Targeting nucleotide excision repair in combination cancer therapy

联合癌症治疗中的靶向核苷酸切除修复

• 批准号: 8652165
• 负责人: JOHN J. TURCHI
• 金额: $ 32.37万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8652165
• 关键词: A-Form DNA; Abbreviations; Address; Alleles; BRCA1 Mutation; BRCA1 gene; Binding; Biochemical; Biology; Cancerous; Carboplatin; Cell Culture Techniques; Cells; Chemicals; Cisplatin; Clinical; Combined Modality Therapy; Coupled; DNA Adducts; DNA Binding; DNA Binding Domain; DNA Damage; DNA Repair; DNA biosynthesis; Data; Defect; Disease; Drug Kinetics; Epithelial ovarian cancer; Estrogen receptor negative; Etoposide; Genetic Transcription; Germ-Line Mutation; Health; Hereditary Breast Carcinoma; High Pressure Liquid Chromatography; Human; Individual; Loss of Heterozygosity; Malignant Neoplasms; Malignant neoplasm of ovary; Mass Spectrum Analysis; Modeling; Nucleotide Excision Repair; Nucleotide Excision Repair Inhibition; Oligonucleotides; Oligosaccharides; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Platinum; Poly(ADP-ribose) Polymerases; Proteins; Regimen; Research; Resistance; Signal Transduction; Structure-Activity Relationship; Therapeutic Effect; Toxic effect; Treatment Protocols; Woman; Xenograft Model; Xeroderma Pigmentosum; base; cancer cell; cell type; chemotherapeutic agent; chemotherapy; combination cancer therapy; cytotoxicity; effective therapy; homologous recombination; inhibitor/antagonist; malignant breast neoplasm; mutant; novel; outcome forecast; progesterone receptor negative; recombinational repair; repaired; replication factor A; response; small molecule; success; tandem mass spectrometry

Abstract First line treatment of ovarian cancer includes combination therapy with a platinum drug (Pt), either cisplatin or carboplatin (1). A major impediment to the successful treatment of epithelial ovarian cancer (EOC) is resistance to Pt-based chemotherapeutic agents (3). Even in EOCs that initially respond to treatment, most will recur and will be Pt resistant; with an extremely poor prognosis as second line therapies are largely ineffective. The difficulties in providing effective treatment of EOC highlights the importance of tailoring therapies based on the biology of the individual disease. Recent advances in our understanding of the homologous recombination (HR)/BRCA pathway in breast and ovarian cancer (4;5) and the common alteration of HR in these cancers has led to targeting poly-ADP-ribose polymerase (PARP) by exploiting the concept of synthetic lethality. While PARP inhibitors have had some success in single agent studies in BRCA mutant cancers, combination of PARP inhibitors with Pt therapy has been considerably less effective. Pt agents impart their therapeutic effect by the formation of Pt-DNA adducts, which block DNA replication and transcription. Repair of Pt-DNA adducts reduces the efficacy of platinum-based treatment and contributes to cellular resistance. Importantly, repair of Pt-DNA damage is catalyzed by the PARP-independent pathways, nucleotide excision repair (NER) and homologous recombination repair (HRR). Thus, in HRR deficient cancers, targeting NER would be expected to have a significant impact on sensitivity to Pt therapy. Germ line mutations in BRCA1 or 2 predispose women to hereditary breast and ovarian cancer which are HRR deficient. Therefore we will address the hypothesis that synthetic lethal interactions can be exploited targeting the NER pathway with small molecules in HRR deficient cancers and, when combined with cisplatin will provide increased efficacy with minimal toxicity. Cisplatin treatment, in combination with an NER inhibitor, will differentially alter the repair capacity of different cells dependent on their HRR status. Non-cancerous, HRR proficient cells can repair or tolerate the cisplatin damage via HRR and thus will have reduced toxicity compared to the HRR deficient cancer cells which are unable to repair the cisplatin damage via either pathway. To address our hypothesis we will employ our recently discovered NER inhibitors targeting the xeroderma pigmentosum group A (XPA) protein (6) and replication protein A (RPA) (7-9) in two specific aims. Aim 1 will develop and characterize novel inhibitors of the XPA protein and assess efficacy in combination with cisplatin in cell culture models of HRR proficient and deficient human ovarian and breast cancers. We will then determine the impact of XPA inhibition in combination with cisplatin therapy on cytotoxicity, DNA damage signaling and repair of cisplatin-DNA damage in cell culture and xenograft models of breast and ovarian cancer. In aim 2 we will determine the mechanism by which small molecules targeting the RPA protein inhibit the RPA-DNA binding interaction, achieve single agent activity and synergize with cisplatin and etoposide in BRCA1 deficient cancers. Our previous data identified two classes of RPA inhibitors, both of which decrease

摘要