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.

von Hippel Lindau（VHL）疾病是一种罕见的遗传疾病，每年36,000名美国人中有1个 平均预期寿命为49年。目前，对于自发性肿瘤没有长期治疗 患者以明显的细胞肾细胞癌（CCRCC）形式出现在体内的患者。 有限的药理治疗可用的饮食修改已成为一个兴趣的话题 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％）的生酮饮食变化 在器官和细胞水平上的代谢优先利用脂肪和酮作为燃料。我有最近的数据 产生的表明，两种产生酮β-羟基丁酸（BHB）的饮食；周期性生酮 饮食（CKD）和含有前酮1,3丁二醇（BD）的饮食，两者都在NCR裸体中收缩皮下肿瘤 来自人类CCRCC细胞系7860的小鼠。此外，喂食A的裸鼠裸鼠具有原位7860个肿瘤 CKD的预期寿命比标准饮食（SD）长58％。当小鼠被喂两个CKD时 在原位注射7860的几周前，CKD喂养小鼠的9/10肾脏显示出最小的肿瘤信号和 SD Fed小鼠的肿瘤的总体肿瘤生长显着低于肾脏肿瘤的生长，这意味着A CKD具有针对CCRCC的明显预防能力。几种人CCRCC细胞系的体外分析 表明BHB的添加停止了这些细胞的生长，但不会显着影响非癌性的生长 肾细胞。此外，在CCRCC细胞中添加BHB显示了几个关键标记的显着变化 诸如Bodipy C11和4-羟基烯烯（4-hn）的铁铁作用，例如TFRC和SLC7A11。 肿瘤以及细胞并在体外停止生长。重要的是要注意，VHL损失最近 与增加对铁铁作用的敏感性有关。考虑到这些数据，我们假设BHB生成了 从CKD和BD从改变基因表达和代谢过程来诱导CCRCC癌症的屈服 细胞。同样，该机制可以推广到与VHL突变相关的几种癌症和 可能被用作预防性，以防止在VHL疾病患者中出现的许多肿瘤。与这些 我希望将生成的数据发表在癌症代谢等高影响相关期刊上 额外的联邦资金，并在更强大的临床前环境中建立这种机制，以铺设 对患者产生影响的基础。