Inhibition of Recombination DNA Repair in Pancreatic Cancer Cells

抑制胰腺癌细胞中的重组 DNA 修复

• 批准号: 7455107
• 负责人: Philip P Connell
• 金额: $ 21.49万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7455107
• 关键词: Biological Assay; Cancer Etiology; Cells; Cessation of life; Clinical Trials; DNA Damage; DNA Repair; Data; Data Analyses; Development; Filament; Goals; Grant; Human; In Vitro; Inhibitory Concentration 50; Libraries; Liquid substance; Malignant neoplasm of pancreas; Outcome; Patients; Pharmaceutical Preparations; Progress Reports; Proteins; Rad51 recombinase; Radiation therapy; Research; Resistance; Robotics; Screening procedure; Single-Stranded DNA; Specificity; Standards of Weights and Measures; Techniques; Testing; United States; Work; base; cancer cell; chemotherapy; high throughput screening; improved; inhibitor/antagonist; monomer; oncology; pancreatic neoplasm; recombinational repair; small molecule; small molecule libraries; therapy resistant; tumor

DESCRIPTION (provided by applicant): Pancreatic cancer remains the 4th leading cause of cancer death in the United States. These tumors appear to be relatively resistant to standard available therapies. An agent capable of sensitizing pancreatic cancer cells to oncology therapies may improve the outcomes of these patients. A central hypothesis of this project is that elevated levels of homologous recombinational (HR) DNA repair can cause human pancreatic tumors to be resistant to some chemotherapies and radiotherapy, and that specific inhibition of HR may help overcome this resistance to therapy. The proposed research plan will develop a multi-step screen for identifying small molecule inhibitors of human RAD51, which is the central protein involved in initiating HR. The initial submission of this project included an aim proposing to develop a high-throughput (HT) assay and to screen a na¿ve library of small molecules in search of compounds that can inhibit the formation of RAD51 filaments on single-stranded DNA. A portion of initial work has been completed and is now summarized in the Preliminary Studies / Progress Report section. The screen of a 10k library identified 72 compounds that inhibit RAD51 filament formation by = 50%. This work successfully validated the filament formation assay as an HT screen, and it provided important information including refinement of assay techniques and data analysis. Using this information, the screen will be now be repeated using a larger starting library (130k compounds) and robotic liquid handling, which will likely yield compounds with even greater activities and specificities (Aim 1). To determine which have specific activities, the compounds resulting from both screens will be tested further in secondary and tertiary assays. Aim 2 will employ a set of in-vitro secondary assays aimed at identifying those compounds that can specifically block particular functions of purified RAD51 protein. In the third aim, compounds will be further characterized with tertiary cell-based assays, to identify the subset capable of sensitizing pancreatic cancer cells to the lethal effects of DNA damaging therapies via HR-specific mechanisms. The ultimate goal is to identify at least one optimal compound suitable for further development in clinical trials as an oncology drug. Pancreatic cancer remains the 4th leading cause of cancer death in the United States. These tumors appear to be relatively resistant to presently available therapies. A drug capable of overcoming the cellular resistance to radiotherapy and/or chemotherapeutic drugs may improve on the outcomes of these patients. The goal of this proposal is to develop an agent capable of sensitizing pancreatic cancer cells to these common oncology therapies.

描述（由申请人提供）：胰腺癌仍然是美国对标准可用疗法的癌症死亡的第四个主要原因。同源重组（HR）TNA修复水平会导致人胰腺对某些化学疗法和放射疗法具有抗性，并且对HR的特定吸入可能有助于克服这种抗药性。启动人力资源的人类Rad51 d。在搜索化合物的小分子中，单链DNA上的rad51的形成已完成，现在在预序研究 /进度报告中总结了10K库的筛选。 = 50％的工作，并通过较大的起始库（130K化合物）和机器人液体处理来获得测定技术和数据分析的信息1）。通过HR特异性机制识别子集的训练，鉴定至少一个适合于临床试验的最佳化合物作为肿瘤药物的第四个主要原因。目前可用的疗法。 。

项目成果

Primary tumor necrosis predicts distant control in locally advanced soft-tissue sarcomas after preoperative concurrent chemoradiotherapy.

• DOI: 10.1016/j.ijrobp.2009.03.015
• 发表时间: 2010-03-15
• 期刊: INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS
• 影响因子: 7
• 作者: MacDermed, Dhara M.;Miller, Luke L.;Peabody, Terrance D.;Simon, Michael A.;Luu, Hue H.;Haydon, Rex C.;Montag, Anthony G.;Undevia, Samir D.;Connell, Philip P.
• 通讯作者: Connell, Philip P.