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

基本信息

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
项目类别：
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

项目摘要

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

抽象的卵巢癌的第一线治疗包括与铂药（PT），顺铂或卡铂（1）。成功治疗上皮卵巢癌（EOC）的主要障碍是对基于PT的化学治疗剂的抗性（3）。即使在最初对治疗作出反应的EOC中，大多数将复发并具有抗PT；由于二线疗法的预后极差很差无效。提供有效治疗的EOC的困难突出了裁缝的重要性基于个体疾病的生物学的疗法。我们对理解的最新进展乳腺癌和卵巢癌的同源重组（HR）/BRCA途径（4; 5）和共同改变这些癌症中HR的人力资源已通过利用概念来靶向多ADP-核糖聚合酶（PARP）综合致死性。虽然PARP抑制剂在BRCA突变体的单一药物研究中取得了一些成功癌症，PARP抑制剂与PT疗法的结合的效果大大降低。 PT代理通过形成PT-DNA加合物来赋予其治疗作用，从而阻止DNA复制和转录。 PT-DNA加合物的修复会降低基于铂的治疗的功效，并有助于细胞阻力。重要的是，PT-DNA损伤的修复是由PARP独立途径催化的，核苷酸切除修复（NER）和同源重组修复（HRR）。因此，在HRR缺乏预计靶向NER对PT治疗的敏感性有重大影响。细菌系 BRCA1或2种妇女的突变患有遗传性乳腺癌和HRR缺乏的卵巢癌。因此，我们将解决以下假设，即可以利用合成致命相互作用来瞄准 HRR缺乏癌症中的小分子的NER途径，与顺铂结合使用通过最小的毒性提供了提高的功效。顺铂治疗，结合NER抑制剂，将差异地改变不同细胞的修复能力，取决于其HRR状态。非癌性 HRR熟练的细胞可以通过HRR修复或耐受顺铂损伤，从而降低毒性与无法通过任何一条途径修复顺铂损伤的HRR缺乏的癌细胞相比。为了解决我们的假设色素A组A（XPA）蛋白（6）和复制蛋白A（RPA）（7-9）在两个具体目标中。目标1意志开发和表征XPA蛋白的新型抑制剂，并评估疗效与顺铂结合在HRR的细胞培养模型中，熟练且缺乏人类卵巢癌和乳腺癌。然后我们会确定XPA抑制与顺铂治疗对细胞毒性，DNA损伤的影响在细胞培养和乳房的异种移植模型中以顺铂DNA损伤的信号传导和修复癌症。在AIM 2中，我们将确定针对RPA蛋白的小分子抑制的机制 RPA-DNA结合相互作用，实现单一药物活性并与顺铂协同和依托泊苷协同作用 BRCA1不足的癌症。我们以前的数据确定了两类的RPA抑制剂，这两种抑制剂均降低