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: 8743197
• 负责人: JOHN J. TURCHI
• 金额: $ 31.4万
• 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/8743197
• 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

DESCRIPTION (provided by applicant): 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

描述（由申请人提供）：卵巢癌的一线治疗包括与铂类药物（Pt）联合治疗，顺铂或卡铂(1)。成功治疗上皮性卵巢癌（EOC）的主要障碍是对基于pt的化疗药物的耐药性(3)。即使在最初对治疗有反应的eoc中，大多数也会复发并对铂耐药；由于二线治疗大多无效，预后极差。提供有效治疗EOC的困难突出了基于个体疾病生物学的定制治疗的重要性。我们对乳腺癌和卵巢癌的同源重组(HR)/BRCA通路的最新了解（4;5）以及这些癌症中常见的HR改变导致了通过利用合成致死的概念靶向聚adp核糖聚合酶（PARP）。虽然PARP抑制剂在BRCA突变型癌症的单药研究中取得了一些成功，但PARP抑制剂与Pt治疗的联合效果明显不佳。Pt药物通过形成Pt-DNA加合物来发挥其治疗作用，Pt-DNA加合物阻断DNA复制和转录。Pt-DNA加合物的修复降低了铂基治疗的疗效，并导致细胞耐药。重要的是，Pt-DNA损伤的修复是由parp独立通路、核苷酸切除修复（NER）和同源重组修复（HRR）催化的。因此，在HRR缺乏的癌症中，靶向NER有望对Pt治疗的敏感性产生重大影响。BRCA1或2的种系突变使女性易患HRR缺乏的遗传性乳腺癌和卵巢癌。因此，我们将提出这样一个假设，即在HRR缺乏的癌症中，可以利用小分子靶向NER通路的合成致命相互作用，当与顺铂联合使用时，将以最小的毒性提供更高的疗效。顺铂治疗与一种内源性神经内酯抑制剂联合使用，会根据不同细胞的HRR状态不同地改变其修复能力。非癌性、HRR熟练的细胞可以通过HRR修复或耐受顺铂损伤，因此与无法通过任何途径修复顺铂损伤的HRR缺陷癌细胞相比，其毒性降低。为了解决我们的假设，我们将使用我们最近发现的NER抑制剂，靶向着色性干皮病A （XPA）蛋白(6)和复制蛋白A (RPA)(7-9)，用于两个特定目的。目的1将开发和表征XPA蛋白的新型抑制剂，并在HRR熟练和缺乏的人类卵巢癌和乳腺癌细胞培养模型中评估与顺铂联合使用的疗效。然后，我们将在乳腺癌和卵巢癌细胞培养和异种移植模型中确定XPA抑制联合顺铂治疗对细胞毒性、DNA损伤信号传导和顺铂-DNA损伤修复的影响。在目标2中，我们将确定靶向RPA蛋白的小分子在BRCA1缺陷癌症中抑制RPA- dna结合相互作用，实现单药活性并与顺铂和依托泊苷协同作用的机制。我们之前的数据确定了两类RPA抑制剂，两者都降低