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

项目摘要/摘要 该项目的首要目标是开发针对谷氨酰胺代谢的精确疗法。 携带PIK3CA突变的结直肠癌(CRC)。作为一种代谢物，谷氨酰胺首先转化为 谷氨酰胺酶促谷氨酸，转氨酶促α-酮戊二酸(α-KG)补充三羧酸 酸(TCA)循环。这项建议是基于我们的初步研究表明：(I)具有PIK3CA的CRCs 谷氨酸丙酮酸转氨酶2(GPT2)上调使突变对谷氨酰胺上瘾； 谷氨酰胺酶抑制剂CB-839抑制PIK3CA突变的结直肠癌移植瘤的生长；(Iii)氨基氧乙酸酯 GPT2和其他转氨酶的抑制剂(AOA)可抑制PIK3CA突变型结直肠癌移植瘤的生长； (Iv)CB-839或AOA均不能抑制WT PIK3CA与结直肠癌移植瘤的生长；及(V)CB-839的联合应用 在异种移植中，5-FU克服了对5-FU的耐药性。在目标1中，我们将通过以下方式阐明这些机制 其中CB-839可增强PIK3CA突变株中5-FU的活性。在目标2中，我们将进行临床试验，以 评价CB-839对伴有PIK3CA突变的结直肠癌患者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更特异的GPT2抑制剂作为工具化合物来验证GPT2作为一种 可行的癌症靶点。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。这些研究将导致一种创新的选择性治疗结直肠癌患者的方法。 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。

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.