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

项目总结 许多组织正在调查为什么一些肺癌患者对放射和免疫治疗反应良好，并 有些人则不这么认为。其中一个变量是肿瘤缺氧，许多组织已经证明它可以显著抑制 这些治疗方式的有效性。临床研究已确认低氧是一种独立的 患者预后不良的指标，但即使这种联系几十年来就已为人所知， FDA批准的干预措施可以在临床上克服缺氧。一些调查人员试图提供更多 氧气进入肿瘤，但由于肿瘤血管形成不良，这种方法仍然受到限制。我们 采取了一种创新的方法，并询问我们是否可以减少对石油的需求，而不是增加供应， 吸氧以减少缺氧。我们发现FDA批准的血管松弛药罂粟碱(PPV)具有关闭- 靶向能力抑制线粒体复合体1，并迅速降低氧耗，在低微摩尔 在体外测试的每种细胞系中的浓度。我们还表明，PPV可以增强 放射和免疫检查点阻断(ICB)在临床前肺癌和其他癌症模型中的应用 使氧气充足的正常组织敏化。减少低氧会逆转免疫豁免权，最终降低- 耗尽T细胞，增加对PD-1阻断有反应的祖细胞。我们最近有了更多 开发了PPV的新衍生物，这些衍生物已经失去了血管松弛能力，并延长了它们的持续时间 行动，使他们可以改进免疫增敏剂。我们现在建议检验PPV可以 有效地加强对肺癌临床前模型的放射和免疫治疗， 在晚期非小细胞肺癌(NSCLC)的护理治疗中加入PPV是可行的。我们有 检查了TCGA数据库，发现肺癌驱动因素Keap1/NRF2途径突变导致 线粒体基因的高水平表达会导致氧代谢升高，从而导致缺氧。 在目标1中，我们将研究致癌基因nrf2激活的人和小鼠细胞和模型肿瘤的作用。 为了确定这些细胞对线粒体功能的依赖，如何增加氧代谢 导致肿瘤缺氧，如果治疗难治的肿瘤被PPV或其衍生物致敏。在目标2中， 我们将在模型肿瘤中研究肿瘤缺氧对T细胞迁移和激活的影响以及如何 PPV或其衍生物减少缺氧后免疫渗出的变化。最后，在目标3中，我们将 进行1期临床试验，以确定添加PPV对接受标准的 晚期非小细胞肺癌先进行CARE化疗，然后进行免疫治疗。我们将在变革中寻求实效 应用配对血氧测定(BOLD)磁共振成像进行肿瘤氧合，以及免疫功能的变化 外周血单核细胞的数量。这些研究将让我们知道是否以及如何使用PPV或其 用于治疗非小细胞肺癌的未来临床试验中的新衍生物。

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.