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.
Public Health Relevance Statement: 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.
NIH Spending Category: Biotechnology; Cancer; Genetics; Lung; Lung Cancer; Orphan Drug; Ovarian Cancer; Rare Diseases
Project Terms: adduct; Animal Model; base; Binding (Molecular Function); Biochemical; Biological Assay; Biological Markers; Biology; cancer cell; cancer therapy; cancer type; Carboplatin; Cell Culture Techniques; Cells; Cessation of life; chemotherapy; Cisplatin; Clinical; Clinical Trials; Combined Modality Therapy; crosslink; Data; Development; Diagnosis; Disease; Disease remission; DNA Adducts; DNA Damage; DNA Double Strand Break; DNA lesion; DNA Repair; DNA-Protein Interaction; effective therapy; Effectiveness; enzyme substrate; Epithelial ovarian cancer; ERCC1 gene; Fluorescence; Gel; Genomic Instability; high throughput screening; homologous recombination; In Vitro; Individual; inhibitor/antagonist; Inhibitory Concentration 50; innovation; Killings; Lead; Libraries; Life; Liquid substance; Malignant neoplasm of lung; Malignant neoplasm of ovary; Malignant neoplasm of testis; Malignant Neoplasms; Manuals; men; Neoadjuvant Therapy; Newly Diagnosed; Non-Small-Cell Lung Carcinoma; Normal Cell; novel; nuclease; Nucleotide Excision Repair; Outcome; overexpression; Pathway interactions; Pharmaceutical Preparations; pharmacophore; Phase; Platinum; Platinum Compounds; Predictive Value; prognostic; Protein Inhibition; protein protein interaction; Proteins; public health medicine (field); Quality of life; recombinational repair; Recurrence; Reliance; Repair Enzymology; repaired; Reporting; Research; Resistance; response; Robotics; Screening procedure; Small Business Innovation Research Grant; small molecule; small molecule libraries; sobriety; Solid Neoplasm; standard of care; statistics; Structure; Structure-Activity Relationship; Substrate Interaction; Therapeutic; therapeutic target; Time; Toxic effect; Treatment Protocols; treatment strategy; tumor; Woman; Work
