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(铂)的联合治疗，顺铂或 卡铂(1)。上皮性卵巢癌(EOC)治疗成功的一个主要障碍是 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，大多数 将复发并对铂耐药；预后极差，因为二线治疗在很大程度上 效果不佳。为EOC提供有效治疗的困难凸显了量体裁衣的重要性 基于个体疾病生物学的治疗方法。我们对生物多样性研究的最新进展 乳腺癌和卵巢癌(4；5)中同源重组(HR)/BRCA通路及其共同改变 在这些癌症中HR的研究已经导致靶向多聚ADP核糖聚合酶(PARP)，通过利用 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 在癌症方面，PARP抑制剂与铂疗法的联合治疗效果要差得多。PT药剂 通过形成铂-DNA加合物来传递其治疗效果，该加合物可以阻止DNA复制和 抄写。铂-DNA加合物的修复降低了基于铂的治疗的疗效，并有助于 细胞阻力。重要的是，铂-DNA损伤的修复是由PARP不依赖的途径催化的， 核苷酸切除修复(NER)和同源重组修复(HRR)。因此，在HRR不足的情况下 靶向NER的癌症有望对铂治疗的敏感性产生重大影响。胚种系 BRCA1或2的突变使女性易患遗传性乳腺癌和卵巢癌，这是HRR缺乏的。 因此，我们将解决这样的假设，即合成致命相互作用可以针对 HRR缺陷性肿瘤中小分子的NER通路，当与顺铂联合使用时，将 以最小的毒性提供更高的疗效。顺铂联合NER抑制剂治疗， 将根据不同细胞的HRR状态而不同地改变其修复能力。非癌性， Hrr熟练细胞可以通过hrr修复或耐受顺铂损伤，从而降低毒性。 与HRR缺陷的癌细胞相比，HRR缺陷的癌细胞无法通过这两种途径中的任何一种修复顺铂损伤。 为了解决我们的假设，我们将使用我们最近发现的针对干皮病的NER抑制剂。 色素A组(XPA)蛋白(6)和复制蛋白A(RPA)(7-9)在两个特定的目的。目标1将 新型XPA蛋白抑制剂的开发和表征及其与顺铂联合应用的疗效评价 在HRR熟练和缺乏人卵巢癌和乳腺癌的细胞培养模型中。到时候我们会的 确定XPA抑制联合顺铂治疗对细胞毒性、DNA损伤的影响 顺铂-DNA损伤在乳腺和卵巢细胞培养及异种移植模型中的信号转导和修复 癌症。在目标2中，我们将确定靶向RPA蛋白的小分子抑制的机制 RPA与DNA的结合作用，实现单药活性，并与顺铂和足叶乙苷协同作用 BRCA1缺陷型癌症。我们之前的数据确定了两类RPA抑制剂，这两种抑制剂都会降低