glycolysis Goals Growth Hypoxia IL17 gene Immune Immune checkpoint inhibitor Immunosuppression Immunotherapeutic agent In Vitro Infiltration KRASG12D Knockout Mice Lung 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 Phosphotransferases Play Positron-Emission Tomography Production Proliferating Pyruvate Regulation Resistance Role T-Cell Activation T-Lymphocyte T-Lymphocyte Subsets TP53 gene Therapeutic Tumor Promotion United States advanced disease analog anti-PD-1 anti-PD1 antibodies blood glucose regulation cell growth clinically relevant directed differentiation effective therapy effector T cell efficacy evaluation fluorodeoxyglucose positron emission tomography glucose metabolism growth promoting activity immunoregulation improved outcome in vitro activity 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 synergism systemic toxicity targeted agent therapeutically effective tumor tumor growth tumor progression

项目摘要

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.

项目概要肺癌是世界上癌症相关死亡人数最多的疾病。癌症（NSCLC）占肺部肿瘤的大多数，这些肿瘤通常在晚期才被发现。当选择有限且生存状况不佳时，迫切需要有效的策略来改善结果。远离这种毁灭性的癌症。非小细胞肺癌普遍表现出高糖酵解率，以支持其快速生长和扩散，这是一个关键的速率限制。糖酵解途径中的步骤由 6-磷酸果糖-1-激酶 (PFK1) 催化。由 2,6-二磷酸果糖 (F26BP) - 由 6-磷酸果糖-2-激酶/2,6-二磷酸果糖酶产生在之前的研究中，我们发现 PFKFB4 酶在 PFKFB1-4 中高表达。 NSCLC 并确定了其在调节这些肿瘤的葡萄糖代谢和生长中的要求。我们开发了一种有效的新型 PFKFB4 小分子抑制剂 MPN-22，可选择性抑制在最近的研究中，我们发现 PFKFB4 可以降低 NSCLC 糖酵解和增殖以及肿瘤生长。发现免疫抑制性 Th17 和 γδT17 细胞表达 F26BP 和 PFKFB4，并且 MPN-22 对患有肺肿瘤的小鼠进行给药会降低这些细胞的频率和活性。 PFKFB4 是 Th17/γδT17 活性所必需的，MPN-22 会降低其活性，从而导致我们进一步推测 MPN-22 会增强抗肿瘤作用。我们建议检查免疫检查点抑制剂（ICIs）有效降低 NSCLC 生长的活性。 MPN-22 抑制 PFKFB4 对 Th17/γδT17 细胞体外发育和活性的影响另外还确定了 MPN-22 对免疫细胞和肿瘤进展的影响及其在治疗中的功效我们预计 MPN-22 将与相关致癌基因驱动的肺癌模型中的 ICI 相结合。显着降低免疫抑制性 T 细胞亚群的活性并提高 ICI 的疗效我们研究的最终目标是开发有效的治疗策略以成功治疗非小细胞肺癌。治疗和改善晚期非小细胞肺癌的预后。