MEK AND PI3K INHIBITION IN THE REGULATION OF PANCREATIC CANCER METABOLISM

MEK 和 PI3K 抑制对胰腺癌代谢的调节

• 批准号: 8052112
• 负责人: LEWIS C. CANTLEY
• 金额: $ 46.03万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8052112
• 关键词: Acute; Adenocarcinoma Cell; Affect; Anabolism; Biochemical; Bioenergetics; Biological; Biological Availability; Biological Markers; Biology; Cancer Etiology; Cell Line; Cessation of life; Clinic; Clinical Trials; Complex; Coupled; Data; Detection; Development; Disease Progression; Drug Delivery Systems; Drug resistance; Early treatment; Future; Generations; Genetic; Genetic Screening; Genetically Engineered Mouse; Glucose; Glutamine; Glycolysis; Goals; Growth; Human; Image; In Vitro; Intervention; Investigation; KRAS2 gene; Label; Lead; MAP Kinase Gene; MEKs; Maintenance; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Measurement; Mediating; Metabolic; Metabolism; Mitochondria; Modeling; Molecular; Molecular Profiling; Monitor; Mus; Mutation; Nutrient; PIK3CG gene; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Phenformin; Positron-Emission Tomography; Process; Radioisotopes; Reading; Regimen; Regulation; Relative (related person); Resistance; Role; Series; Signal Pathway; Signal Transduction; Suppressor Mutations; Testing; Therapeutic; Therapy Clinical Trials; Tumor Suppressor Proteins; base; biobank; genetic analysis; glucose uptake; human FRAP1 protein; human SMO protein; imaging modality; in vivo; inhibitor/antagonist; insight; metaplastic cell transformation; minimally invasive; molecular imaging; mouse model; neoplastic cell; resistance mechanism; response; smoothened signaling pathway; tumor; tumor growth; uptake

The vast majority of pancreatic ductal adenocarcinomas (PDAC) involve activating mutations in KRAS (KRAS*) and as with other KRAS* cancers, PDAC show minimal response to existing therapies used in the clinic. While no satisfactory KRAS*-speclfic drugs are currently available, inhibitors of MEK and PI3K (MEKi and PI3Ki)¿pathways necessary for KRAS*-mediated cellular transformation in vitro, are now being introduced into clinical trials. The central hypothesis guiding this project is that PDAC utilize the PI3K and MEK pathways In a redundant way to drive tumor growth and that a critical role for these pathways Involves the regulation of tumor metabolism. The overall goals of this proposal are to determine the impact of MEKi/PI3Ki on PDAC cell signaling, metabolism, and therapeutic response. These efforts will be coupled with an investigation of metabolic biomarkers for MEK/PI3K signaling and identification of mechanisms of therapeutic resistance which would be critical in future therapeutic trials. The Aims are: 1. Determine the impact of MEK/PI3K inhibition in PDAC. Genetically engineered mouse models as well as genomically characterized organotypic human PDAC cultures will be used to compare the cellular responses and signaling pathway alterations provoked by genetic or pharmacologic MEKi/PI3Ki against the backdrop of different combinations of tumor suppressor mutations found in human PDAC. 2. Determine the impact of MEK/PISK inhibition on PDAC metabolism. Glutamine and glucose are the main nutrients used by tumor cells for energy generation and for anabolic processes. The contribution of these nutrients to PDAC metabolism in vivo and the impact of MEKi/PI3Ki on their utilization will be determined using a series of radioisotope labeling, molecular imaging, and LC-MS approaches. These studies will give insight Into the regulation of PDAC metabolism and define biomarkers for the activity of these pathways. 3. Determine the mechanisms of resistance to MEKi/PI3Ki in PDAC. Preliminary studies indicate that mouse PDAC models will eventually develop acquired resistance to MEKi/PI3Ki. The mechanisms of acquired resistance will be explored by a series of phosphoproteomics and genetic analyses. In addition, as a means to increase the bi

绝大多数胰腺导管腺癌（PDAC）涉及KRAS（KRAS*）中的激活突变，并且与其他KRAS* 癌症一样，PDAC对临床中使用的现有疗法显示出最小的响应。虽然目前还没有令人满意的KRAS* 特异性药物，但KRAS* 介导的体外细胞转化所必需的MEK和PI 3 K（MEKi和PI 3 Ki）通路的抑制剂现在正被引入临床试验。指导该项目的中心假设是PDAC以冗余的方式利用PI 3 K和MEK途径来驱动肿瘤生长，并且这些途径的关键作用涉及肿瘤代谢的调节。本提案的总体目标是确定MEKi/PI 3 Ki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/PI 3 K信号传导的代谢生物标志物的研究和治疗抗性机制的鉴定相结合，这在未来的治疗试验中至关重要。目标是：1.测定MEK/PI 3 K抑制对PDAC的影响。将使用基因工程小鼠模型以及基因组学表征的器官型人PDAC培养物来比较在人PDAC中发现的肿瘤抑制突变的不同组合的背景下由遗传或药理学MEKi/PI 3 Ki引起的细胞应答和信号传导途径改变。2.确定MEK/PISK抑制对PDAC代谢的影响。谷氨酰胺和葡萄糖是肿瘤细胞用于能量产生和合成代谢过程的主要营养物质。将使用一系列放射性同位素标记、分子成像和LC-MS方法来确定这些营养素对体内PDAC代谢的贡献以及MEKi/PI 3 Ki对其利用的影响。这些研究将深入了解PDAC代谢的调节，并定义这些途径活性的生物标志物。3.确定PDAC对MEKi/PI 3 Ki的耐药机制。初步研究表明，小鼠PDAC模型最终将发展对MEKi/PI 3 Ki的获得性抗性。获得性抗性的机制将通过一系列磷酸化蛋白质组学和遗传分析来探索。此外，作为一种手段，以增加双