Project 4: Targeting Glutamine Metabolism in Colorectal Cancer Harboring PIK3CA Mutations

项目 4：针对携带 PIK3CA 突变的结直肠癌中的谷氨酰胺代谢

• 批准号: 10227755
• 负责人: Zhenghe Wang
• 金额: $ 23.25万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-14 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10227755
• 关键词: Aminooxyacetate; Antineoplastic Agents; Apoptosis; Autophagocytosis; Basic Science; Biological Assay; Biological Markers; Biological Sciences; Biopsy; Cancer Etiology; Cancer Model; Cancer Science; Cells; Cessation of life; Citric Acid Cycle; Clinical; Clinical Trials; Collaborations; Colon Carcinoma; Colorectal Cancer; Communication; DNA; Data; Dependence; Development; Disease; Dose; Drug Combinations; Enzymes; Fluorouracil; Gene Expression; Genes; Glutamates; Glutaminase; Glutamine; Goals; Growth; Human; Knock-in Mouse; Knock-out; Malignant Neoplasms; Metabolism; Modeling; Molecular; Mus; Mutate; Mutation; Nature; Nutrient; Oncogenes; Oncogenic; Oral; PIK3CA gene; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Precision therapeutics; Prodrugs; Production; Pyruvate; RNA; Resistance; Structure; Technology; Testing; Therapeutic Effect; Therapeutic Index; Transaminases; United States; Up-Regulation; Uridine Phosphorylase; Work; Xenograft procedure; addiction; alpha ketoglutarate; angiogenesis; base; cancer cell; capecitabine; colon cancer patients; design; enzyme pathway; fluoropyrimidine; genome editing; improved; inhibitor/antagonist; innovation; knock-down; metastatic colorectal; mouse model; mutant; novel; novel therapeutics; patient derived xenograft model; personalized approach; phase I trial; small hairpin RNA; success; targeted treatment; tissue culture; tool; tumor; tumor growth; tumor xenograft

PROJECT SUMMARY/ABSTRACT The overarching goal of this project is to develop precision therapies that target glutamine metabolism of colorectal cancers (CRCs) that harbor PIK3CA mutations. As a metabolite, glutamine is first converted to glutamate by glutaminase and then to α-ketoglutarate (α-KG) by transaminases to replenish the tricarboxylic acid (TCA) cycle. This proposal is based on our preliminary studies showing that: (i) CRCs with PIK3CA mutations are addicted to glutamine through upregulation of glutamate pyruvate transaminase 2 (GPT2); (ii) a glutaminase inhibitor, CB-839, suppresses the growth of PIK3CA mutant CRC xenografts; (iii) aminooxyacetate (AOA), an inhibitor of GPT2 and other aminotransferases, inhibits the growth of PIK3CA mutant CRC xenografts; (iv) neither CB-839 nor AOA inhibit growth of CRC xenograft with WT PIK3CA; and (v) combination of CB-839 with 5-FU overcomes resistance to 5-FU alone in xenografts. In Aim 1, we will elucidate the mechanisms by which CB-839 augments the activity of 5-FU in PIK3CA mutant CRCs. In Aim 2, we will perform clinical trials to assess the pharmacodynamic effects and clinical activity of CB-839 in CRC patients with PIK3CA mutant tumors. In Aim 3, we will develop more potent and specific GPT2 inhibitors as tool compounds to validate GPT2 as a viable cancer target. One of the PIs (ZW) co-discovered that PIK3CA is highly mutated in many human cancers, including ~20% of CRCs. These studies will lead to an innovative selective approach to treating CRC patients whose tumors harbor PIK3CA mutations, and development of novel GPT2 inhibitors that could be further developed as potential anti-cancer drugs.

项目总结/文摘