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最常见的癌症，导致高发病率 死亡人数增加，而且更多的幸存者经历了与治疗相关的毒性反应。 雄激素剥夺疗法（ADT）是局部晚期和转移性病例治疗的基石， 尽管它会导致许多负面影响，包括胰岛素抵抗增加和糖尿病发生。这 强化雄激素受体靶向药物（ARTA）在提高总体生存率的同时，加剧了这些 负面影响。大多数患有 PC 的男性年龄较大，因此面临或已经患有合并症的风险，例如 糖尿病和心脏病；这些往往是对死亡的最大威胁。 ADT 引起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。 ADT 期间，胰岛素、瘦素和 IGF1 水平均升高；更高层次是相连的 具有更具攻击性的 PC，可能会导致去势抵抗。我们在人类研究中表明，间歇性 使用模拟禁食饮食 (FMD) 禁食可以有利地改变胰岛素、葡萄糖和 IGF1/IGFBP。我们的口蹄疫 试验涉及患者服用极低热量植物性 FMD 5 天，而在第 6-28 天期间，患者 吃他们想吃的东西，但欧洲临床营养和代谢学会鼓励他们吃 癌症幸存者指南。此外，我们表明这种方法可以延缓多只小鼠的肿瘤进展 型号包括 PC。基于上述情况，我们假设使用 FMD 进行间歇性禁食会延迟 PC 接受强化 ADT 治疗的男性的进展并改善代谢健康。为了检验这个假设，我们 提出一项使用 FMD 与标准进行间歇性禁食干预的三中心随机对照试验 对转移性去势敏感 PC (mCSPC) 患者进行 6 个月的护理，开始强化 ADT 或不进行化疗。我们将首次测试 FMD 对 PSA 最低点改善的影响，PSA 最低点是早期的 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 IGF1 的变化 将 PSA 最低点作为一种机制联系起来，这种饮食方法可以通过这种机制改善癌症结果，并将 进一步寻求定义对这种饮食最敏感的 PC 分子子集。 该试验的结果将对 PC 患者产生直接影响，包括转移性和潜在的 PC 患者 接受 ADT 疗程和明确治疗的更多人群。每年可能有数千名男性 预防糖尿病和其他心血管危险因素的发展或恶化，这些危险因素是 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，改善肿瘤控制并延缓 去势抵抗会降低发病率，特别是骨骼并发症，并提高生存率。电脑 研究界将深入了解代谢毒性和激素途径与下一个的相互作用 一代 ARTA 以及使用 FMD 识别从间歇性禁食中获益最多的分子亚型。