Overcoming Hypoxic Resistance in Non-Small Cell Lung Cancer By Targeting Mitochondrial Metabolism

通过靶向线粒体代谢克服非小细胞肺癌的缺氧抵抗

基本信息

批准号：
10275968
负责人：
Nicholas C. Denko
金额：
$ 65.04万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10275968
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 Prognostic Marker 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/antagonist innovation mRNA sequencing migration mitochondrial metabolism mutant neoplastic cell novel novel strategies phase I trial phosphoric diester hydrolase progenitor programs radiation resistance radiation response response standard of care theories tumor tumor DNA tumor hypoxia tumor microenvironment vascular bed

项目摘要

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.

项目概要许多团体正在调查为什么一些肺癌患者对放射疗法和免疫疗法反应良好，并且有些则不然。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肿瘤缺氧。这些治疗方式的有效性。临床研究已确定缺氧是一种独立的疾病患者预后不良的预后指标，但尽管这种联系已为人所知数十年，但还没有 FDA 批准的干预措施可以在临床上克服缺氧问题。一些研究人员试图提供更多向肿瘤提供氧气，但由于肿瘤脉管系统形成不良，这种方法仍然受到限制。我们我们采取了创新的方法，并询问我们是否可以减少需求，而不是增加供应，吸氧以减少缺氧。我们发现 FDA 批准的血管舒张药罂粟碱 (PPV) 有一个副作用：以低微摩尔浓度抑制线粒体复合物 1 并快速降低耗氧量的目标能力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效果将 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治疗难治性肿瘤对 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。