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: 8527743
• 负责人: Meredith A Morgan
• 金额: $ 28.56万
• 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/8527743
• 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; chemoradiation; 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.

描述（由申请人提供）：我们最近证明 Chk1 的小分子抑制剂可消除胰腺癌细胞中的 G2 检查点并抑制 HRR（同源重组修复）。重要的是，Chk1 抑制优先使 p53 突变肿瘤细胞敏感，K-Ras 突变也可能赋予 Chk1 抑制敏感性。 PARP 抑制剂已证明作为单一药物和放射增敏剂在具有其他 DNA 损伤修复缺陷的细胞中具有优先功效。因此，我们假设抑制 HRR（通过 Chk1 抑制剂 MK-8776）和 PARP1（通过奥拉帕尼）将选择性地使胰腺癌细胞对辐射敏感。我们工作的长期目标是通过选择性靶向 DNA 修复途径（结合放化疗）来改善胰腺癌（和其他 p53/K-Ras 突变肿瘤）患者的预后。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胰腺癌放化疗，并了解 Chk1 和 PARP1 抑制的致敏和肿瘤细胞选择性机制。在具体目标 1 中，我们将通过 Chk1 和 PARP1 抑制确定肿瘤细胞选择性和放射增敏机制。我们将测试这样的假设：Chk1 和 PARP1 的联合抑制通过选择性增加 p53 和 K-Ras 突变胰腺癌细胞中未修复的双链断裂来产生对 DNA 损伤（辐射和吉西他滨辐射）的协同敏化。我们将利用正常细胞以及同基因 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 抑制联合产生的放射增敏机制，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产生放射增敏作用，我们将选择性地操纵 MK-8776 对 HRR 与 G2 检查点的抑制作用。在具体目标 2 中，我们将测试这样的假设：Chk1 和 PARP1 联合抑制选择性地使 p53 和 K-Ras 突变型胰腺肿瘤异种移植物对辐射和吉西他滨辐射敏感，而对正常组织的敏感程度最低。我们将鉴定 p53 和 K-Ras 突变的患者来源的胰腺肿瘤，并确定 Chk1 和 PARP1 联合抑制对吉西他滨和放射敏感性的功效。为了了解与致敏相关的机制，我们将分析目标 1 中确定的关键 DNA 损伤反应蛋白。十二指肠毒性（胰腺照射的剂量限制毒性）将根据 Chk1 和 PARP1 抑制结合放射和吉西他滨进行评估-辐射。成功完成这些目标将通过提供新的治疗选择以及用于患者选择的生物标志物来影响胰腺癌患者的治疗。我们的业绩记录和研究团队使我们很有可能成功实现这些目标并将其转化为临床。