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

基本信息

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
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

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.

项目摘要：许多小组正在调查为什么某些肺癌患者对无线电和免疫治疗和有些没有。一个变量是肿瘤缺氧，许多组表明它可以显着抑制了这些治疗方式的有效性。临床研究已将缺氧确定为患者结果不佳的独立预后指标，但即使已知这种联系几十年来，没有FDA批准的干预措施来克服缺氧。一些调查人员试图为了向肿瘤输送更多的氧气，但是由于肿瘤形成较差，这种方法仍然受到限制脉管系统。我们采取了一种创新的方法，询问我们是否可以减少对需求，而不是增加氧气的供应减少缺氧。我们发现，FDA批准的血管毛磷脂（PPV）具有在低微摩尔中，抑制线粒体复合物1并迅速降低氧气消耗1的非目标能力在体外测试的每个细胞系中的浓度。我们还表明，PPV可以提高肺和其他癌症的临床前模型中的辐射和免疫检查点阻滞（ICB），没有敏化氧化良好的正常组织。减少缺氧会逆转免疫特权，降低终极耗尽的T细胞，并增加对PD-1阻滞有反应的祖细胞。我们最近有开发了PPV的新衍生物，这些衍生物已经失去了血管肌的能力并增加了其持续时间采取行动，以便可以改善免疫敏感器。现在，我们建议检验PPV可以的假设有效地增强了肺癌临床前模型的无线电治疗和免疫治疗，并为晚期非小细胞肺癌（NSCLC）的护理疗法添加PPV是可行的。我们有检查了TCGA数据库，发现KEAP1/NRF2途径中的肺癌驱动器突变导致高水平的线粒体基因表达会导致氧代谢升高，导致缺氧。在AIM 1中，我们将研究致癌NRF2激活人和鼠细胞的影响，并模拟肿瘤为了确定这些细胞对线粒体功能的依赖性，如何增加氧代谢有助于肿瘤缺氧，如果PPV或其衍生物对治疗 - 难治性肿瘤敏感。在AIM 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通过PPV或其衍生物减少缺氧后，免疫浸润变化。最后，在目标3中，我们将执行1期临床试验，以确定对接受标准的患者的添加是否可行护理化学疗法，然后进行晚期NSCLC的免疫疗法。我们将寻求改变的有效性使用配对的血液水平测定（BOLD）MRI和免疫变化的肿瘤氧合外周血单核细胞的种群。这些研究将使我们知道是否以及如何使用PPV或它 NSCLC治疗的未来临床试验中的新衍生物。