Diversity Supplement R01CA262388: Overcoming Hypoxic Resistance in Non-Small Cell Lung Cancer By Targeting Mitochondrial Metabolism

多样性补充剂 R01CA262388：通过靶向线粒体代谢克服非小细胞肺癌的缺氧抵抗

• 批准号: 10595436
• 负责人: Nicholas C. Denko
• 金额: $ 21.63万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-22 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10595436
• 关键词: Address; Antigens; Antioxidants; Blood; Blood Pressure; Blood Vessels; Cancer Model; Cancer Patient; Cell Line; Cell Respiration; Cell Transplantation; Cell model; Cells; Chemoresistance; Chronic; Clinical; Clinical Research; Clinical Treatment; Clinical Trials; Complex; DNA sequencing; Data; Data Set; Databases; Dependence; Dose; Drops; Effectiveness; Electron Transport; Engineering; Enrollment; Equilibrium; Erectile dysfunction; FDA approved; Future; Gastrointestinal tract structure; Gene Expression; Genes; Genetic; Genetic Transcription; Human; Hypoxia; Image; Immune; Immunocompetent; Immunophenotyping; Immunotherapy; Infiltration; Intervention; Intravenous infusion procedures; Lead; Lung; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of lung; Maximum Tolerated Dose; Metabolic; Metabolism; Mitochondria; Modality; Modeling; Mus; Muscle relaxants; Mutation; Neoplasm Transplantation; Non-Small-Cell Lung Carcinoma; Normal tissue morphology; Oncogenic; Outcome; Oxidative Phosphorylation; Oxygen; Oxygen Consumption; PD-1 blockade; Papaverine; Parents; Pathway interactions; Patient-Focused Outcomes; Patients; Perfusion; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacology; Phase I Clinical Trials; Phenotype; Physiology; Population; Pre-Clinical Model; Process; Radiation; Radiation therapy; Radio; Radioimmunotherapy; Refractory; Reporter; Research Personnel; Resistance; Safety; Side; Smooth Muscle; System; T-Cell Activation; T-Lymphocyte; Testing; The Cancer Genome Atlas; Theft; Therapeutic; Tumor Oxygenation; Tumor-infiltrating immune cells; Up-Regulation; Vascular resistance; Vasospasm; anti-PD-1; base; cancer therapy; chemoradiation; chemotherapy; design; driver mutation; exhaust; exhaustion; imaging study; immune checkpoint blockade; improved; in vitro testing; inhibitor; innovation; mRNA sequencing; migration; mitochondrial metabolism; mutant; neoplastic cell; novel; novel strategies; phase I trial; phosphoric diester hydrolase; progenitor; prognostic indicator; programs; radiation resistance; radiation response; response; standard of care; theories; treatment response; tumor; tumor DNA; tumor hypoxia; tumor microenvironment; vascular bed

PROJECT SUMMARY: Many groups are investigating why some lung cancer patients respond well to radio- and immuno-therapies and some do not. One variable is tumor hypoxia, and many groups have shown it can significantly inhibit the effectiveness to these therapeutic modalities. Clinical studies have identified hypoxia as an independent prognostic indicator of poor patient outcomes, but even though this connection has been known for decades, no FDA-approved intervention exists to clinically overcome hypoxia. Some investigators have tried to deliver more oxygen to the tumor, but this approach remains constrained due to the poorly formed tumor vasculature. We have taken an innovative approach and asked if we can reduce demand for, rather than increase supply of, oxygen to reduce hypoxia. We have found that the FDA-approved vasorelaxant papaverine (PPV) has an off- target ability to inhibit mitochondrial complex 1, and reduce oxygen consumption rapidly, in low micromolar concentrations in every cell line tested in vitro. We have also shown that PPV can enhance the effectiveness of radiation and immune checkpoint blockade (ICB) in preclinical models of lung and other cancers, without sensitizing well-oxygenated normal tissue. Reducing hypoxia reverses immune privilege, decreases terminally- exhausted T cells, and increases progenitors that are responsive to PD-1 blockade. We have more recently developed new derivatives of PPV that have lost their vasorelaxant capability and increased their duration of action so that they can be improved immuno-sensitizers. We now propose to test the hypothesis that PPV can effectively enhance the radio- and immuno-therapeutic treatment of preclinical models of lung cancer, and that it is feasible to add PPV to standard of care therapy for advanced non-small cell lung cancer (NSCLC). We have examined TCGA databases and found that lung cancer driver mutations in the KEAP1/NRF2 pathway lead to high levels of mitochondrial gene expression that can cause elevated oxygen metabolism contributing to hypoxia. In Aim 1, we will investigate the effects of oncogenic NRF2 activation human and murine cells and model tumors to determine the dependence of these cells on mitochondrial function, how increased oxygen metabolism contributes to tumor hypoxia, and if therapy-refractory tumors are sensitized by PPV or its derivatives. In Aim 2, we will examine the effect of tumor hypoxia on the migration and activation of T-cells in model tumors and how the immune infiltrate changes after reduction of hypoxia with PPV or its derivatives. Finally, in Aim 3 we will perform a phase 1 clinical trial to determine if the addition of PPV is feasible for patients receiving standard of care chemoradiation followed by immunotherapy for advanced NSCLC. We will look for effectiveness in changing tumor oxygenation using paired blood level oxygen determination (BOLD) MRIs, and for changes in immune populations of peripheral blood mononuclear cells. These studies will let us know if, and how, to use PPV or its novel derivatives in future clinical trials for the treatment of NSCLC.

