Time-Restricted Eating and Cancer: Clinical Outcomes, Mechanisms, and Moderators

限时饮食与癌症：临床结果、机制和调节因素

• 批准号: 10179205
• 负责人: Jane C. Figueiredo
• 金额: $ 77.95万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10179205
• 关键词: Acute; Adverse effects; Adverse event; Affect; Aftercare; Alabama; Animal Model; Animals; Antioxidants; Anxiety; Apoptosis; Autophagocytosis; Behavior; Behavioral; Blood Pressure; Body mass index; CASP3 gene; Caloric Restriction; Cancer Patient; Cell Death; Cells; Characteristics; Chemotherapy and/or radiation; Clinical; Clinical Trials; Common Terminology Criteria for Adverse Events; Comprehensive Cancer Center; Counseling; DNA Damage; Data; Diagnosis; Diet; Dietary intake; Disease; Eating; Enrollment; Equilibrium; European Organization for Research and Treatment of Cancer; Excision; Family; Fasting; Fatty acid glycerol esters; Gamma-H2AX; Health; Heterogeneity; Hour; Human; Hunger; In complete remission; Intermittent fasting; Interview; Lead; Life; Life Style; Los Angeles; Malignant Neoplasms; Measures; Mediating; Medical; Medical center; Mental Depression; Molecular; Moods; Newly Diagnosed; Operative Surgical Procedures; Outcome; Oxidative Stress; Participant; Pathologic; Pathway interactions; Patient Outcomes Assessments; Patient-Focused Outcomes; Patients; Peripheral Blood Mononuclear Cell; Physical activity; Quality of life; Questionnaires; Randomized; Randomized Controlled Trials; Rectal Cancer; Rectal Neoplasms; Regimen; Reporting; Resistance; Risk; Schedule; Seminal; Serum; Site; Sleep; Social Functioning; Somatomedins; Stress; Structure; Symptoms; Testing; Time; Time Study; Time-restricted feeding; Toxic effect; Treatment outcome; Treatment-related toxicity; Tumor Tissue; Universities; Weight; Woman; Work; actigraphy; active method; aged; anti-cancer; arm; base; cancer care; cancer regression; cancer therapy; cardiometabolism; cell growth; chemoradiation; chemotherapy; clinical implementation; cytotoxic; daily functioning; ethnic diversity; feasibility trial; improved; indexing; innovation; insulin sensitivity; men; neoplastic cell; nutrition; oxidation; pilot trial; post intervention; predict clinical outcome; prospective; protein expression; psychosocial; racial diversity; recruit; reduced food intake; social; standard of care; theories; treatment arm; tumor

