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

开发 RUVBL1/2 抑制剂作为 NSCLC 的放射增敏剂和免疫刺激剂

基本信息

批准号：
10733863
负责人：
Esra Akbay
金额：
$ 55.14万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10733863
关键词：
ATP phosphohydrolase Affect Antibodies Antineoplastic Agents Biochemical Biological Assay Cancer Etiology Cancer Patient Cancer cell line Cells Cessation of life Chromatin Clinical Combined Modality Therapy DNA Damage DNA Double Strand Break DNA Repair DNA Repair Pathway DNA-PKcs DNA-dependent protein kinase Development Disease External Beam Radiation Therapy Genes Human Immune Immune checkpoint inhibitor Immune response Immunologic Stimulation Immunotherapy In Vitro In complete remission Ionizing radiation Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Microscopy Minority Modality Modeling Natural Immunity Non-Small-Cell Lung Carcinoma Nonhomologous DNA End Joining Normal Cell Normal tissue morphology Operative Surgical Procedures Oral Outcome PI-3-kinase-related kinase Pathway interactions Patients Pharmaceutical Preparations Platinum Proteins Pulmonary Fibrosis Radiation Radiation Toxicity Radiation therapy Radiation-Sensitizing Agents Radiosensitization Recurrence Research Research Personnel Resistance Resources Role Signal Transduction Site Specificity Structure of parenchyma of lung Systemic Therapy Testing Therapeutic Therapeutic Studies Toxic effect Treatment Efficacy Treatment-related toxicity Tumor Burden United States Woman Work acute toxicity anti-PD-1 anti-PD1 antibodies anti-cancer antitumor effect ataxia telangiectasia mutated protein cancer immunotherapy cancer therapy checkpoint inhibition chemotherapy cytotoxic drug development efficacy evaluation efficacy testing genetic variant immune cell infiltrate improved in vivo inhibitor lung cancer cell mRNA Expression men molecular targeted therapies mouse model new therapeutic target novel novel therapeutic intervention novel therapeutics precision medicine response synergism taxane timeline tumor

项目摘要

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.

肺癌是第二大常见恶性肿瘤，也是男性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%。局部和区域性非小细胞肺癌经常单独或联合使用外照射放射治疗。结合使用铂类药物和紫杉烷的手术和化疗。转移性非小细胞肺癌是通常采用全身疗法进行治疗，例如化疗、靶向分子疗法、免疫疗法检查点抑制剂单独或组合。化疗和靶向分子疗法不提供对转移性疾病的持久完全缓解，只有少数患有转移性疾病的患者才能实现免疫检查点抑制剂。此外，接受过治疗的局部和区域性 NSCLC 复发也很常见。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，但受到内在的限制修复 DNA 损伤并赋予 RT 抗性的细胞机制。因此，需要新的试剂克服 DNA 修复机制并增强放疗对 NSCLC 的治疗效果并增加免疫检查点抑制剂的反应率。我们建议抑制 ATP 酶 RUVBL1 和 RUVBL2 与口服抑制剂是一种有效的癌症选择性放射增敏策略，通过降低三个关键 DNA 损伤修复因子 DNA- 的蛋白质水平，有效阻断 DNA 修复途径 PKcs 和 ATM/AR，存在于 NSCLC 细胞中，但不在正常细胞中。由于这项独特的活动，我们预计 RUVBL1/2抑制剂将比特异性DNA-PKcs/ATM/AR更有效地增强IR的抗肿瘤作用体外和体内均具有较低的放射毒性。此外，我们认为 RUVBL1/2 抑制会引发免疫刺激，因此在治疗上将与 IR 和免疫检查点抑制剂产生协同作用。这个项目将 (1) 通过 RUVBL1/2 抑制确定放射增敏的功效、特异性和决定因素，(2) 表征单独 RUVBL1/2 抑制以及与放射组合的免疫刺激作用，以及 (3) 研究 RUVBL1/2 抑制与 IR 和免疫检查点抑制相结合的治疗潜力。如果我们的项目成功完成，它可能会为非小细胞肺癌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。