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: 10428508
• 负责人: Jane C. Figueiredo
• 金额: $ 86.78万
• 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/10428508
• 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.

抽象的 在动物模型中，禁食与化学疗法结合可能会导致肿瘤的完全消退。急性禁食是 被认为可以将肿瘤细胞感知化学疗法和放射的细胞毒性作用，同时保护健康 细胞通过增加压力抗性 - 一种被称为差异应力敏化理论的现象。 但是，扩展热量限制的潜在风险阻碍了临床实施。时间限制的饮食 （TRE）是一个承诺的替代方案，涉及在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可能更可持续。此外，我们的飞行员数据建议 TRE具有多种抗癌作用：它降低了IGF-1水平，降低了氧化应激，上调 抗氧化剂防御，并增强自噬。我们建议在癌症中进行TRE的首次临床试验 接受主动治疗的患者以及任何形式间歇性的最大随机对照试验 癌症患者禁食。我们将重点关注直肠癌，因为它是肿瘤的仅有的伴侣之一 可以在治疗前后测量大小和特征。我们将注册300个新诊断 年龄≥18岁（BMI≥18.5kg/m2）的局部直肠癌患者（II-III期）。所有参与者都将获得标准 在Cedars-Sinai医学癌症（加利福尼亚州洛杉矶）或大学的肿瘤学治疗期间 阿拉巴马州奥尼尔综合癌症中心（伯明翰，阿拉巴马州），并随机分为两种饮食之一 时间表：（1）控制时间表：12小时或更长时间的每日饮食期； （2）TRE：每天8小时饮食期（16 每天禁食时间）。参与者将被抛在一起以保持体重。所有端点将在 至少三次：在化学放疗（基线）之前的诊断后，化学放疗治疗后， 和肿瘤切除术（干预后）。我们的主要目的是确定TRE如何影响临床结果， 包括与治疗相关的不良反应（基于CTCAE V.5的毒性指数），患者报告的结果 （Pro-CTCAE）和生活质量（EORTC QLQ-C30）以及临床（CCR）和病理（PCR）完整 响应率。 AIM 2测试差异压力敏化理论 - 该理论的第一个完整检验 人类。我们测试TRE是否通过IGF-1途径作用以增加健康细胞中的应激性抗性 （通过γ-H2AX和总抗氧化能力测量的DNA损伤和抗氧化剂防御措施， 分别）并增强肿瘤细胞死亡（通过激活的caspase-3和 LC3-I/LC3-II，分别）。 AIM 3比较情绪，社交功能，睡眠，饮食和 跨干预臂（控制与TRE）的每日体育活动，并探索这些变化如何与 干预臂预测临床结果。我们预计这项创新的试验将有助于改善癌症治疗 结果并重塑癌症患者的护理标准。