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: 10643869
• 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/10643869
• 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; Oncology; Operative Surgical Procedures; Outcome; Oxidative Stress; Participant; Pathologic; Pathway interactions; Patient Outcomes Assessments; Patient-Focused Outcomes; Patients; Peripheral Blood Mononuclear Cell; Physical activity; Proliferating; Quality of life; Questionnaires; Randomized; Randomized, Controlled Trials; Rectal Cancer; Rectal Neoplasms; Regimen; Reporting; Resistance; Risk; Schedule; Seminal; Serum; Shapes; 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; cancer care; cancer regression; cancer therapy; cardiometabolism; cell growth; chemoradiation; chemotherapy; clinical implementation; comparison control; 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 在动物模型中，禁食和化疗相结合可以导致肿瘤完全消退。急性禁食是 被认为可以使肿瘤细胞对化疗和放射的细胞毒作用敏感，同时保护健康 通过提高细胞的抗应力能力--这种现象被称为差异应力敏化理论。 然而，延长热量限制的潜在风险阻碍了临床应用。限时进食 (Tre)是一种很有前途的替代方案，它包括在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有几种抗癌作用：降低IGF-1水平，减少氧化应激，上调 抗氧化剂防御，并增强自噬。我们建议进行首个tre治疗癌症的临床试验。 正在接受积极治疗的患者，以及任何形式的间歇治疗的最大随机对照试验 癌症患者的禁食。我们将重点关注直肠癌，因为它是仅有的几种肿瘤 可以测量治疗前后的大小和特征。我们将招收300名新确诊患者 局限性直肠癌患者(II-III期)，年龄18岁(≥，≥18.5 kg/m2)。所有参赛者都将收到标准 在锡达斯-西奈医学癌症(加利福尼亚州洛杉矶)或加州大学的肿瘤学治疗期间的护理 阿拉巴马州奥尼尔综合癌症中心(亚利桑那州伯明翰)，随机选择两种饮食之一 时间表：(1)控制表：每天进食12小时或更长时间；(2)TRE：每天8小时进食期(16 每日禁食小时数)。参与者将得到保持体重的建议。所有端点的测量值均为 至少三次：在化疗开始前的诊断时(基线)，在化疗治疗之后， 肿瘤切除时(介入后)。我们的主要目标是确定TrE如何影响临床结果， 包括与治疗有关的不良反应(毒性指数以CTCAE V.5为基础)、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)完成 应答率。目标2测试差异应力敏化理论--该理论的第一个完整测试 人类。我们测试tre是否通过igf-1途径提高健康细胞的抗应激能力。 (DNA损伤和抗氧化防御以伽马-H_2AX和总抗氧化能力衡量， 分别)和促进肿瘤细胞死亡(通过激活的caspase-3和 LC 3-I/LC 3-II)。目标3比较情绪、社交功能、睡眠、饮食和 跨干预臂的日常体力活动(控制组与tre组)，并探索这些变化如何与 干预武器以预测临床结果。我们希望这项创新的试验将有助于改善癌症治疗。 结果，并重塑对癌症患者的护理标准。

项目成果

The influence of experimental confederate peers on children's food intake: A systematic review and meta-analysis.

• DOI: 10.1016/j.appet.2021.105863
• 发表时间: 2022-02-01
• 期刊: Appetite
• 影响因子: 5.4
• 作者: Sharps MA;Coulthard H;Salvy SJ;Ryan S;Fallon V
• 通讯作者: Fallon V

Time-Limited Eating and Continuous Glucose Monitoring in Adolescents with Obesity: A Pilot Study.

• DOI: 10.3390/nu13113697
• 发表时间: 2021-10-21
• 期刊: Nutrients
• 影响因子: 5.9
• 作者: Vidmar AP;Naguib M;Raymond JK;Salvy SJ;Hegedus E;Wee CP;Goran MI
• 通讯作者: Goran MI

External food cue responsiveness and emotional eating in adolescents: A multimethod study.

• DOI: 10.1016/j.appet.2021.105789
• 发表时间: 2022-01-01
• 期刊: Appetite
• 影响因子: 5.4
• 作者: Schneider-Worthington CR;Smith KE;Roemmich JN;Salvy SJ
• 通讯作者: Salvy SJ