Targeting the ERCC1/XPF nuclease for cancer therapy

描述(申请人提供)：铂类药物(铂)是实体肿瘤治疗中最常用的处方化疗药物，也是睾丸癌治疗方案的一部分。虽然铂治疗肺癌的一线疗法最初往往有效，但对铂的耐药性导致这种疾病仍然是男性和女性中最致命的癌症，夺走的生命比接下来的四种癌症的总和还要多。同样，一旦对铂治疗(铂)产生耐药性，上皮性卵巢癌(EOC)就会一致致命。 观察到的。为了解决这一持续而重大的临床问题，我们将探索铂治疗的机制，即诱导DNA损伤，以修复铂-DNA损伤为目标的新治疗策略。顺铂和卡铂均通过链内铂-DNA加合物的形成发挥化疗作用。这些加合物通过核苷酸切除修复(NER)途径修复，该途径依赖ERCC1/XPF核酸酶来切除铂损伤的DNA。PT治疗还会产生链间铂-DNA加合物，这些加合物被认为是通过DNA双链断裂/同源重组途径修复的。该途径还依赖于ERCC1/XPF核酸酶。ERCC1在肺癌中已被广泛研究，在许多临床试验中，ERCC1的表达与铂治疗的反应呈负相关，为靶向该核酸酶提供了临床和生物学验证的理由。在ERCC1阳性的癌症中抑制ERCC1/XPF可能在增强细胞对顺铂的敏感性方面非常有效，而在ERCC1低表达的癌症中ERCC1/XPF活性的进一步降低可能会增强顺铂的活性和更大的肿瘤杀伤力，最终影响总体生存。虽然，在没有铂治疗的情况下，XPF/ERCC1抑制对正常细胞的影响可能很小，但与铂治疗联合使用时，确实存在正常细胞毒性的可能性。然而，大量癌症对ERCC1过表达的依赖，以及癌症中潜在的合成致死作用与其他基因组不稳定机制的相互作用，支持了观察到毒性降低和增加铂治疗窗口的可能性。因此，我们将继续进行高通量筛选(HTS)的优化和实施，以确定ERCC1/XPF核酸酶活性的特异和有效抑制剂。将在二次化验和选定的铅分子中确认命中。这些研究的成功完成将支持SBIR的第二阶段应用，以进行先导化合物的开发，并评估化合物在细胞培养和非小细胞肺癌(NSCLC)动物模型中的活性，以降低ERCC1/XPF核酸酶活性，增强顺铂的有效性，并最终提高存活率。 公共卫生相关性：本申请中提出的研究与公共健康直接相关，因为我们正在开发治疗癌症的新疗法。这项工作的成功完成有可能对那些被诊断为癌症的人产生影响，他们将接受基于铂的治疗。对于那些被诊断为癌症的人来说，提供更有效的治疗方案对于提高总体存活率和生活质量至关重要。

DESCRIPTION (provided by applicant): Platinum based agents (Pt) are the most commonly prescribed chemotherapeutics used in the treatment of solid tumors and are part of the curative treatment regimen for testicular cancer. While front line Pt therapy for lung cancer is often initially effective, resistance to Pt contributes to this disease remaining the most deadly cancer in both men and women, claiming more lives than the next four cancer types combined. Similarly, epithelial ovarian cancer (EOC) is uniformly fatal once resistance to Pt therapy (Pt) is observed. To impact this continuing and significant clinical problem, we will exploit the mechanism of Pt-therapy, the induction of DNA damage, in a novel treatment strategy targeting repair of the platinum-DNA lesions. Both cisplatin and carboplatin impart their chemotherapeutic effect by the formation of intrastrand Pt-DNA adducts. These adducts are repaired by the nucleotide excision repair (NER) pathway which relies on the ERCC1/XPF nuclease to excise the Pt-damaged DNA. Pt therapy also generates interstrand Pt-DNA adducts which are thought to be repaired via a DNA double strand break/homologous recombination pathway. This pathway also relies on the ERCC1/XPF nuclease. ERCC1 has been extensively studied in lung cancer with expression inversely correlated with response to Pt therapy in numerous clinical trials providing the clinically and biologically validated rationales for targeting this nuclease. Inhibition of ERCC1/XPF in ERCC1 positive cancers is likely to be highly effective in sensitizing cells to cisplatin while the further reduction of ERCC1/XPF activity in ERCC1 low expression cancers holds the potential for enhanced activity of cisplatin and greater tumor killing to ultimately impact overall survival. While, the effect of XPF/ERCC1 inhibition on normal cells is likely to be minimal in the absence of Pt-treatment, the potential for normal cell toxicity in combination with Pt- therapy does exist. However, the reliance of a large number of cancers on overexpression of ERCC1 and potential synthetic lethal interactions in cancer with other mechanism of genome instability, support the possibility that reduced toxicity will be observed and an increase in the Pt therapeutic window can be achieved. Therefore, we will pursue the optimization and implementation of a high-throughput screen (HTS) to identify specific and potent inhibitors of ERCC1/XPF nuclease activity. Hits will be confirmed in secondary assays and lead molecules selected. Successful completion of these studies will support a phase II SBIR application to pursue lead compound development and assess compound activity in cell culture and animal models of non- small cell lung cancer (NSCLC) for the ability to reduce ERCC1/XPF nuclease activity, enhance cisplatin effectiveness and ultimately increase survival. PUBLIC HEALTH RELEVANCE: The research proposed in this application is directly relevant to public health in that we are developing novel therapies for the treatment of cancer. Successful completion of this work has the potential to impact those individuals diagnosed with cancer that will receive platinum-based therapy. Providing a more effective treatment regimen is essential to increase overall survival and enhance quality of life for those diagnosed with cancer.