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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.

肺癌是第二常见的恶性肿瘤，也是两名男性癌症相关死亡的主要原因