项目摘要：许多团体正在调查为什么一些肺癌患者对放射和治疗反应良好 免疫疗法，有些则没有。其中一个变量是肿瘤缺氧，许多研究小组已经证明它可以 显着抑制这些治疗方式的有效性。临床研究已确定缺氧 患者预后不良的独立预后指标，但即使这种联系已为人所知 几十年来，FDA 批准的任何干预措施都无法在临床上克服缺氧。一些研究人员尝试过 向肿瘤输送更多氧气，但由于肿瘤形成不良，这种方法仍然受到限制 脉管系统。我们采取了创新的方法，询问是否可以减少而不是增加需求 供应氧气，减少缺氧。我们发现 FDA 批准的血管舒张剂罂粟碱 (PPV) 抑制线粒体复合物 1 的脱靶能力，并在低微摩尔浓度下快速降低耗氧量 体外测试的每个细胞系中的浓度。我们还表明，PPV 可以提高 肺癌和其他癌症临床前模型中的放射和免疫检查点阻断（ICB），无需 使氧合良好的正常组织敏感。减少缺氧会逆转免疫特权，最终降低- 耗尽 T 细胞，并增加对 PD-1 阻断做出反应的祖细胞。我们最近还有更多 开发了 PPV 的新衍生物，这些衍生物失去了血管舒张能力并增加了其持续时间 从而使它们成为提高免疫增敏剂的作用。我们现在建议检验 PPV 可以的假设 有效增强肺癌临床前模型的放射和免疫治疗 将 PPV 添加到晚期非小细胞肺癌 (NSCLC) 的标准护理治疗中是可行的。我们有 检查 TCGA 数据库，发现 KEAP1/NRF2 通路中的肺癌驱动突变导致 高水平的线粒体基因表达可能导致氧代谢升高，从而导致缺氧。 在目标 1 中，我们将研究致癌 NRF2 激活人类和小鼠细胞以及模型肿瘤的影响 确定这些细胞对线粒体功能的依赖性，如何增加氧代谢 如果难治性肿瘤对 PPV 或其衍生物敏感，则会导致肿瘤缺氧。在目标 2 中， 我们将研究肿瘤缺氧对模型肿瘤中 T 细胞迁移和激活的影响以及如何 用 PPV 或其衍生物减少缺氧后，免疫浸润发生变化。最后，在目标 3 中，我们将 进行 1 期临床试验，以确定添加 PPV 对于接受标准治疗的患者是否可行 对晚期非小细胞肺癌进行护理放化疗，然后进行免疫治疗。我们将寻求变革的有效性 使用配对血氧水平测定 (BOLD) MRI 进行肿瘤氧合，以及免疫变化 外周血单个核细胞群。这些研究将让我们知道是否以及如何使用 PPV 或其 未来治疗非小细胞肺癌临床试验中的新型衍生物。