Using dietary glutamine supplementation for melanoma prevention and targeted therapy

使用膳食谷氨酰胺补充剂预防黑色素瘤和靶向治疗

• 批准号: 10211274
• 负责人: MEI KONG
• 金额: $ 43.67万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10211274
• 关键词: Affect; Amino Acids; Animals; BRAF gene; Cancer Intervention; Cancer Patient; Cell Culture System; Cell Proliferation; ChIP-seq; Citric Acid Cycle; Clinical; Clinical Trials; Data; Development; Diet; Dietary Intervention; Dietary Supplementation; Environment; Epigenetic Process; Genes; Glutamine; Goals; Histones; Hypermethylation; Immune checkpoint inhibitor; Immunocompetent; Immunotherapy; Implant; In Vitro; Laboratories; MEKs; Melanoma Cell; Metabolism; Modeling; Modification; Molecular; Monitor; Mutate; Neoplasm Metastasis; Nutritional; Oncogenes; Oncogenic; Oxygen; Pathway interactions; Patients; Play; Prevention; Prevention therapy; Process; Reporting; Research; Resistance; Role; Solid Neoplasm; Source; Supplementation; T cell response; T-Lymphocyte; Testing; Time; Xenograft procedure; alpha ketoglutarate; anti-PD1 antibodies; base; cancer cell; cancer therapy; cofactor; combinatorial; dietary; dietary control; effector T cell; epigenetic regulation; exhaustion; experimental study; falls; histone demethylase; histone methylation; improved; in vivo; inhibitor/antagonist; insight; interest; melanoma; metabolomics; mouse model; neoplastic cell; novel therapeutics; patient derived xenograft model; preclinical study; prevent; response; side effect; targeted treatment; transcriptome sequencing; treatment response; tumor; tumor growth; tumor metabolism; tumor xenograft

PROJECT SUMMARY Despite recent advances in cancer metabolism, whether and how nutritional interventions affect tumor development, metastasis and therapeutic response are still poorly understood. Thus, the goal of this study is to elucidate the effect of glutamine supplementation on tumor development and therapeutic responses, and eventually provide molecular evidence that nutritional interventions on cancer patients can inhibit tumor growth and sensitize tumors to treatments. Using metabolomic analysis, we and others have found that, compared to other amino acids, many solid tumor cells are situated in a glutamine poor environment in vivo. Interestingly, we found that glutamine deficiency in melanoma tumors resulted in cancer cell de-differentiation and resistance to treatment due to increased histone methylation levels. This finding further prompted us to test if increases in glutamine levels through dietary supplementation can be detrimental to tumor cells that have been well adapted to a low glutamine environment. Our preliminary data demonstrated that supplementation of glutamine in the diet is sufficient to increase tumoral α-ketoglutarate levels and leads to decreased histone methylation in melanoma patient-derived xenograft (PDX) tumors. Importantly, we found that high glutamine diet significantly hinders tumor growth and decreases expression of melanoma-associated oncogenes compared to control diet. In support with this, accumulating evidence from in vivo experiments demonstrate that glutamine is not an essential nutritional source to support TCA cycle and tumor growth. Thus, we hypothesize that dietary glutamine supplementation inhibits melanoma tumor growth and sensitizes tumor cells to current treatments via epigenetic reprogramming. In this proposal, we will 1) determine the effect of dietary glutamine supplementation on melanoma tumor growth, metabolism and oncogene expression in vivo; 2) determine the molecular mechanisms by which glutamine supplementation inhibits tumor growth; 3) investigate the effect of glutamine supplementation in response to BRAF/MEK inhibitors and immunotherapy for melanoma treatment. Despite many proven clinical benefits of glutamine supplementation to cancer patients, recent in vitro studies showing that tumor cells are avid glutamine consumers led to cautionary usage of dietary glutamine on cancer patients. Completion of the proposed studies will provide insight into glutamine driven epigenetic regulation and its effect on tumor growth. The results of these studies will reveal a novel therapeutic direction for using dietary glutamine supplementation to prevent tumor growth and enhance therapeutic responses without detrimental side effects.

项目摘要 尽管癌症代谢的最新进展，营养干预是否以及如何影响肿瘤 发展、转移和治疗反应仍然知之甚少。因此，本研究的目的是 阐明谷氨酰胺补充对肿瘤发展和治疗反应的影响， 最终为癌症患者的营养干预可以抑制肿瘤生长提供分子证据 并使肿瘤对治疗敏感。使用代谢组学分析，我们和其他人发现，与 除了其他氨基酸之外，许多实体瘤细胞在体内位于谷氨酰胺贫乏的环境中。有趣的是，我们 发现黑色素瘤肿瘤中谷氨酰胺缺乏导致癌细胞去分化和对 治疗由于组蛋白甲基化水平增加。这一发现进一步促使我们测试， 通过饮食补充的谷氨酰胺水平可能对已经良好适应的肿瘤细胞有害 低谷氨酰胺环境。我们的初步数据表明，在饮食中补充谷氨酰胺 足以增加肿瘤α-酮戊二酸水平，并导致黑色素瘤中组蛋白甲基化降低 患者来源的异种移植（PDX）肿瘤。重要的是，我们发现高谷氨酰胺饮食显著阻碍肿瘤 与对照饮食相比，生长和降低黑素瘤相关癌基因的表达。支持 这一点，从体内实验中积累的证据表明，谷氨酰胺不是一种必需的营养物质， 来源，以支持TCA循环和肿瘤生长。因此，我们假设饮食中补充谷氨酰胺 抑制黑色素瘤肿瘤生长并通过表观遗传重编程使肿瘤细胞对当前治疗敏感。 在这项提案中，我们将1）确定饮食中补充谷氨酰胺对黑色素瘤肿瘤生长的影响， 体内代谢和癌基因表达; 2）确定谷氨酰胺 补充谷氨酰胺抑制肿瘤生长; 3）研究补充谷氨酰胺对响应于 BRAF/MEK抑制剂和用于黑色素瘤治疗的免疫疗法。尽管有许多已证实的临床益处， 补充谷氨酰胺的癌症患者，最近的体外研究表明，肿瘤细胞是贪婪的谷氨酰胺 消费者对癌症患者饮食中谷氨酰胺的谨慎使用。完成拟议的研究 将提供深入了解谷氨酰胺驱动的表观遗传调控及其对肿瘤生长的影响。的结果予以 研究将揭示一个新的治疗方向，使用饮食补充谷氨酰胺，以防止肿瘤 生长和增强治疗反应而没有有害的副作用。