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.

肺癌是两名男性中第二常见的恶性肿瘤，也是癌症相关死亡的主要原因美国的妇女和非小细胞肺癌（NSCLC）占所有病例的85％。局部和区域NSCLC经常单独使用外束放射疗法治疗结合使用基于铂的药物和紫杉烷的手术和化学疗法。转移性NSCLC是通常接受全身疗法，例如化学疗法，靶向分子疗法，免疫治疗单独或组合检查点抑制剂。化学疗法和靶向分子疗法不提供对转移性疾病的持久完全反应，只有在少数患者中才能实现免疫检查点抑制剂。同样，复发对于用局部和区域NSCLC治疗很常见放射疗法（RT）。 RT通过在NSCLC细胞中引起DNA损伤具有细胞毒性活性，但受固有的限制修复DNA损伤并赋予RT的耐药性的细胞机制。因此，需要新颖的代理商克服DNA修复机制并增强RT在NSCLC中的治疗功效并增加免疫检查点抑制剂的应答率。我们建议抑制ATPases Ruvbl1和带有口服抑制剂的RUVBL2是一种有效的癌症选择性策略，用于放射敏感性，通过降低三个关键DNA损伤修复因子的蛋白质水平，DNA-通过降低DNA修复途径有效地阻断DNA修复途径 NSCLC细胞中的PKC和ATM/AR，但在正常细胞中不在。由于这种独特的活动，我们期望与特定的DNA-PKC/ATM/AR相比体外和体内以及较少的放射性毒性。另外，我们建议RUVBL1/2抑制会引起免疫刺激，因此将与IR和免疫检查点抑制剂进行治疗协同。这个项目意志（1）确定Ruvbl1/2抑制作用的放射敏化的功效，特异性和决定因素，（2）表征RUVBL1/2抑制作用并与辐射结合的免疫刺激作用，（3）研究RUVBL1/2抑制与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，则可以为NSCLC制定新的治疗策略提供框架患者，可以改善这种难以治疗的疾病的临床结果。