Genetics and Biology of Pancreatic Ductal Adenocarcinoma

此次更新申请的目标是深入了解PI3K和RAS-MAPK信号传导以及控制胰腺导管腺癌（PDAC）的合作途径，以指导突出药物开发候选药物的临床试验，并在这些途径中确定新的治疗点。该项目由基础和临床研究人员组成的多学科团队组成，他们在肿瘤生物学、小鼠遗传学、癌症代谢、PI3K信号和功能基因组学方面有着良好的合作记录和互补优势。该计划包括3个高度互动的项目(项目1:DePinho。哈恩和秦。DFCI;项目2;坎特。BIDMC和Bardeesy。MGH：项目3：杰克和范德海登。以确定KRAS*合成致死基因在PDAC发育和维持中的作用、PDAC中PI3K/MEK通路共灭的影响及相关耐药机制、MEK/PI3K抑制对PDAC代谢的影响、抑制谷氨酰胺代谢对PDAC的影响为综合目标。项目1将采用全基因组RNAi和生物信息学分析来鉴定和验证与MEKi或Pi3Ki协同抑制KRAS* PDACs的可药物共灭靶点。此外，将进行体内基因筛选，以确定获得性耐药或与Pl3K/MEK信号通路协同作用的其他可药物靶点。项目2将解决核心假设，即KRAS*驱动的PDAC以冗余的方式利用PI3K和MAPK途径来驱动肿瘤生长，并且这些途径的关键作用涉及维持肿瘤代谢。项目2将确定MEKi/PlSKi对PDAC细胞信号传导、代谢和治疗反应的影响。这些努力将与MEK/Pl3K信号的代谢生物标志物的研究和治疗耐药机制的鉴定相结合，这将对指导该领域未来的治疗试验至关重要。项目3将通过开发用于细胞培养和移植模型的条件RNAi系统，以及设计用于允许在原位肿瘤中条件删除基因的复杂基因工程小鼠模型，研究一系列潜在治疗靶点在肿瘤维持中的重要性。这些项目将由高度创新的分子成像核心（Weissleder， MGH）实现。实验病理学（Loda/Chu）生物银行（Thaver， MGH）。小鼠工程（DePinho/Homer， DFCI）：并由行政核心协助提供科学和财政监督（DePinho, DFCl）。

The goal for this renewal application is to gain in-(depth knowledge of PI3K and RAS-MAPK signaling and cooperating pathways governing pancreatic ductal adenocarcinoma (PDAC) to guide clinical trials with prominent drug development candidates and to identify new therapeutic points of attack in these pathways. The program project consists of a multiple-disciplinary team of basic and clinical investigators with a strong track record of working together and with complementary strengths in tumor biology, mouse genetics, cancer metabolism, PI3K signaling and functional genomics. The Program consists of 3 highly interactive projects (Project 1: DePinho. Hahn and Chin. DFCI; Project 2; Cantley. BIDMC and Bardeesy. MGH: Project 3: Jacks and Van der Heiden. MIT) with the integrating goals of determining the roles of KRAS* synthetic lethal genes in PDAC development and maintenance, the effect of co-extinction of PI3K/MEK pathways In PDAC and associated drug resistance mechanisms, the Impact of MEK/PI3K inhibition on PDAC metabolism, and the effect of inhibiting glutamine metabolism on PDAC. Project 1 will employ whole genome RNAi and bioinformatics analyses to identify and validate druggable co extinction targets that synergize with MEKi or Pi3Ki in suppressing KRAS* PDACs. In addition, context specific gain of function in vivo genetic screens will be performed to identify additional druggable targets underlying acquired resistance or playing cooperative roles with Pl3K/MEK signaling. Project 2 will address the central hypothesis that KRAS*-driven PDAC utilizes the PI3K and MAPK pathways in a redundant way to drive tumor growth and that a critical role for these pathways involves the maintenance of tumor metabolism. Project 2 will determine the impact of MEKi/PlSKi on PDAC cell signaling, metabolism, and therapeutic response. These efforts will be coupled with an investigation of metabolic biomarkers for MEK/Pl3K signaling and identification of mechanisms of therapeutic resistance which would be critical in guiding future therapeutic trials in this area. Project 3 will investigate the importance of a series of potential therapeutic targets in tumor maintenance by developing both conditional RNAi systems for use in cell culture and transplant models as well as sophisticated genetically-engineered mouse models designed to allow conditional deletion of genes in autochthonous tumors. These Projects will be enabled by highly innovative cores for Molecular Imaging (Weissleder, MGH). Experimental Pathology (Loda/Chu. DFCl), Biobank (Thaver, MGH). and Mouse Engineering (DePinho/Homer, DFCI): and assisted by an administrative core to provide scientific and fiscal oversight (DePinho, DFCl).