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.

项目概要/摘要 该项目的总体目标是开发针对谷氨酰胺代谢的精准疗法 含有 PIK3CA 突变的结直肠癌 (CRC)。作为代谢物，谷氨酰胺首先转化为 通过谷氨酰胺酶转化为谷氨酸，然后通过转氨酶转化为α-酮戊二酸（α-KG）以补充三羧酸 酸（TCA）循环。该提案基于我们的初步研究表明： (i) 具有 PIK3CA 的 CRC 突变通过谷氨酸丙酮酸转氨酶 2 (GPT2) 的上调而对谷氨酰胺上瘾； (二) 谷氨酰胺酶抑制剂 CB-839 可抑制 PIK3CA 突变型 CRC 异种移植物的生长； (iii) 氨氧乙酸盐 (AOA) 是一种 GPT2 和其他转氨酶抑制剂，可抑制 PIK3CA 突变型 CRC 异种移植物的生长； (iv) CB-839和AOA均不抑制具有WT PIK3CA的CRC异种移植物的生长； (v) CB-839的组合 与 5-FU 一起克服了异种移植物中对单独 5-FU 的耐药性。在目标 1 中，我们将通过以下方式阐明其机制： 其中 CB-839 增强 PIK3CA 突变 CRC 中 5-FU 的活性。在目标 2 中，我们将进行临床试验 评估 CB-839 在患有 PIK3CA 突变肿瘤的 CRC 患者中的药效学作用和临床活性。 在目标 3 中，我们将开发更有效、更特异的 GPT2 抑制剂作为工具化合物，以验证 GPT2 作为一种药物。 可行的癌症目标。其中一位 PI (ZW) 共同发现 PIK3CA 在许多人类癌症中高度突变， 包括约 20% 的 CRC。这些研究将带来治疗结直肠癌患者的创新选择性方法 其肿瘤含有 PIK3CA 突变，新型 GPT2 抑制剂的开发可能会进一步 被开发为潜在的抗癌药物。