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*) 的激活突变，与其他 KRAS* 癌症一样，PDAC 对临床使用的现有疗法反应甚微，但目前尚无令人满意的 KRAS* 特异性药物。 、MEK 和 PI3K 抑制剂（MEKi 和 PI3Ki）¿ KRAS* 介导的体外细胞转化的必要途径现已被引入临床试验，指导该项目的中心假设是 PDAC 以冗余方式利用 PI3K 和 MEK 途径来驱动肿瘤生长，并且这些途径发挥着关键作用。该提案的总体目标是确定 MEKi/PI3Ki 对 PDAC 细胞信号传导、代谢和治疗反应的影响。 MEK/PI3K 信号传导和治疗耐药机制的识别对于未来的治疗试验至关重要： 1. 确定 MEK/PI3K 抑制对 PDAC 基因工程小鼠模型以及基因组特征的人类 PDAC 培养物的影响。将用于在人类 PDAC 中发现的肿瘤抑制突变的不同组合的背景下，比较由遗传或药理学 MEKi/PI3Ki 引起的细胞反应和信号通路改变。 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，这些营养物质对体内PDAC代谢的贡献以及MEKi/PI3Ki的影响。这些研究将通过一系列放射性同位素标记、分子成像和 LC-MS 方法来确定它们的利用情况，并深入了解 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/PI3Ki的耐药机制 初步研究表明，小鼠PDAC模型最终会产生对MEKi/PI3Ki的获得性耐药。另外，将通过一系列磷酸化蛋白质组学和遗传分析来探索获得性耐药的机制。 ，作为增加 bi 的一种手段