Targeting the ERCC1/XPF nuclease for cancer therapy

靶向 ERCC1/XPF 核酸酶进行癌症治疗

• 批准号: 8454969
• 负责人: Robert Feltgen
• 金额: $ 29.99万
• 依托单位: NERX BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-26 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8454969
• 关键词: Animal Model; Binding; Biochemical; Biological Assay; Biological Markers; Biology; Carboplatin; Cell Culture Techniques; Cells; Cessation of life; Cisplatin; Clinical; Clinical Trials; Combined Modality Therapy; DNA Adducts; DNA Damage; DNA Double Strand Break; DNA Repair; DNA lesion; DNA-Protein Interaction; Data; Development; Diagnosis; Disease; Disease remission; ERCC1 gene; Effectiveness; Epithelial ovarian cancer; Fluorescence; Gel; Genomic Instability; In Vitro; Individual; Inhibitory Concentration 50; Lead; Libraries; Life; Liquid substance; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of ovary; Malignant neoplasm of testis; Manuals; Neoadjuvant Therapy; Newly Diagnosed; Non-Small-Cell Lung Carcinoma; Normal Cell; Nucleotide Excision Repair; Outcome; Pathway interactions; Pharmaceutical Preparations; Phase; Platinum; Platinum Compounds; Predictive Value; Protein Inhibition; Proteins; Public Health; Quality of life; Recurrence; Reliance; Repair Enzymology; Reporting; Research; Resistance; Robotics; Screening procedure; Small Business Innovation Research Grant; Solid Neoplasm; Structure; Structure-Activity Relationship; Substrate Interaction; Therapeutic; Time; Toxic effect; Treatment Protocols; Woman; Work; adduct; base; cancer cell; cancer therapy; cancer type; chemotherapy; crosslink; effective therapy; enzyme substrate; high throughput screening; homologous recombination; inhibitor/antagonist; innovation; killings; men; novel; nuclease; overexpression; pharmacophore; prognostic; protein protein interaction; recombinational repair; repaired; response; small molecule; small molecule libraries; sobriety; standard of care; statistics; therapeutic target; treatment strategy; tumor

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.

描述（由申请方提供）：铂类药物（Pt）是实体瘤治疗中最常用的处方化疗药物，是睾丸癌治愈性治疗方案的一部分。虽然肺癌的一线铂治疗最初通常是有效的，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，夺去的生命比接下来的四种癌症类型的总和还要多。类似地，一旦对铂治疗（Pt）的耐药性消失，上皮性卵巢癌（EOC）是一致致命的。 观察为了影响这一持续和重要的临床问题，我们将利用铂治疗的机制，诱导DNA损伤，在一种新的治疗策略，靶向修复铂-DNA病变。顺铂和卡铂都通过形成链内Pt-DNA加合物来赋予其化疗作用。这些加合物通过核苷酸切除修复（NER）途径修复，该途径依赖于ERCC 1/XPF核酸酶切除Pt损伤的DNA。铂疗法还产生链间Pt-DNA加合物，其被认为通过DNA双链断裂/同源重组途径修复。该途径还依赖于ERCC 1/XPF核酸酶。ERCC 1已在肺癌中进行了广泛研究，在许多临床试验中，ERCC 1的表达与对Pt治疗的反应呈负相关，为靶向这种核酸酶提供了临床和生物学验证的依据。在ERCC 1阳性癌症中抑制ERCC 1/XPF可能在使细胞对顺铂敏感方面非常有效，而在ERCC 1低表达癌症中ERCC 1/XPF活性的进一步降低具有增强顺铂活性和更大肿瘤杀伤的潜力，从而最终影响总生存期。虽然在没有Pt治疗的情况下，XPF/ERCC 1抑制对正常细胞的影响可能是最小的，但与Pt治疗组合确实存在正常细胞毒性的可能性。然而，大量癌症对ERCC 1过表达的依赖以及癌症中与其他基因组不稳定机制的潜在合成致死相互作用，支持了观察到毒性降低并可以实现Pt治疗窗口增加的可能性。因此，我们将追求高通量筛选（HTS）的优化和实施，以鉴定ERCC 1/XPF核酸酶活性的特异性和有效的抑制剂。将在二次试验中确认命中，并选择先导分子。这些研究的成功完成将支持II期SBIR应用，以追求先导化合物开发并评估化合物在非小细胞肺癌（NSCLC）的细胞培养物和动物模型中的活性，以降低ERCC 1/XPF核酸酶活性、增强顺铂有效性并最终增加存活率。 公共卫生相关性：本申请中提出的研究与公共卫生直接相关，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影响那些被诊断患有癌症的人，他们将接受铂类药物治疗。提供更有效的治疗方案对于提高癌症患者的总体生存率和生活质量至关重要。