Deriving Combinatorial Strategies for Therapy of Pancreatic Cancer

制定胰腺癌治疗的组合策略

基本信息

批准号：
7434534
负责人：
MICHAEL A. WHITE
金额：
$ 21.98万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-06-01 至 2010-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7434534
关键词：
3-Dimensional Adherent Culture Adoption Animal Model Apoptosis Automobile Driving Cell Communication Cell Line Cell Survival Cells Classification Complex Coupled Dependency Development Drug Combinations Drug resistance Ductal Epithelium Effectiveness Epithelial Cells Epithelium Event Exposure to Extracellular Matrix Gene Targeting Genes Genetic Genome Goals Hand Human Intervention Libraries Malignant Neoplasms Malignant neoplasm of pancreas Mediating Modeling Molecular Molecular Analysis Molecular Target Monitor Neck Normal Cell Normal tissue morphology Oncogenes Oncogenic Pancreas Pancreatic Adenocarcinoma Pathway interactions Pharmaceutical Preparations Pharmacotherapy Population Heterogeneity Pre-Clinical Model Prevention strategy Proteins Recruitment Activity Refractory Regulation Research Research Personnel Rolfing Scientist Screening procedure Signal Transduction Small Interfering RNA Stromal Cells System Testing Tissues Toxic effect Translations Treatment Protocols Xenograft Model Xenograft procedure anti-cancer therapeutic base cancer cell cell behavior chemotherapeutic agent combinatorial coping cyclopamine design high throughput screening interest killings loss of function monolayer mouse model neoplastic cell novel novel therapeutics response therapeutic target tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The cell autonomous molecular events that drive the initiation and progression of pancreatic cancers are multifarious and complex. This context makes identification of effective intervention and prevention strategies a seemingly daunting task. However, widespread evidence suggests that a unifying principle governing formation of a "minimal oncogenic platform" is the co-dependent aberrant regulation of core machinery driving proliferation and suppressing apoptosis. Linchpin proteins recruited to drive these pathways during tumorigenesis likely represent optimal intervention targets in a heterogeneous population of cancer cells. We have established that high-throughput siRNA-mediated loss-of-function analysis can reveal novel linchpin proteins selectively supporting the survival of cancer cells versus normal epithelia. This approach can now be pursued on a genome-wide scale for an unbiased comprehensive analysis of the molecular framework supporting pancreatic cancer cell survival. Here we will combine an in-hand arrayed genome-wide human siRNA library with high-throughput cell-based screening platforms for broad-spectrum identification of optimal genetic targets for focused development of effective chemotherapeutic agents. Our goal is the identification of optimal molecular targets to help guide rational design of novel combinatorial drug-based therapies for human pancreatic cancer. Our immediate objective is to advance this goal by the comprehensive identification of genes that support drug resistance in treatment-refractory human pancreatic cancer cells. Agents that target these gene products or the pathways they regulate will be prime candidates for effective multi-drug therapies. Our approach is to combine a genome-wide siRNA array with a validated high-throughput cell-based screening platform to identify gene targets that expose enhanced-sensitivity to known chemotherapeutic compounds. Our Specific Aims are: 1) To identify molecular targets selectively supporting drug resistance in human pancreatic cell lines, and 2) To validate the effectiveness of candidate targets within an orthotopic xenograft model of pancreatic cancer. The approach we describe here will facilitate the unambiguous identification of linchpin proteins selectively required for survival of pancreatic cancer cells upon exposure to gemcitibine orcyclopamine, two drugs respectively representing the commonly used but less-than-effective current therapy versus an effective agent in preclinical models yet to be tested in humans. This information will 1) guide rational selection of available drugs and drug combinations for development of new intervention and/or prevention strategies, and 2) help identify novel pharmaceutically tractable therapeutic targets whose inhibition will have minimal impact on normal cells.

描述（由申请人提供）：驱动胰腺癌发生和进展的细胞自主分子事件是多种多样且复杂的。这种背景使得确定有效的干预和预防策略成为一项看似艰巨的任务。然而，广泛的证据表明，控制“最小致癌平台”形成的统一原则是驱动增殖和抑制细胞凋亡的核心机制的相互依赖的异常调节。在肿瘤发生过程中招募来驱动这些途径的关键蛋白可能代表异质癌细胞群中的最佳干预靶点。我们已经确定，高通量 siRNA 介导的功能丧失分析可以揭示选择性支持癌细胞相对于正常上皮细胞存活的新型关键蛋白。现在可以在全基因组范围内采用这种方法，对支持胰腺癌细胞存活的分子框架进行公正的综合分析。在这里，我们将把现有的全基因组人类 siRNA 文库与高通量细胞筛选平台相结合，以广谱鉴定最佳遗传靶标，从而集中开发有效的化疗药物。我们的目标是确定最佳分子靶点，以帮助指导人类胰腺癌新型组合药物疗法的合理设计。我们的近期目标是通过全面鉴定支持难治性人类胰腺癌细胞耐药性的基因来推进这一目标。针对这些基因产物或其调节途径的药物将成为有效的多药疗法的主要候选者。我们的方法是将全基因组 siRNA 阵列与经过验证的高通量细胞筛选平台相结合，以确定对已知化疗化合物具有增强敏感性的基因靶标。我们的具体目标是：1）确定选择性支持人类胰腺细胞系耐药性的分子靶点，2）验证胰腺癌原位异种移植模型中候选靶点的有效性。我们在此描述的方法将有助于明确识别暴露于吉西他滨或环巴明后胰腺癌细胞存活所需的关键蛋白，这两种药物分别代表常用但效果不佳的当前疗法与临床前模型中的有效药物进行人体测试。这些信息将 1) 指导合理选择可用药物和药物组合，以开发新的干预和/或预防策略，2) 帮助确定新的药物易处理的治疗靶点，其抑制对正常细胞的影响最小。