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）：胰腺癌是一种致命疾病，即使是最具侵略性的细胞毒性化学疗法方案，通常也是难治性的。胰腺癌化学疗法的最新进展导致了反应率的一些改善。但是，大多数患者仍然无法从治疗中受益。回答 化学疗法通常通过凋亡（一种编程细胞死亡形式）发生。我们的目标是确定其功能丧失会增强胰腺癌细胞敏感性的基因 凋亡。 BH3分析是对癌细胞凋亡敏感性或“启动”的良好表征的上游测量，已显示与某些癌症类型的化学疗法和疾病预后的反应相关。我们将利用一种称为RNAi-BH3筛选（肋骨筛选）的新型筛选方法，该方法使用合并的慢病毒递送的SHRNA和BH3分析技术结合了功能丧失的基因筛查。在这种方法中，我们将确定其敲低的基因会导致在几个胰腺细胞系中凋亡的启动增强。基于这种功能遗传筛查的丧失，我们将尝试鉴定针对这些基因的已知小分子，并确定它们是否改变了凋亡启动和化学敏感性。最后，我们建议通过确定新鲜患者衍生的胰腺癌样品对BH3谱和化学敏感性的影响来评估已鉴定基因或小分子的潜在临床实用性。这种基因和小分子的成功鉴定不仅会改善我们对化学治疗反应的理解，而且还可以用作新颖的生物标志物或治疗靶标。