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Project 2-Identifying and exploiting metabolic vulnerabilities in PDAC

项目 2 - 识别和利用 PDAC 中的代谢漏洞

基本信息

批准号：
10170990
负责人：
RONALD ANTHONY DEPINHO
金额：
$ 73.11万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-12-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10170990
关键词：
Acute Address Alanine Amino Acids Antigen Presentation Autophagocytosis Bioenergetics Biogenesis Biology CD8-Positive T-Lymphocytes CRISPR screen Cancer Gene Mutation Cell Communication Citric Acid Cycle Clinic Coupled Data Dependence Exhibits Fibroblasts Fostering Funding Gene Mutation Genetic Genetically Engineered Mouse Genotype Glucose Glutamine Glycolysis Goals Growth Homeostasis Immune Immune Evasion Immune response Immune signaling Immunosuppression Impairment Inflammatory Interferons KRAS2 gene Lead Link Lysosomes MADH4 gene MEK inhibition Maintenance Malignant Neoplasms Mediating Metabolic Metabolic Pathway Metabolism Mitochondria Modeling Mutation Myelogenous NADP Nucleotide Biosynthesis Nutrient Organelles Oxidation-Reduction Pancreatic Ductal Adenocarcinoma Pathway interactions Patients Phenotype Play Population Pre-Clinical Model Process Production Regulation Role STK11 gene Series Signal Transduction Source Squalene System T-Lymphocyte TP53 gene Testing Therapeutic Tumor Immunity Tumor Suppressor Proteins Work cancer cell cell stroma fatty acid oxidation genetic variant glucose metabolism inhibition of autophagy insight metabolic profile mutant novel pancreatic ductal adenocarcinoma model paracrine pre-clinical programs response synergism therapeutic development therapeutically effective tumor tumor growth tumor metabolism tumor microenvironment

项目摘要

Project 2 - Abstract/Summary Our mechanistic work has established general principles of metabolic reprogramming in PDAC, revealing therapeutic insights that show dramatic effects in preclinical models (alanine metabolism blockade) as well as benefit in the clinic (autophagy inhibition). In this next cycle, we seek to address two key questions to enable us to most effectively define and exploit metabolic vulnerabilities in PDAC. First, how do the different concurrent cancer gene mutations that define PDAC subsets influence cancer cell metabolism and the metabolic interplay with the TME? Secondly, what role does regulation of mitochondria, organelles central to integration of metabolism and innate immune signals, play in metabolic reprogramming and cancer-stroma cell interactions in genetic subsets of Kras* PDAC? By developing a series of novel GEM models and patient-derived KRAS* PDAC models representing major genotypes, we have identified pronounced genetically-driven differences in tumor cell metabolism and cancer-immune cell interactions. We hypothesize that cooperating genetic alterations drive distinct metabolic programs and associated vulnerabilities in cancer cells. Moreover, we predict that immune differences will further influence cancer cell metabolism in these distinct genetic settings. To address these hypotheses, we propose the following aims: #1 Determine the influence of major PDAC gene mutations on metabolic programs;; #2 Assess role of the autophagy/lysosome system on tumor-TME crosstalk in genetic subsets of PDAC;; and, #3 Investigate mitochondrial regulation and relationship to metabolism and inflammatory signaling in PDAC subsets.

项目2 -摘要/摘要我们的机械工作已经建立了PDAC中代谢重编程的一般原则，揭示了在临床前模型中显示出显著效果的治疗见解（丙氨酸代谢阻断）以及在下一个周期，我们寻求解决两个关键问题，使我们能够在临床上受益（自噬抑制）。最有效地定义和利用PDAC中的代谢漏洞。首先，不同的并发定义PDAC亚群的癌症基因突变影响癌细胞代谢和代谢相互作用在TME？其次，线粒体，细胞器的调节在整合中起什么作用？代谢和先天免疫信号，在代谢重编程和癌症-间质细胞相互作用中发挥作用， Kras基因亚型 * PDAC？通过开发一系列新型GEM模型和患者衍生的KRAS* PDAC 代表主要基因型的模型，我们已经确定了明显的基因驱动的差异，在肿瘤细胞代谢和癌细胞免疫细胞相互作用。我们假设，协同遗传改变驱动不同的代谢程序和相关的脆弱性的癌细胞。此外，我们预测，免疫在这些不同的遗传背景下，差异将进一步影响癌细胞的代谢。假设，我们提出了以下目标：#1确定主要PDAC基因突变对代谢程序; EST#2评估自噬/溶酶体系统在遗传学中对肿瘤-细胞TME串扰的作用 PDAC的亚群; Escherichand，#3研究线粒体调节以及与代谢和炎症的关系 PDAC子集中的信令。