Selective Sensitization of Pancreatic Cancer to Therapy by Chk1 and PARP1 Inhibit

胰腺癌对 Chk1 和 PARP1 抑制疗法的选择性增敏

• 批准号: 8372495
• 负责人: Meredith A Morgan
• 金额: $ 30.32万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8372495
• 关键词: Address; Base Excision Repairs; Biological Markers; Cancer Patient; Cell Cycle; Cells; Checkpoint kinase 1; Clinic; Clinical Research; Clinical Trials; DNA Damage; DNA Double Strand Break; DNA Repair; DNA Repair Pathway; Defect; Dependence; Development; Dose-Limiting; Foundations; Future; Goals; Institution; Ionizing radiation; Knowledge; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Modeling; Mutation; Nonhomologous DNA End Joining; Normal Cell; Normal tissue morphology; Outcome; PARP inhibition; Pancreas; Pathway interactions; Patient Selection; Patients; Poly Adenosine Diphosphate Ribose; Poly(ADP-ribose) Polymerases; Proteins; Radiation; Radiation Induced DNA Damage; Radiation-Sensitizing Agents; Radiosensitization; Relative (related person); Research Personnel; Role; Survival Rate; Testing; Therapeutic; Toxic effect; Translating; Translations; Work; base; cancer cell; cell injury; gemcitabine; homologous recombination; improved; in vivo; inhibitor/antagonist; irradiation; mutant; neoplastic cell; pancreatic cancer cells; pancreatic neoplasm; pre-clinical; recombinational repair; response; small molecule; tumor; tumor growth; tumor xenograft

DESCRIPTION (provided by applicant): We have recently shown that small molecule inhibitors of Chk1 abrogate the G2 checkpoint and inhibit HRR (homologous recombination repair) in pancreatic cancer cells. Importantly, Chk1 inhibition preferentially sensitizes p53-mutant tumor cells and K-Ras mutation may also confer sensitivity to Chk1 inhibition. PARP inhibitors have demonstrated preferential efficacy as single agents and as radiosensitizers in cells with other DNA damage repair defects. Thus, we hypothesize that inhibition of HRR (by the Chk1 inhibitor MK-8776) and PARP1 (by olaparib) will selectively sensitize pancreatic cancer cells to radiation. The long-term goal of our work is to improve the outcome of patients with pancreatic cancer (and other p53/K- Ras -mutant tumors) by selectively targeting DNA repair pathways (in combination with chemoradiation). The goals of this application are to combine inhibitors of DNA damage response pathways in order to improve gemcitabine-based chemoradiotherapy for pancreatic cancer as well as to understand the mechanisms of sensitization and tumor cell selectivity by Chk1 and PARP1 inhibition. In Specific Aim 1 we will determine the mechanisms of tumor cell selectivity and radiosensitization by Chk1 and PARP1 inhibition. We will test the hypothesis that combined inhibition of Chk1 and PARP1 produce synergistic sensitization to DNA damage (radiation and gemcitabine-radiation) by increasing unrepaired double strand breaks selectively in p53- and K-Ras mutant pancreatic cancer cells. We will utilize normal cells as well as isogenic p53 and K-Ras cancer cells to determine the roles of p53 and K-Ras in selectivity. To address the mechanisms of radiosensitization in response to the combination of Chk1 and PARP1 inhibition in cancer cells, we will assess DNA damage, DNA damage responses, and HRR. To determine how Chk1 and PARP1 inhibitors interact to produce radiosensitization we will selectively manipulate the inhibitory effects of MK-8776 on HRR versus the G2 checkpoint. In Specific Aim 2 we will test the hypothesis that combined Chk1 and PARP1 inhibition selectively sensitize p53 and K-Ras mutant pancreatic tumor xenografts to radiation and gemcitabine-radiation with minimal normal tissue sensitization. We will identify p53 and K- Ras -mutant patient-derived pancreatic tumors and determine the efficacy of combined Chk1 and PARP1 inhibition on sensitization to gemcitabine and radiation. To understand the mechanisms associated with sensitization, we will analyze key DNA damage response proteins identified in Aim 1. Duodenal toxicity, the dose limiting toxicity for irradiation of the pancreas, will be assessed in response to Chk1 and PARP1 inhibition in combination with radiation and gemcitabine-radiation. Successful completion of these aims will IMPACT therapy for patients with pancreatic cancer by providing new therapy options as well as biomarkers for patient selection. Our track record and team of investigators make it highly likely that we will succeed in the completion of these aims and their translation to the clinic. PUBLIC HEALTH RELEVANCE: The long-term goal of our work is to improve the outcome of patients with pancreatic cancer by selectively targeting DNA repair pathways (in combination with chemoradiation). The goals of this application are to combine inhibitors of DNA damage response pathways in order to improve gemcitabine-based chemoradiotherapy for pancreatic cancer as well as to understand the mechanisms of sensitization and tumor cell selectivity by Chk1 and PARP1 inhibition. Successful completion of this project will IMPACT therapy for patients with pancreatic cancer by providing new therapy options as well as biomarkers for patient selection.