ABSTRACT Combining fasting with chemotherapy can cause complete tumor regression in animal models. Acute fasting is thought to sensitize tumor cells to the cytotoxic effects of chemotherapy and radiation, while protecting healthy cells by increasing stress resistance—a phenomenon known as the Differential Stress Sensitization theory. However, the potential risks of extended caloric restriction hamper clinical implementation. Time-restricted eating (TRE) is a promising alternative, which involves eating within a period of 10 hours or less, followed by fasting for at least 14 hours daily. Because of its simplicity, TRE may be more sustainable. Moreover, our pilot data suggest that TRE has several anti-cancer effects: it decreases IGF-1 levels, reduces oxidative stress, upregulates antioxidant defenses, and enhances autophagy. We propose to conduct the first clinical trial of TRE in cancer patients undergoing active treatment, as well as the largest randomized controlled trial of any form of intermittent fasting in cancer patients. We will focus on rectal cancer because it is one of only a couple cancers where tumor size and characteristics can be measured before and after treatment. We will enroll 300 newly diagnosed localized rectal cancer patients (stage II-III) aged ≥18 (BMI ≥ 18.5 kg/m2). All participants will receive the standard of care during oncological treatment at Cedars-Sinai Medical Cancer (Los Angeles, CA) or the University of Alabama O’Neal Comprehensive Cancer Center (Birmingham, AL) and be randomized to one of two eating schedules: (1) control schedule: 12-hour or longer daily eating period; (2) TRE: 8-hour daily eating period (16 hours of daily fasting). Participants will be counseled to maintain their weight. All endpoints will be measured at least three times: at diagnosis prior to the onset of chemoradiation (baseline), after chemoradiation treatment, and at tumor resection (post-intervention). Our primary aim is to determine how TRE affects clinical outcomes, including treatment-related adverse effects (toxicity index based on CTCAE v.5), patient-reported outcomes (PRO-CTCAE) and quality of life (EORTC QLQ-C30), and clinical (cCR) and pathological (pCR) complete response rates. Aim 2 tests the Differential Stress Sensitization Theory—the first complete test of this theory in humans. We test whether TRE acts through the IGF-1 pathway to increase stress resistance in healthy cells (DNA damage and antioxidant defenses as measured by gamma-H2AX and total antioxidant capacity, respectively) and enhance tumor cell death (apoptosis and autophagy as measured by activated caspase-3 and LC3-I/LC3-II, respectively). Aim 3 compares longitudinal changes in mood, social functioning, sleep, diet, and daily physical activity across intervention arms (control vs. TRE) and explore how these changes interact with intervention arms to predict clinical outcomes. We expect this innovative trial will help improve cancer treatment outcomes and reshape the standard of care for cancer patients.

摘要 禁食与化疗相结合可以在动物模型中导致肿瘤完全消退。急性禁食是 被认为使肿瘤细胞对化疗和放疗的细胞毒性作用敏感，同时保护健康。 细胞通过增加应力抵抗力-一种被称为差异应力敏化理论的现象。 然而，延长热量限制的潜在风险阻碍了临床实施。限时饮食 (TRE)是一个很有前途的替代方案，包括在10小时或更短的时间内进食，然后禁食 每天至少14小时。由于其简单性，TRE可能更具可持续性。此外，我们的试点数据表明， TRE具有多种抗癌作用：降低IGF-1水平，减少氧化应激， 抗氧化防御，并增强自噬。我们建议进行第一次TRE癌症临床试验 接受积极治疗的患者，以及任何形式的间歇性 癌症患者禁食我们将关注直肠癌，因为它是仅有的几种肿瘤之一， 可以在处理之前和之后测量尺寸和特性。我们将招募300名新诊断的 年龄≥18岁（BMI ≥ 18.5 kg/m2）的局限性直肠癌患者（II-III期）。所有参与者将获得标准 在Cedars-Sinai Medical Cancer（洛杉矶，CA）或University of 亚拉巴马奥尼尔综合癌症中心（伯明翰，AL），并被随机分为两个吃 时间表：（1）控制时间表：每天进食12小时或更长时间;（2）TRE：每天进食8小时（16 每日禁食时间）。将建议参与者保持体重。所有终点将在 至少3次：在放化疗开始前诊断时（基线），放化疗治疗后， 以及在肿瘤切除时（干预后）。我们的主要目的是确定TRE如何影响临床结果， 包括治疗相关不良反应（基于CTCAE v.5的毒性指数）、患者报告结局 （PRO-CTCAE）和生活质量（EORTC QLQ-C30），以及临床（cCR）和病理（pCR）完整 答复率。目标2测试差应力敏化理论-第一个完整的测试，这一理论在 人类我们测试TRE是否通过IGF-1途径来增加健康细胞的应激抵抗力 (DNA通过γ-H2 AX和总抗氧化能力测量的损伤和抗氧化防御， 分别）和增强肿瘤细胞死亡（细胞凋亡和自噬，如通过活化的半胱天冬酶-3和 LC 3-I/LC 3-II）。目标3比较情绪、社会功能、睡眠、饮食和 干预组之间的日常体力活动（对照组与TRE组），并探讨这些变化如何与 干预组预测临床结果。我们希望这项创新的试验将有助于改善癌症治疗 结果和重塑癌症患者的护理标准。