Investigation of therapeutic modulators of apoptotic priming in pancreatic cancer

胰腺癌细胞凋亡引发的治疗调节剂的研究

• 批准号: 8896608
• 负责人: ANTHONY G LETAI
• 金额: $ 18.81万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8896608
• 关键词: Apoptosis; Apoptotic; Biological Markers; Cancer cell line; Cell Death; Chemotherapy-Oncologic Procedure; Clinical; Cytotoxic Chemotherapy; Disease; Drug Targeting; Evaluation; Gene Targeting; Genes; Genetic Screening; Genome; Goals; Health; Human; Investigation; Knowledge; Malignant neoplasm of pancreas; Measurement; Mitochondria; Outcome; Patients; Phenotype; Proteins; RNA Interference; Refractory; Resistance; Sampling; Techniques; Technology; Therapeutic; Time; Translating; base; cancer cell; cancer type; chemotherapy; genome-wide; improved; loss of function; novel; novel strategies; novel therapeutic intervention; outcome forecast; pancreatic cancer cells; pancreatic cell line; response; screening; small hairpin RNA; small molecule; therapeutic target

DESCRIPTION (provided by applicant): Pancreatic cancer is a deadly disease that is typically refractory to even the most aggressive cytotoxic chemotherapy regimens. Recent advances in chemotherapy for pancreatic cancer have led to some improvement in response rates; however, the majority of patients still do not substantially benefit from therapy. Responses to chemotherapy commonly occur through apoptosis, a form of programmed cell death. Our goal is to identify genes whose loss of function enhances sensitivity of pancreatic cancer cells to apoptosis. BH3 profiling is a well-characterized upstream measurement of the apoptotic sensitivity or "priming" of cancer cells and has been shown to correlate with response to chemotherapy and disease prognosis in certain cancer types. We will utilize a novel screening approach called RNAi-BH3 Screening (RiB Screening) that combines loss-of-function genetic screening using pooled lentivirally delivered shRNAs with the technology of BH3 profiling. In this approach, we will identify genes whose knockdown results in enhanced priming for apoptosis across several pancreatic cell lines. Based on this loss of function genetic screen, we will attempt to identify known small molecules targeting these genes, and determine whether they alter apoptotic priming and chemosensitivity. Finally, we propose to evaluate potential clinical utility of identified genes or small molecules by determining their effect on BH3 Profiles and chemosensitivity in fresh patient-derived pancreatic cancer samples. The successful identification of such genes and small molecules will not only improve our understanding of chemotherapeutic response, but could also serve as novel biomarkers or therapeutic targets.

描述（由申请人提供）：胰腺癌是一种致命的疾病，即使是最积极的细胞毒性化疗方案通常也难以治愈。胰腺癌化疗的最新进展导致缓解率有所提高；然而，大多数患者仍然没有从治疗中获益。回应 化疗通常通过细胞凋亡（一种程序性细胞死亡形式）发生。我们的目标是鉴定其功能丧失可增强胰腺癌细胞对细胞因子的敏感性的基因。 细胞凋亡。 BH3 分析是癌细胞凋亡敏感性或“启动”的一种充分表征的上游测量，并已被证明与某些癌症类型的化疗反应和疾病预后相关。我们将利用一种称为 RNAi-BH3 筛选（RiB 筛选）的新型筛选方法，该方法将使用汇集的慢病毒传递的 shRNA 进行功能丧失遗传筛选与 BH3 分析技术相结合。在这种方法中，我们将鉴定一些基因，这些基因的敲低会导致几种胰腺细胞系细胞凋亡的启动增强。基于这种功能丧失遗传筛选，我们将尝试识别针对这些基因的已知小分子，并确定它们是否改变细胞凋亡引发和化学敏感性。最后，我们建议通过确定其对来自患者的新鲜胰腺癌样本中的 BH3 谱和化疗敏感性的影响来评估已识别基因或小分子的潜在临床效用。这些基因和小分子的成功鉴定不仅将提高我们对化疗反应的理解，而且还可以作为新的生物标志物或治疗靶点。