Using dietary glutamine supplementation for melanoma prevention and targeted therapy

项目总结 尽管最近在癌症代谢方面取得了进展，但营养干预是否以及如何影响肿瘤 肿瘤的发生、转移和治疗反应仍然知之甚少。因此，这项研究的目标是 阐明补充谷氨酰胺对肿瘤发生和治疗反应的影响 最终提供对癌症患者进行营养干预可以抑制肿瘤生长的分子证据 并使肿瘤对治疗敏感。利用新陈代谢分析，我们和其他人发现，与 在其他氨基酸中，许多实体瘤细胞在体内处于谷氨酰胺缺乏的环境中。有趣的是，我们 发现黑色素瘤中谷氨酰胺缺乏导致癌细胞去分化和对 由于组蛋白甲基化水平增加而导致的治疗。这一发现进一步促使我们测试是否增加了 饮食补充中的谷氨酰胺水平对已经适应良好的肿瘤细胞是有害的。 低谷氨酰胺的环境。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减少 患者来源的异种移植瘤(PDX)。重要的是，我们发现高谷氨酰胺饮食显著抑制肿瘤 与对照饮食相比，黑色素瘤相关癌基因的生长和表达减少。在支持中 这一点，来自活体实验的越来越多的证据表明，谷氨酰胺不是一种必要的营养物质 来源支持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，并通过表观遗传重新编程使肿瘤细胞对当前的治疗方法敏感。 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生长的影响， 体内代谢和癌基因表达；2)决定谷氨酰胺的分子机制 补充谷氨酰胺抑制肿瘤生长；3)研究补充谷氨酰胺对 BRAF/MEK抑制剂和免疫疗法治疗黑色素瘤。尽管许多已被证实的临床好处是 为癌症患者补充谷氨酰胺，最近的体外研究表明，肿瘤细胞是贪婪的谷氨酰胺 消费者导致癌症患者谨慎使用饮食中的谷氨酰胺。完成拟议的研究 将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。这些研究的结果 研究将揭示饮食中补充谷氨酰胺预防肿瘤的新治疗方向 生长和增强治疗反应，没有有害的副作用。

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.