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：
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
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/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

项目摘要

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）：卵巢癌的第一线治疗包括与铂药（PT）的联合治疗，即顺铂或卡铂（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，大多数人也会复发并具有抗PT。由于二线疗法的预后极低，因此基本上无效。提供有效治疗的EOC的困难突出了基于个体疾病的生物学调整疗法的重要性。我们对乳腺癌和卵巢癌中同源重组（HR）/BRCA途径的了解的最新进展（4; 5）以及这些癌症中HR的共同改变导致靶向多-ADP-ribose聚合酶（PARP），通过利用合成溶解度的概念来实现多-ADP-ribose聚合酶（PARP）。尽管PARP抑制剂在BRCA突变癌中的单药研究中取得了一些成功，但PARP抑制剂与PT疗法的组合效果相当大得多。 PT代理通过形成PT-DNA加合物的形成，从而赋予其治疗作用，从而阻止DNA复制和转录。 PT-DNA加合物的修复可降低基于铂的治疗的功效，并有助于细胞耐药性。重要的是，PT-DNA损伤的修复是由PARP独立途径，核苷酸切除修复（NER）和同源重组修复（HRR）催化的。因此，在HRR不足的癌症中，预计靶向NER对PT治疗的敏感性有重大影响。 HRR缺乏HRR的BRCA1或2种妇女易感性女性的细菌系突变。因此，我们将解决以下假设：在HRR缺乏癌症中，可以利用与小分子靶向NER途径的合成致死相互作用，并且与顺铂相结合时，将提供最小的毒性疗效。顺铂治疗与NER抑制剂结合使用，将差异地改变不同细胞的修复能力，取决于其HRR状态。与HRR缺乏的癌细胞相比，非癌性HRR熟练的细胞可以通过HRR修复或耐受顺铂损伤，因此毒性将降低，而HRR缺乏的癌细胞无法通过任何一条途径来修复顺铂损伤。为了解决我们的假设，我们将在两个具体的目标中采用靶向靶向心胚层色素A组（XPA）蛋白（6）和复制蛋白A（RPA）（RPA）（7-9）的NER NER抑制剂。 AIM 1将开发并表征XPA蛋白的新型抑制剂，并评估与顺铂在HRR熟练和缺乏人类卵巢和乳腺癌的细胞培养模型中结合使用顺铂。然后，我们将确定XPA抑制作用与顺铂治疗对细胞毒性，DNA损伤信号传导以及顺铂DNA损伤的修复以及乳腺癌和卵巢癌的异种移植模型的影响。在AIM 2中，我们将确定针对RPA蛋白的小分子抑制RPA-DNA结合相互作用，实现单一药物活性并与顺铂和依托泊苷协同作用的机制。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