Utilization of Fasting Mimicking Diets to Treat and Prevent Clear Cell Renal Cell Carcinoma

利用模拟禁食饮食治疗和预防透明细胞肾细胞癌

• 批准号: 10529914
• 负责人: Sean Murphy
• 金额: $ 4.83万
• 依托单位: UNIVERSITY OF NOTRE DAME
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10529914
• 关键词: 4 hydroxynonenal; Adolescent; Adult; Affect; Age; American; BODIPY; Blood flow; Butylene Glycols; Carbohydrates; Cell Death; Cell Line; Cells; Cessation of life; Clear cell renal cell carcinoma; Clinical; Clinical Trials; Cystic kidney; Data; Diet; Diet Modification; Dietary Supplementation; Disease; FRAP1 gene; Fasting; Fatty acid glycerol esters; Funding; Gene Expression; Glucose; Glycolysis; Goals; Growth; Health; Human; In Vitro; Individual; Injections; Intervention; Investigation; Journals; Ketones; Kidney; Knowledge; Life; Life Expectancy; Life Style; Lipid Peroxidation; Malignant Epithelial Cell; Malignant Neoplasms; Metabolic; Metabolism; Methods; Mind; Monitor; Mus; Mutation; Nature; Nude Mice; Organ; Oxidative Stress; Patients; Periodicity; Pharmaceutical Preparations; Pharmacological Treatment; Phenotype; Play; Polycystic Kidney Diseases; Proliferating; Prophylactic treatment; Publishing; Rattus; Receptor Protein-Tyrosine Kinases; Renal carcinoma; Research; Role; Series; Signal Transduction; TFRC gene; Testing; Therapeutic Intervention; Tyrosine Kinase Inhibitor; VHL gene; VHL mutation; Vascular Endothelial Growth Factors; Von Hippel-Lindau Syndrome; Work; angiogenesis; bHLH-PAS factor HLF; beta-Hydroxybutyrate; cancer cell; cancer type; cell growth; experimental study; improved; in vivo; interest; ketogenic diet; kidney cell; neoplastic cell; pancreatic neoplasm; pre-clinical; prevent; prophylactic; rare genetic disorder; side effect; subcutaneous; survival outcome; tumor; tumor growth; tumor metabolism; tumor microenvironment

Von Hippel Lindau (VHL) disease is a rare genetic disorder effecting 1 in 36,000 Americans every year with an average life expectancy of 49 years. Currently, there is no long-term treatment for the spontaneous tumors that patients develop across their body, markedly, kidneys in the form of Clear Cell Renal Cell Carcinoma (ccRCC). With limited pharmacological treatments available dietary modifications have become a topic of interest for several cancer types. Notably a ketogenic diet containing high fat (>80%) and low carbohydrate (<10%) alters metabolism at the organ and cellular level to preferentially utilize fats and ketones for fuel. Recent data I have generated suggests that two diets that generate the ketone beta-hydroxybutyrate (BHB); the Cyclical Ketogenic Diet (CKD) and a diet containing pre-ketone 1,3 butanediol (BD), both shrink subcutaneous tumors in NCr Nude mice from the human ccRCC cell line 7860. Furthermore, nude mice with orthotopic 7860 tumors who are fed a CKD had a life expectancy 58% longer than those on a standard diet (SD). When mice were fed a CKD for two weeks before orthotopic injections of 7860, 9/10 kidneys in CKD fed mice showed minimal tumor signal and overall tumor growth was significantly lower than that of tumor growth in kidneys in SD fed mice, implying that a CKD has significant prophylactic capabilities against ccRCC. In-vitro analysis of several human ccRCC cell lines shows that BHB addition halts growth of these cells but does not significantly affect growth of non-cancerous kidney cells. Furthermore, BHB addition to ccRCC cells shows significant changes in several key markers of ferroptosis such as TFRC and SLC7A11 with BODIPY C11 and 4-hydroxynonenal (4-HN) being upregulated in tumors as well as cells and halting growth in-vitro. It is important to note that VHL loss has recently been associated with an increase sensitivity to ferroptosis. With these data in mind we hypothesize that BHB generated from a CKD and BD alters gene expression and metabolic processes to induce ferroptosis in ccRCC cancer cells. Also, that this mechanism could be generalized to several cancers associated with VHL mutations and potentially be utilized as a prophylactic to prevent many tumors that arise in those with VHL disease. With these data to be generated I hope to publish in high impact relevant journals such as Cancer Metabolism, apply for additional federal funding, and establish this mechanism in more robust pre-clinical settings to lay the groundwork to make real life impacts on patients.

冯·希佩尔·林道 (VHL) 病是一种罕见的遗传性疾病，每年影响 36,000 分之一的美国人。 平均预期寿命49岁。目前，尚无针对自发性肿瘤的长期治疗方法。 患者全身（特别是肾脏）出现透明细胞肾细胞癌（ccRCC）。 由于可用的药物治疗有限，饮食改变已成为人们感兴趣的话题 几种癌症类型。值得注意的是，含有高脂肪（>80%）和低碳水化合物（<10%）的生酮饮食会改变 器官和细胞水平的新陈代谢优先利用脂肪和酮作为燃料。我最近的数据 生成表明两种饮食会产生酮β-羟基丁酸酯（BHB）；周期性生酮 饮食 (CKD) 和含有前酮 1,3 丁二醇 (BD) 的饮食均可缩小 NCr Nude 的皮下肿瘤 来自人类 ccRCC 细胞系 7860 的小鼠。此外，用原位 7860 肿瘤喂养的裸鼠 CKD 患者的预期寿命比标准饮食 (SD) 患者的预期寿命长 58%。当小鼠被喂食 CKD 两次时 在原位注射 7860 之前几周，CKD 喂养的小鼠中的 9/10 肾脏显示出最小的肿瘤信号，并且 总体肿瘤生长显着低于 SD 喂养小鼠肾脏肿瘤生长，这意味着 CKD 对 ccRCC 具有显着的预防能力。几种人类 ccRCC 细胞系的体外分析 表明添加 BHB 会阻止这些细胞的生长，但不会显着影响非癌性细胞的生长 肾细胞。此外，将 BHB 添加到 ccRCC 细胞中显示出几个关键标志物的显着变化 铁死亡如 TFRC 和 SLC7A11，其中 BODIPY C11 和 4-羟基壬烯醛 (4-HN) 在 肿瘤以及细胞并在体外停止生长。值得注意的是，VHL 损失最近已 与铁死亡敏感性增加有关。考虑到这些数据，我们假设 BHB 生成了 CKD 和 BD 改变基因表达和代谢过程，诱导 ccRCC 癌症铁死亡 细胞。此外，这种机制可以推广到与 VHL 突变相关的几种癌症， 可能用作预防剂来预防 VHL 疾病患者出现的许多肿瘤。有了这些 要生成的数据我希望在癌症代谢等高影响力相关期刊上发表，申请 额外的联邦资金，并在更强大的临床前环境中建立这一机制，以奠定 为患者的现实生活带来影响的基础工作。