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

Von Hippel Lindau（VHL）病是一种罕见的遗传性疾病，每年影响36，000名美国人中的1人， 平均寿命49岁。目前，没有针对自发性肿瘤的长期治疗， 患者在他们的身体上发展，明显地，肾以透明细胞肾细胞癌（ccRCC）的形式发展。 由于可用的药理学治疗有限，饮食改变已成为受试者感兴趣的话题。 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%）的生酮饮食改变了 在器官和细胞水平的代谢，优先利用脂肪和酮的燃料。我最近的数据 产生的结果表明，两种饮食产生酮β-羟基丁酸酯（BHB）;循环生酮 饮食（CKD）和含前酮1，3丁二醇（BD）的饮食均使NCr裸小鼠皮下肿瘤缩小。 来自人ccRCC细胞系7860的小鼠。此外，给具有原位7860肿瘤的裸鼠喂食 CKD的预期寿命比标准饮食（SD）的人长58%。当小鼠被喂食CKD两周后， 在原位注射7860前7周，CKD喂养小鼠中9/10的肾脏显示最小肿瘤信号， 总体肿瘤生长显著低于SD喂养小鼠肾脏中的肿瘤生长，这意味着 CKD对ccRCC具有显著的预防能力。几种人ccRCC细胞系的体外分析 显示BHB的加入阻止了这些细胞的生长，但不显著影响非癌细胞的生长。 肾细胞此外，向ccRCC细胞中添加BHB显示了几种关键标志物的显著变化， 铁凋亡，如TFRC和SLC 7A 11，BODIPY C11和4-羟基壬烯醛（4-HN）在 肿瘤以及细胞和停止体外生长。值得注意的是，VHL损失最近已被 与对铁凋亡的敏感性增加有关。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以诱导ccRCC癌症中的铁凋亡 细胞此外，这种机制可以推广到与VHL突变相关的几种癌症， 潜在地用作预防剂以预防在患有VHL疾病的那些中出现的许多肿瘤。与这些 我希望在高影响力的相关期刊上发表的数据，如癌症代谢，申请 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， 使真实的生活对患者产生影响的基础。

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.