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 卵巢癌的一线治疗包括与铂类药物（Pt）的联合治疗，所述铂类药物为顺铂或顺铂。 卡铂（1）。上皮性卵巢癌（EOC）成功治疗的主要障碍是 对铂类化疗药物的耐药性（3）。即使在最初对治疗有反应的EOC中， 将复发，并将对铂耐药;预后极差，因为二线治疗主要是 无效。在为平机会提供有效治疗方面的困难，凸显了量体裁衣的重要性 基于个体疾病的生物学的疗法。最近我们对生物多样性认识的进展 乳腺癌和卵巢癌中的同源重组（HR）/BRCA通路（4;5）和常见的改变 HR在这些癌症中的作用已经导致通过利用以下概念靶向聚ADP核糖聚合酶（PARP）： 合成杀伤力虽然PARP抑制剂在BRCA突变体的单药研究中取得了一些成功， 在癌症中，PARP抑制剂与Pt疗法的组合的有效性显著降低。铂剂 通过形成Pt-DNA加合物来赋予它们的治疗效果，Pt-DNA加合物阻断DNA复制， 转录。Pt-DNA加合物的修复降低了铂类治疗的疗效，并有助于 细胞抵抗力重要的是，Pt-DNA损伤的修复由PARP非依赖性途径催化， 核苷酸切除修复（NER）和同源重组修复（HRR）。因此，在HRR不足时， 癌症，靶向NER将预期对Pt疗法的敏感性具有显著影响。种系 BRCA 1或2的突变使妇女易患HRR缺陷的遗传性乳腺癌和卵巢癌。 因此，我们将讨论这样的假设，即可以利用合成致死相互作用来靶向 NER途径与HRR缺陷型癌症中的小分子，当与顺铂联合使用时， 以最小的毒性提供增加的功效。顺铂治疗，与NER抑制剂组合， 将根据不同细胞的HRR状态不同地改变其修复能力。不是癌症， HRR熟练的细胞可以通过HRR修复或耐受顺铂损伤，因此将具有降低的毒性 与不能通过任一途径修复顺铂损伤的HRR缺陷癌细胞相比。 为了解决我们的假设，我们将采用我们最近发现的针对干皮病的NER抑制剂， 色素沉着症组A（XPA）蛋白（6）和复制蛋白A（RPA）（7-9）。目标1将 开发和表征XPA蛋白的新型抑制剂，并评估与顺铂联合使用的疗效 在HRR熟练和缺乏的人卵巢癌和乳腺癌的细胞培养模型中。然后我们将 确定XPA抑制与顺铂治疗组合对细胞毒性、DNA损伤 乳腺癌和卵巢癌细胞培养和异种移植模型中顺铂-DNA损伤的信号传导和修复 癌在目标2中，我们将确定靶向RPA蛋白的小分子抑制 RPA-DNA结合相互作用，实现了单一药剂活性，并与顺铂和依托泊苷在 BRCA 1缺陷型癌症我们以前的数据确定了两类RPA抑制剂，它们都降低了