Targeting DNA damage response pathways for the treatment of advanced lung cancer

靶向 DNA 损伤反应途径治疗晚期肺癌

基本信息

批准号：
8776675
负责人：
MICHAEL L. FREEMAN
金额：
$ 22.49万
依托单位：
CUMBERLAND PHARMACEUTICALS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-22 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8776675
关键词：
Address Adenocarcinoma Analytical Chemistry Body Weight Cachexia Cancer Patient Cell Survival Cells Cessation of life Chemicals Chest Clinical Clinical Trials Coupled Curative Surgery DNA Damage DNA Double Strand Break DNA Repair DNA Repair Pathway Data Diagnosis Disease Dose Drug Formulations Effectiveness Exhibits Failure Fibrosis Future Goals Growth Human Intravenous Ionizing radiation Lesion Longevity Lung Malignant Neoplasms Malignant neoplasm of lung Measures Mediating Molecular Mus Mutation Non-Malignant Non-Small-Cell Lung Carcinoma Normal Cell Normal tissue morphology Outcome Pathway interactions Patients Pharmaceutical Preparations Pharmacologic Substance Phase Play Pre-Clinical Model Predisposition Primary Neoplasm Probability Proliferating Proteins Pulmonary Fibrosis Radiation Radiation Oncology Radiation Therapy Oncology Group Radiation therapy Radiation-Sensitizing Agents Radiobiology Radiosensitization Regimen Relative (related person)Research Respiratory physiology Role Severities Solvents Squamous cell carcinoma Staging Stress Structure of parenchyma of lung Survival Rate Synthesis Chemistry Therapeutic Time Toxic effect Treatment Protocols Universities analytical method cancer cell cancer radiation therapy coping effective therapy homologous recombination improved innovation irradiation mouse model neoplastic cell novel novel therapeutic intervention nucleophosmin product development programs public health relevance recombinational repair repaired respiratory imaging response safety study standard of care therapy outcome tumor tumor growth tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): There is an urgent, unmet need for novel therapeutic approaches that are efficacious against lung cancer. Ranking first among cancer deaths in the U.S., this disease has 5-year relative survival rates of <20%. Most lung cancers are non-small cell (NSCLC, 85% of cases). Curative surgery is not an option for the 80% of NSCLC patients who present with advanced stage III cancer. For these patients chemo/radiation therapy remains the standard of care, and presently there is no effective strategy to improve radiation therapy outcomes. The central innovative theme of the proposed research is: a newly identified chemical entity YTR107 sensitizes human tumor cells to the lethal effects of ionizing radiation. YTR107 is efficacious in genetically diverse tumor types because its novel intracellular target plays a key role in homologous recombination, a critical DNA repair pathway utilized by dividing cells, including proliferative tumor cells. Targeting a key component of the DNA damage response pathway used by proliferating tumor cells (not quiescent differentiated cells) is a promising, novel therapeutic approach for NSCLCs. Genetic changes in these tumors result in high levels of replication stress and endogenous DNA damage. Constant replication stress renders tumor cells less competent to cope with additional exogenous DNA damage inflicted by therapeutic ionizing radiation. Radiation therapy combined with YTR107 may be ideally used on NSCLCs because ionizing radiation inflicts potentially lethal DNA double strand breaks and because YTR107 interferes with repair of these breaks by interfering with homologous recombination. Our ultimate product is an intravenous formulation of YTR107 used in combination with patients' radiotherapy regimens to effectively control primary tumor growth without promoting normal tissue damage. This outcome is paramount for preserving lung function and decreasing both cachexia severity and the probability of metastatic disease. Phase I goals for this collaborative research program at Cumberland Pharmaceuticals and Vanderbilt University are to: (1) demonstrate that YTR107 is an efficacious radiosensitizing agent in preclinical models of human NSCLC and (2) evaluate normal tissue toxicity by assessing whether YTR107 increases susceptibility to radiation-induced pulmonary fibrosis. YTR107 will change the standard of care for radiotherapy patients and improve therapeutic outcomes for intractable lung cancers, namely improved tumor response to irradiation with minimal drug effects on normal tissues.

描述（由申请人提供）：对针对肺癌有效的新型治疗方法有一种紧急，未满足的需求。该疾病在美国的癌症死亡中排名第一，相对存活率<20％。大多数肺癌是非小细胞（NSCLC，占病例的85％）。对于患有晚期III期癌症的NSCLC患者中，有80％的NSCLC患者不能选择治疗手术。对于这些患者，化学/放射治疗仍然是护理的标准，目前尚无改善放射治疗结果的有效策略。拟议的研究的中心创新主题是：新鉴定的化学实体YTR107使人类肿瘤细胞对电离辐射的致命作用敏感。 YTR107在遗传多样的肿瘤类型中具有有效性，因为其新型细胞内靶标在同源重组中起关键作用，这是通过分裂细胞（包括增殖性肿瘤细胞）使用的关键DNA修复途径。针对通过增殖肿瘤细胞（而非静态分化细胞）使用的DNA损伤反应途径的关键成分是NSCLC的一种有希望的新型治疗方法。这些肿瘤的遗传变化导致高水平的复制应力和内源性DNA损伤。恒定复制应力使肿瘤细胞较少能够应对治疗电离辐射造成的其他外源性DNA损伤。与YTR107结合使用的辐射疗法可以在NSCLC上使用，因为电离辐射会造成潜在致命的DNA双链断裂，并且YTR107通过干扰同源重组来干扰这些断裂的修复。我们的最终产物是与患者放射疗法相结合的YTR107的静脉配方，可有效控制原发性肿瘤生长而不促进正常组织损伤。这种结果对于保留肺功能并降低了病虫病的严重程度和转移性疾病的概率至关重要。该协作研究计划的第一阶段目标在坎伯兰药品和范德比尔特大学（Vanderbilt University）进行：（1）证明YTR107是人NSCLC临床前模型中的一种有效的放射激素敏感剂，（2）通过评估YTR107是否会评估YTR107是否会增加易于启发性的肺脉冲纤维纤维纤维，以评估正常的组织毒性。 YTR107将改变放射疗法患者的护理标准，并改善顽固性肺癌的治疗结果，即改善了肿瘤对照射的反应，对正常组织的药物影响最小。