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

使用模拟禁食饮食进行间歇性禁食以改善前列腺癌控制和代谢结果

• 批准号: 10639416
• 负责人: Tanya Dorff
• 金额: $ 72.23万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10639416
• 关键词: Affect; Androgen Receptor; Biology; Body Weight; Calories; Cancer Control; Cancer Patient; Cancer Survivor; Cardiovascular system; Castrate sensitive prostate cancer; Castration; Cells; Cessation of life; Clinical; Clinical Nutrition; Clinical Trials; Communities; Consumption; Data; Diabetes Mellitus; Diet; Disease Progression; Eating; European; Fasting; Fatty acid glycerol esters; Glucose; Glycosylated hemoglobin A; Guidelines; Health; Heart Diseases; Hormonal; Hormones; Human; IGF1 gene; Insulin; Insulin Resistance; Insulin-Like Growth-Factor-Binding Proteins; Intermittent fasting; Intervention; Leptin; Link; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Mediating; Metabolic; Metabolism; Metastatic Prostate Cancer; Molecular; Morbidity - disease rate; Mus; Outcome; Pathway interactions; Patients; Persons; Phase; Plants; Population; Randomized; Randomized, Controlled Trials; Resistance; Risk; Risk Reduction; Role; Second Primary Cancers; Serum; Signal Transduction; Site; Societies; Survivors; Testing; Testosterone; Thinness; Time; Toxic effect; Treatment-related toxicity; Tumor Tissue; abiraterone; androgen deprivation therapy; anti-cancer; anticancer research; cancer subtypes; cardiovascular risk factor; chemotherapy; comorbidity; design; diabetes risk; dietary approach; enzalutamide; experience; healthy volunteer; high risk; high risk men; improved; insight; men; mimetics; molecular subtypes; mortality; mouse model; next generation; phase II trial; predictive signature; prevent; primary outcome; prostate cancer model; prostate cancer progression; prostate cancer risk; prostate cancer survivors; randomized trial; response; side effect; skeletal; standard of care; targeted agent; transcriptomics; tumor; tumor progression; waist circumference

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.

抽象的 前列腺癌（PC）仍然是影响美国男性的最常见癌症，这两者都高 死亡人数数量，但还有更多与治疗相关毒性的幸存者数量。 雄激素剥夺疗法（ADT）是局部晚期和转移病例的治疗基石， 尽管它会导致无数的负面影响，包括增加胰岛素抵抗和入射糖尿病。这 加强雄激素受体靶向剂（ARTA），同时改善总体生存率，加剧这些 负面影响。大多数有PC的男性年龄较大，因此有合并症或已经患有合并症的风险 糖尿病和心脏病；这些通常代表了他们对死亡率的最大威胁。 ADT引起的代谢变化也可能会对男性产生不利影响，以通过 促进癌症进展。在ADT期间，胰岛素，瘦素和IGF1水平都在增加；较高的链接 具有更具侵略性的PC，可能会驱动cast割阻力。我们在人类研究中表明了间歇性 禁食饮食（FMD）禁食可以有利地改变胰岛素，葡萄糖和IGF1/IGFBP。我们的FMD 试验涉及食用非常低热量的植物性FMD 5天的患者，而在第6-28天，患者 吃了他们想要的东西，但鼓励根据欧洲临床营养和新陈代谢吃饭 癌症幸存者指南。此外，我们表明这种方法可以延迟多个小鼠的肿瘤进展 包括PC在内的型号。基于上述内容，我们假设使用FMD间歇性禁食将延迟PC 通过加强ADT治疗的男性的进展并改善了代谢健康。为了检验这一假设，我们 提出了使用FMD与标准的间歇性禁食干预的三个位置随机对照试验 从加强ADT开始的转移性castration敏感PC（MCSPC）的患者的护理6个月 或没有化学疗法。我们将第一次测试FMD对PSA Nadir改善的影响，早期 临床终点与更好的存活密切相关。我们还将衡量胰岛素和IGF1的变化如何 将PSA Nadir与这种饮食方法改善癌症结局的一种机制相关，并将 进一步寻求定义对这种饮食最有反应的PC的分子子集。 该试验的结果将对转移性和潜在的PC患者产生直接影响 接受确定治疗的ADT课程的人口较大。每年成千上万的男人可能是 阻止糖尿病和其他心血管危险因素发展或加剧 通过使用FMD，他们最大的死亡率威胁。适用于转移PC的男性，改善肿瘤控制和延迟 cast割耐药性会降低发病率，尤其是骨骼并发症，并提高生存率。 PC 研究界将深入了解代谢毒性和与下一步的荷尔蒙途径相互作用 ARTA代以及使用FMD从间歇性禁食中受益最大的分子亚型。