Intermittent Fasting using a Fasting-Mimetic Diet to Improve Prostate Cancer Control and Metabolic Outcomes

摘要 前列腺癌（PC）仍然是影响美国男性的最常见癌症， 死亡人数，但也有更多的幸存者经历治疗相关的毒性。 雄激素剥夺疗法（ADT）是局部晚期和转移性病例治疗的基石， 尽管它会导致无数的负面影响，包括增加胰岛素抵抗和糖尿病。的 强化的雄激素受体靶向药物（阿尔塔）在改善总生存率的同时， 负面影响大多数PC男性年龄较大，因此有患或已经患上合并症的风险，如 糖尿病和心脏病;这些疾病往往是死亡率的最大威胁。 ADT诱导的代谢变化也可能对PC死亡高风险男性产生不利影响， 促进癌症进展。在ADT期间，胰岛素、瘦素和IGF 1水平都增加;更高的水平与 更积极的PC，并可能驱动去势抵抗。我们在人类研究中发现， 使用禁食模拟饮食（FMD）禁食可以有利地改变胰岛素、葡萄糖和IGF 1/IGFBPs。我们的FMD 试验涉及患者食用非常低热量的植物性FMD 5天，而在第6-28天，患者 吃他们想吃的东西，但根据欧洲临床营养和代谢学会的建议， 癌症幸存者指南。此外，我们发现这种方法可以在多个小鼠中延迟肿瘤进展。 包括PC在内的各种型号。基于上述，我们假设使用FMD间歇性禁食将延迟PC 在接受强化ADT治疗的男性中进展并改善代谢健康。为了验证这个假设，我们 建议进行一项三个地点的随机对照试验，使用FMD与标准进行间歇性禁食干预 转移性去势敏感性PC（mCSPC）患者开始接受强化ADT治疗6个月， 或不化疗。我们将首次测试FMD对PSA最低点改善的影响， 临床终点与更好的生存率密切相关。我们还将测量胰岛素和IGF 1 与PSA最低点相关，这是这种饮食方法改善癌症预后的一种机制， 进一步寻求定义对这种饮食最敏感的PC的分子子集。 这项试验的结果将对PC患者产生直接影响，包括转移性和潜在的 接受ADT疗程和确定性治疗的较大人群。每年有成千上万的人 预防糖尿病和其他心血管危险因素的发展或恶化， 他们最大的死亡威胁是使用口蹄疫。对于患有转移性PC的男性，改善肿瘤控制并延迟 去势抵抗将降低发病率，特别是骨骼并发症，并提高存活率。个人电脑 研究界将深入了解代谢毒性和激素途径的相互作用， 阿尔塔代以及使用FMD鉴定从间歇性禁食中获益最多的分子亚型。

ABSTRACT Prostate cancer (PC) remains the most common cancer affecting men in the US, resulting in both a high number of deaths but also an even greater number of survivors experiencing treatment-related toxicities. Androgen deprivation therapy (ADT) is a cornerstone of therapy for both locally advanced and metastatic cases, though it results in myriad negative effects, including increased insulin resistance and incident diabetes. The intensified androgen receptor targeted agents (ARTA), while improving overall survival, exacerbate these negative effects. Most men with PC are older, thus at risk of, or already suffering from, comorbidities such as diabetes and heart disease; these often represent their greatest threat to mortality. The ADT-induced metabolic changes may also adversely impact men at high risk of PC death by promoting cancer progression. During ADT, insulin, leptin and IGF1 levels all increase; higher levels are linked with more aggressive PC and may drive castration resistance. We showed in human studies that intermittent fasting using a fasting-mimicking diet (FMD) can favorably change insulin, glucose and IGF1/IGFBPs. Our FMD trials involved patients consuming a very low-calorie plant-based FMD for 5 days while during days 6-28, patients ate what they wanted, but were encouraged to eat per European Society for Clinical Nutrition and Metabolism guidelines for cancer survivors. Further, we showed this approach can delay tumor progression in multiple mouse models including PC. Based upon the above, we hypothesize that intermittent fasting using a FMD will delay PC progression and improve metabolic health in men being treated with intensified ADT. To test this hypothesis, we propose a three-site randomized controlled trial of an intermittent fasting intervention using a FMD vs. standard of care for 6 months in patients with metastatic castration sensitive PC (mCSPC) starting on intensified ADT with or without chemotherapy. For the first time, we will test the effect of FMD on improvement in PSA nadir, an early clinical endpoint strongly correlated with better survival. We will also measure how changes in insulin and IGF1 associate with PSA nadir as one mechanism by which this dietary approach improves cancer outcomes and will further seek to define a molecular subset of PCs which are most responsive to this diet. The results of this trial will have immediate impact for PC patients, both metastatic and potentially the larger population who receive a course of ADT with definitive therapy. Thousands of men each year could be prevented from developing or having exacerbation of diabetes and other cardiovascular risk factors, which are their greatest mortality threat, by using a FMD. For men with metastatic PC, improving tumor control and delaying castration resistance would reduce morbidity, particularly skeletal complications, and improve survival. The PC research community will gain insight into metabolic toxicity and hormonal pathway interactions with the next- generation ARTA as well as identify molecular subtypes that benefit most from intermittent fasting using a FMD.