描述（由申请人提供）：我们最近表明，CHK1的小分子抑制剂消除了G2检查点并抑制胰腺癌细胞中的HRR（同源重组修复）。重要的是，CHK1抑制优先敏感p53突变肿瘤细胞，而K-RAS突变也可能赋予对CHK1抑制的敏感性。 PARP抑制剂已显示出具有其他DNA损伤修复缺陷的细胞中的单个药物和放射敏剂的优先效力。因此，我们假设对HRR的抑制（通过CHK1抑制剂MK-8776）和PARP1（由Olaparib）将有选择地使胰腺癌细胞敏感到辐射。我们工作的长期目标是通过选择性靶向DNA修复途径（结合化学放疗），改善胰腺癌患者（和其他p53/k-ras肿瘤）的结果。该应用的目标是结合DNA损伤反应途径的抑制剂，以改善基于吉西他滨的化学放射疗法对胰腺癌的化学疗法，并了解CHK1和PARP1抑制的敏化机制和肿瘤细胞的选择性。在特定目标1中，我们将确定CHK1和PARP1抑制作用的肿瘤细胞选择性和放射敏化的机制。我们将检验以下假设，即CHK1和PARP1结合的抑制作用通过在P53和K-RAS突变型胰腺癌细胞中选择性地增加未经修复的双链断裂，从而对DNA损伤（辐射和吉西他滨放射）产生协同敏感性。我们将利用正常细胞以及等源性p53和K-RAS癌细胞来确定p53和k-Ras在选择性中的作用。为了解决癌细胞中CHK1和PARP1抑制的响应的放射激素化的机理，我们将评估DNA损伤，DNA损伤反应和HRR。为了确定CHK1和PARP1抑制剂如何相互作用以产生放射敏化，我们将选择性地操纵MK-8776对HRR对HRR与G2检查点的抑制作用。在特定的目标2中，我们将测试以下假设：CHK1和PARP1抑制选择性地敏化p53和K-RAS突变体胰腺肿瘤异种移植物与辐射和吉西他滨辐射的辐射和吉西他滨辐射具有最小的正常组织敏化。我们将确定p53和K-RAS的患者衍生的胰腺肿瘤，并确定CHK1和PARP1抑制对吉西他滨和辐射的敏化的功效。为了了解与敏化相关的机制，我们将分析AIM 1中确定的关键DNA损伤反应蛋白。十二指肠毒性，限制胰腺照射的剂量限制毒性，将对CHK1和PARP1抑制在与辐射和吉西甲甲苯甲甲苯性甲苯性甲苯性；；这些目标的成功完成将通过提供新的治疗选择以及用于选择患者的生物标志物来影响胰腺癌患者的治疗。我们的往绩记录和调查人员团队使我们很有可能在完成这些目标及其转化为诊所的完成中取得成功。 公共卫生相关性：我们工作的长期目标是通过选择性靶向DNA修复途径（结合化学放疗）来改善胰腺癌患者的结果。该应用的目标是结合DNA损伤反应途径的抑制剂，以改善基于吉西他滨的化学放射疗法对胰腺癌的化学疗法，并了解CHK1和PARP1抑制的敏化机制和肿瘤细胞的选择性。该项目的成功完成将通过提供新的治疗选择以及用于选择患者的生物标志物来影响胰腺癌患者的治疗。