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

肺癌是两人第二常见的恶性肿瘤，也是两人癌症相关死亡的主要原因。 在美国，非小细胞肺癌(NSCLC)约占所有病例的85%。 局部性和区域性非小细胞肺癌通常采用外照射治疗。 与手术和使用铂类药物和紫杉烷进行化疗相结合。转移性非小细胞肺癌是 通常采用全身治疗，如化疗、靶向分子治疗、免疫 检查点抑制剂单独或联合使用。化疗和靶向分子疗法不能提供 对转移性疾病的持久完全应答，这只能在少数患有 免疫检查点抑制剂。此外，局部和区域性非小细胞肺癌的复发也很常见。 放射治疗(RT)。RT通过引起非小细胞肺癌细胞DNA损伤而具有细胞毒活性，但受内源性限制 修复DNA损伤并赋予RT抵抗力的细胞机制。因此，需要新型的试剂。 为克服DNA修复机制，提高RT治疗非小细胞肺癌的疗效，增加 免疫检查点抑制剂的应答率。我们认为，对ATPase RUVBL1和 RUVBL2和口服抑制剂是一种有效的肿瘤选择性放射增敏策略， 通过降低三个关键的DNA损伤修复因子DNA-2的蛋白水平，有效阻断DNA修复途径 PKcs和ATM/AR在非小细胞肺癌细胞中表达，而在正常细胞中不表达。由于这一独特的活动，我们预计 RUVBL1/2抑制剂比特异性DNA-PKcs/ATM/AR更有效地增强IR的抗肿瘤作用 在体外和体内，并引起较小的辐射毒性。此外，我们认为RUVBL1/2抑制可诱导免疫 因此，它将与IR和免疫检查点抑制剂在治疗上产生协同作用。这个项目 将(1)通过抑制RUVBL1/2来确定放射增敏的有效性、特异性和决定因素，(2) 表征RUVBL1/2抑制单独和与辐射联合应用的免疫刺激作用，以及(3) 研究RUVBL1/2抑制联合IR和免疫检查点抑制的治疗潜力。 如果我们的项目成功完成，可能会为非小细胞肺癌的新治疗策略提供框架 这可能会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.