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

描述(由申请人提供)：存在对肺癌有效的新的治疗方法的迫切而未得到满足的需求。在美国癌症死亡人数中排名第一，这种疾病的5年相对存活率为20%。大多数肺癌是非小细胞肺癌(NSCLC，85%的病例)。对于80%患有晚期III期癌症的非小细胞肺癌患者来说，根治性手术不是一个选择。对于这些患者来说，化疗/放射治疗仍然是治疗的标准，目前还没有有效的战略来改善放射治疗的结果。这项拟议研究的中心创新主题是：一种新发现的化学实体YTR107使人类肿瘤细胞对电离辐射的致命效应敏感。YTR107对不同遗传类型的肿瘤有效，因为其新的细胞内靶点在同源重组中发挥关键作用，同源重组是包括增殖肿瘤细胞在内的分裂细胞所利用的关键DNA修复途径。靶向增殖中的肿瘤细胞(而不是静止的分化细胞)所使用的DNA损伤反应通路的关键成分是治疗非小细胞肺癌的一种有前途的新方法。这些肿瘤中的基因变化导致高水平的复制应激和内源性DNA损伤。持续的复制压力使肿瘤细胞更不能应对治疗性电离辐射造成的额外外源DNA损伤。放射治疗联合YTR107可能是治疗非小细胞肺癌的理想方法，因为电离辐射会导致潜在的致命性DNA双链断裂，而且YTR107通过干扰同源重组来干扰这些断裂的修复。我们的最终产品是YTR107静脉制剂，与患者的放射治疗方案相结合，在不促进正常组织损伤的情况下有效控制原发肿瘤的生长。这一结果对于保护肺功能和降低恶病质的严重程度和转移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第一阶段目标是：(1)证明YTR107在人类NSCLC的临床前模型中是一种有效的放射增敏剂，以及(2)通过评估YTR107是否增加辐射引起的肺纤维化的敏感性来评估正常组织毒性。YTR107将改变放射治疗患者的护理标准，改善难治性肺癌的治疗结果，即在对正常组织的药物影响最小的情况下，提高肿瘤对放射的反应。

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.