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）：卵巢癌的一线治疗包括与铂类药物 (Pt)（顺铂或卡铂）的联合治疗 (1)。成功治疗上皮性卵巢癌 (EOC) 的一个主要障碍是对铂基化疗药物的耐药性 (3)。即使在最初对治疗有反应的 EOC 中，大多数也会复发并且对 Pt 产生耐药性；由于二线疗法基本上无效，因此预后极差。提供 EOC 有效治疗的困难凸显了根据个体疾病的生物学特性制定治疗方案的重要性。我们对乳腺癌和卵巢癌同源重组 (HR)/BRCA 途径 (4;5) 以及这些癌症中 HR 常见改变的理解的最新进展，导致通过利用聚 ADP 核糖聚合酶 (PARP) 来靶向综合杀伤力的概念。虽然 PARP 抑制剂在 BRCA 突变癌症的单药研究中取得了一些成功，但 PARP 抑制剂与 Pt 疗法的联合治疗效果却相当差。 Pt 药物通过形成 Pt-DNA 加合物来发挥治疗作用，该加合物阻止 DNA 复制和转录。 Pt-DNA 加合物的修复会降低铂类治疗的功效并导致细胞耐药。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 缺陷的癌症中，靶向 NER 预计会对 Pt 治疗的敏感性产生重大影响。 BRCA1 或 2 的种系突变使女性容易患上 HRR 缺陷的遗传性乳腺癌和卵巢癌。因此，我们将提出这样的假设：可以利用针对 HRR 缺陷癌症中的小分子的 NER 途径的合成致死相互作用，并且当与顺铂组合时将提供更高的疗效和最小的毒性。顺铂治疗与 NER 抑制剂相结合，将根据 HRR 状态不同地改变不同细胞的修复能力。非癌性、HRR 熟练的细胞可以通过 HRR 修复或耐受顺铂损伤，因此与无法通过任一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，我们将采用最近发现的 NER 抑制剂，针对着色性干皮病 A 组蛋白 (XPA) 蛋白 (6) 和复制蛋白 A (RPA) (7-9)，以实现两个特定目标。目标 1 将开发和表征新型 XPA 蛋白抑制剂，并评估与顺铂联合在 HRR 充足和缺乏的人类卵巢癌和乳腺癌细胞培养模型中的疗效。然后，我们将确定 XPA 抑制与顺铂治疗联合对细胞毒性、DNA 损伤信号传导以及乳腺癌和卵巢癌细胞培养和异种移植模型中顺铂-DNA 损伤修复的影响。在目标 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、实现单药活性并在 BRCA1 缺陷型癌症中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，它们都降低了