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: 10662541
• 负责人: Sean Murphy
• 金额: $ 4.77万
• 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/10662541
• 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; Monitor; Mus; Mutation; Nature; Nude Mice; Organ; Oxidative Stress; Oxidative Stress Induction; Patients; 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; Starvation; 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; carcinogenesis; 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)病是一种罕见的遗传性疾病，每年每36,000名美国人中就有1人患有 平均预期寿命为49岁。目前，还没有针对自发性肿瘤的长期治疗方法 患者全身都会发生肾透明细胞癌(CcRCC)。 由于可获得的药物治疗有限，饮食修改已成为 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类作为燃料。我最近的数据 生成表明有两种饮食生成酮-β-羟基丁酸酯(BHB)；循环性生酮 饮食(CKD)和含有前酮1，3丁二醇(BD)的饮食都能缩小NCR裸鼠的皮下肿瘤 来自人肾癌细胞系7860的小鼠。此外，荷瘤7860的裸鼠经灌胃后， CKD的预期寿命比标准饮食(SD)的人长58%。当小鼠喂食两份CKD时 在原位注射7860前几周，CKD喂养的小鼠9/10的肾脏显示出最低的肿瘤信号和 在喂食SD的小鼠中，肾脏的总体肿瘤生长显著低于肿瘤生长，这意味着 CKD对ccRCC具有显著的预防作用。几种人肾小管癌细胞系的体外分析 结果表明，BHB的加入阻止了这些细胞的生长，但对非癌症细胞的生长没有显著影响 肾脏细胞。此外，在ccRCC细胞中加入bHb后，几个关键标志物显示出显著的变化 铁下垂，如TFRC和SLC7A11伴BODIPY C11和4-羟基壬烯醛(4-HN)上调 肿瘤以及细胞，并在体外停止生长。值得注意的是，VHL损失最近一直是 与对铁性下垂的敏感度增加有关。考虑到这些数据，我们假设BHB产生了 CKD和BD改变基因表达和代谢过程诱导ccRCC癌中铁下垂 细胞。此外，这种机制可以推广到几种与VHL突变和 可能被用作预防VHL疾病患者出现的许多肿瘤的预防性药物。有了这些 将生成的数据我希望发表在癌症代谢等影响较大的相关期刊上，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，为 为给患者带来现实生活的影响奠定基础。