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

• 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
• 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

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）：对有效治疗肺癌的新型治疗方法存在迫切的未满足的需求。在美国癌症死亡人数中排名第一，这种疾病的5年相对存活率<20%。大多数肺癌是非小细胞肺癌（NSCLC，85%的病例）。对于80%的晚期III期NSCLC患者，根治性手术不是一种选择。对于这些患者，化疗/放疗仍然是护理标准，目前还没有有效的策略来改善放疗结果。该研究的核心创新主题是：一种新发现的化学实体YTR 107使人类肿瘤细胞对电离辐射的致死效应敏感。YTR 107在遗传多样性肿瘤类型中是有效的，因为其新的细胞内靶点在同源重组中起关键作用，同源重组是分裂细胞（包括增殖性肿瘤细胞）利用的关键DNA修复途径。靶向增殖肿瘤细胞（而不是静止分化细胞）使用的DNA损伤反应途径的关键组分是NSCLC的一种有前途的新型治疗方法。这些肿瘤中的遗传变化导致高水平的复制应激和内源性DNA损伤。恒定的复制应激使肿瘤细胞不太有能力科普治疗性电离辐射造成的额外外源性DNA损伤。与YTR 107组合的放射疗法可以理想地用于NSCLC，因为电离辐射造成潜在致命的DNA双链断裂，并且因为YTR 107通过干扰同源重组而干扰这些断裂的修复。我们的最终产品是YTR 107的静脉制剂，与患者的放疗方案结合使用，以有效控制原发性肿瘤生长，而不会促进正常组织损伤。这一结果对于保护肺功能、降低恶病质严重程度和转移性疾病的可能性至关重要。坎伯兰制药公司和范德比尔特大学的这项合作研究计划的I期目标是：（1）证明YTR 107是人类NSCLC临床前模型中有效的放射增敏剂和（2）通过评估YTR 107是否增加对放射诱导的肺纤维化的易感性来评估正常组织毒性。YTR 107将改变放射治疗患者的护理标准，改善难治性肺癌的治疗效果，即改善肿瘤对放射的反应，同时对正常组织的药物作用最小。