Development of a RUVBL1/2 Inhibitor as a Radiosensitizer and Immune Stimulator for NSCLC

肺癌是第二常见的恶性肿瘤，也是两人癌症相关死亡的主要原因 非小细胞肺癌（NSCLC）占所有病例的约85%。 局限性和区域性NSCLC通常单独或联合使用外照射放射治疗。 联合手术和使用铂类药物和紫杉烷类的化疗。转移性NSCLC是 通常用全身疗法如化学疗法、靶向分子疗法、免疫疗法或免疫疗法治疗。 检查点抑制剂单独或组合。化疗和靶向分子治疗不能提供 转移性疾病的持久完全缓解，仅在少数患有 免疫检查点抑制剂。此外，复发是常见的局部和区域性NSCLC治疗， 放射治疗（RT）。RT通过在NSCLC细胞中引起DNA损伤而具有细胞毒活性，但受到内在的 修复DNA损伤并赋予对RT抗性的细胞机制。因此，需要新的试剂 克服DNA修复机制，增强RT在NSCLC中的治疗效果， 免疫检查点抑制剂的反应率。我们认为，抑制ATP酶RUVBL 1和RUVBL 2的表达， RUVBL 2与口服抑制剂是一种有效的癌症选择性放射增敏策略， 通过降低三种关键DNA损伤修复因子的蛋白水平，有效地阻断DNA修复途径， PKcs和ATM/AR在NSCLC细胞中表达，而在正常细胞中不表达。由于这种独特的活动，我们预计， RUVBL 1/2抑制剂将比特异性DNA-PKcs/ATM/AR更有效地增强IR的抗肿瘤作用 且引起较少放射毒性。此外，我们还提出RUVBL 1/2抑制剂可增强免疫功能， 刺激，因此将与IR和免疫检查点抑制剂在治疗上协同作用。这个项目 将（1）通过RUVBL 1/2抑制确定放射增敏的疗效、特异性和决定因素，（2） 表征RUVBL 1/2抑制单独和与辐射组合的免疫刺激作用，和（3） 研究RUVBL 1/2抑制与IR和免疫检查点抑制组合的治疗潜力。 如果我们的项目成功完成，它可能为NSCLC的新治疗策略提供框架 患者，这可以改善这种难以治疗的疾病的临床结果。

Lung cancer is the second most common malignancy and the leading cause of cancer-related death in both men and women in the United States, and non-small cell lung cancer (NSCLC) accounts for ~85% of all cases. Localized and regional NSCLC are frequently treated with external beam radiation therapy alone or in combination with surgery and chemotherapy using platinum-based drugs and taxanes. Metastatic NSCLC is typically treated with systemic therapies such as chemotherapy, targeted molecular therapies, immune checkpoint inhibitors alone or in combination. Chemotherapy and targeted molecular therapies do not offer durable complete responses for metastatic disease, which can be achieved only in the minority of patients with immune checkpoint inhibitors. Also, recurrence is common for localized and regional NSCLC treated with radiation therapy (RT). RT has cytotoxic activity by causing DNA damage in NSCLC cells but is limited by intrinsic cellular mechanisms that repair DNA damage and confer resistance to RT. Thus, there is a need for novel agents to overcome DNA repair mechanisms and enhance the therapeutic efficacy of RT in NSCLC and increase the response rates for immune checkpoint inhibitors. We propose that the inhibition of the ATPases RUVBL1 and RUVBL2 with an orally available inhibitor is an effective and cancer-selective strategy for radiosensitization that efficiently blocks DNA repair pathways by reducing protein levels of three key DNA damage repair factors, DNA- PKcs and ATM/AR, in NSCLC cells but not in normal cells. Because of that unique activity, we expect that the RUVBL1/2 inhibitor will be more effectively enhance the antitumor effects of IR than specific DNA-PKcs/ATM/AR in vitro and in vivo and elicit less radiotoxicity. Also, we propose that the RUVBL1/2 inhibition elicits immune stimulation, and therefore will therapeutically synergize with IR and immune checkpoint inhibitors. This project will (1) determine the efficacy, specificity and determinants of radiosensitization by RUVBL1/2 inhibition, (2) characterize immune stimulatory effects of RUVBL1/2 inhibition alone and in combination with radiation, and (3) study the therapeutic potential of RUVBL1/2 inhibition in combination with IR and immune checkpoint inhibition. If our project is successfully completed, it may provide the framework for a new therapeutic strategy for NSCLC patients, which could improve clinical outcomes for this hard-to-treat disease.