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

项目总结/摘要 该项目的总体目标是开发针对谷氨酰胺代谢的精确疗法， 结直肠癌（CRC）携带PIK 3CA突变。作为代谢物，谷氨酰胺首先转化为 谷氨酸通过转氨酶，然后α-酮戊二酸（α-KG），以补充三羧酸 酸循环（TCA）。该建议基于我们的初步研究，研究表明：（i）PIK 3CA的CRC 突变通过谷氨酸丙酮酸转氨酶2（GPT 2）的上调而对谷氨酰胺成瘾;（ii）a 转氨酶抑制剂CB-839抑制PIK 3CA突变CRC异种移植物的生长; (AOA)GPT 2和其他氨基转移酶的抑制剂，抑制PIK 3CA突变CRC异种移植物的生长; (iv)CB-839和AOA均不抑制具有WT PIK 3CA CRC异种移植物的生长;和 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机制： CB-839增强PIK 3CA突变型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PIK 3CA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，我们将开发更有效和特异性的GPT 2抑制剂作为工具化合物，以验证GPT 2作为一种有效的抑制剂。 可行的癌症靶点其中一位PI（ZW）共同发现PIK 3CA在许多人类癌症中高度突变， 包括约20%的CRC。这些研究将导致一种创新的选择性方法来治疗CRC患者 其肿瘤含有PIK 3CA突变，以及开发新型GPT 2抑制剂， 作为潜在的抗癌药物。

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.