Using Ketogenic Diets to Enhance Radio-Chemo-Therapy Response: A Phase I Trial

使用生酮饮食增强放射化疗反应：一期试验

• 批准号: 8175225
• 负责人: JOHN M. BUATTI
• 金额: $ 18.64万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8175225
• 关键词: Adjuvant; Adverse effects; Blood; Blood Glucose; Cancer Etiology; Cancer Patient; Carbohydrates; Case Study; Cells; Cessation of life; Chronic; Combination Drug Therapy; Complement; Consumption; DNA; Data; Defect; Development; Diet; Dietary Intervention; Disease; Epilepsy; Fatty acid glycerol esters; Future; Glucose; Glycemic Index; Glycolysis; Human; Hydrogen Peroxide; Investigation; Ketones; Ketoses; Ketosis; Lipid Peroxidation; Malignant neoplasm of brain; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Metabolic; Metabolism; Mitochondria; Mus; Nature; Non-Small-Cell Lung Carcinoma; Normal Cell; Operative Surgical Procedures; Outcome; Oxidative Stress; Patients; Phase I Clinical Trials; Phase II/III Trial; Production; Proteins; Radiation; Radiation therapy; Radio; Relative (related person); Respiration; Serum; Solutions; Survival Rate; Testing; Therapeutic; Toxic effect; Translating; United States; Urine; Xenograft procedure; base; cancer care; cancer cell; cancer therapy; cost effective; feeding; glucose metabolism; glucose uptake; improved; indexing; innovation; ketogenic diet; malignant stomach neoplasm; mouse model; novel therapeutic intervention; outcome forecast; oxidation; pre-clinical; response; standard care; stem; Adjuvant; Adverse effects; Blood; Blood Glucose; Cancer Etiology; Cancer Patient; Carbohydrates; Case Study; Cells; Cessation of life; Chronic; Combination Drug Therapy; Complement; Consumption; DNA; Data; Defect; Development; Diet; Dietary Intervention; Disease; Epilepsy; Fatty acid glycerol esters; Future; Glucose; Glycemic Index; Glycolysis; Human; Hydrogen Peroxide; Investigation; Ketones; Ketoses; Ketosis; Lipid Peroxidation; Malignant neoplasm of brain; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Metabolic; Metabolism; Mitochondria; Mus; Nature; Non-Small-Cell Lung Carcinoma; Normal Cell; Operative Surgical Procedures; Outcome; Oxidative Stress; Patients; Phase I Clinical Trials; Phase II/III Trial; Production; Proteins; Radiation; Radiation therapy; Radio; Relative (related person); Respiration; Serum; Solutions; Survival Rate; Testing; Therapeutic; Toxic effect; Translating; United States; Urine; Xenograft procedure; base; cancer care; cancer cell; cancer therapy; cost effective; feeding; glucose metabolism; glucose uptake; improved; indexing; innovation; ketogenic diet; malignant stomach neoplasm; mouse model; novel therapeutic intervention; outcome forecast; oxidation; pre-clinical; response; standard care; stem

DESCRIPTION (provided by applicant): Locally advanced non-small cell lung cancer (NSCLC) and pancreatic cancer both have a poor prognosis with five year survival rates ranging between 5-20%. The most common therapies include a combination of chemotherapy, radiation therapy, and when possible, surgery. However, given the poor outcomes, new complementary approaches which improve outcome are highly desirable. One promising and innovative complementary approach that potentially exploits fundamental metabolic differences between cancer cells and normal cells is the ketogenic diet (KD). Ketogenic diets are relatively non-toxic and have been used safely for years as a treatment for epilepsy. Ketogenic diets contain a high proportion of fat relative to protein and carbohydrates and result in elevated blood ketone levels and a lower glycemic index which force cells to rely more heavily on mitochondrial respiration, as opposed to glycolysis, for energy production. Cancer cells, relative to normal cells, have increased glucose uptake and are believed to exist in a state of chronic metabolic oxidative stress. It has been proposed, with significant supporting data, that cancer cells utilize increased glucose metabolism to generate reducing equivalents that are necessary to facilitate the decomposition of hydroperoxides as an adaptive response to metabolic oxidative stress caused by cancer cell specific dysfunctional mitochondrial O2 metabolism. If ketogenic diets limit glucose metabolism and force cells to derive energy from mitochondrial metabolism, it is reasonable to propose that these diets will also selectively enhance oxidative stress in cancer cells (relative to normal cells). The overarching hypothesis is that ketogenic diets (KD) will be clinically well tolerated and selectively enhance responses of non-small cell lung cancer (NSCLC) and pancreatic cancer to chemo-radio- sensitization via an oxidative stress mechanism. This is based on preliminary data in mice with human NSCLC or pancreas cancer xenografts fed KD during radiotherapy demonstrate enhanced therapeutic responses and increases in parameters indicative of oxidative stress with no evidence of adverse effects. To translate these exciting preclinical observations into human trials the current proposal will determine the tolerance of subjects with locally advanced NSCLC and pancreatic cancer to a prolonged (6.5-7.5 week) KD while receiving concurrent standard chemo-radiation therapy. Furthermore, subject blood will be analyzed for evidence of increases in parameters indicative of ketosis (serum ketones and blood glucose) as well as parameters of oxidative stress (lipid peroxidation, DNA oxidation, and protein oxidation). Successful completion of these studies will confirm the ability of subjects to tolerate a KD with concurrent chemo-radiation as well as assess the impact of the diet on metabolism and indices of oxidative stress. Successful completion of this study will allow for future trials to assess the potential for a KD to be used as an adjuvant to cancer therapy with the potential of increasing the efficacy of standard therapies for NSCLC and pancreatic cancer. PUBLIC HEALTH RELEVANCE: The prognosis for patients receiving radio-chemo-therapy for the treatment of locally advanced NSCLC and pancreatic cancer remains poor; therefore, easily implemented, relatively non-toxic dietary interventions that show promise to improve outcome are highly desirable. Furthermore, ketogenic diets show promise for exploiting inherent oxidative metabolic differences between cancer cells and normal cells to improve standard therapeutic outcomes. Thus, the development of a ketogenic diet, as a complementary adjuvant to standard therapy, could have a significant influence on improving standard cancer care.

描述（由申请人提供）：局部晚期的非小细胞肺癌（NSCLC）和胰腺癌的预后较差，五年生存率在5-20％之间。最常见的疗法包括化学疗法，放射治疗以及可能的手术结合。但是，鉴于结果不佳，高度希望提高结果的新互补方法。生酮饮食（KD）是一种有前途和创新的互补方法，该方法可能利用癌细胞和正常细胞之间的基本代谢差异。 生酮饮食相对无毒，多年来一直被安全地用作癫痫的治疗方法。相对于蛋白质和碳水化合物，生酮饮食含有高比例的脂肪，并导致血酮水平升高和较低的血糖指数，迫使细胞更严重地依赖于线粒体的呼吸，而不是糖酵解，而不是糖酵解。癌细胞相对于正常细胞，葡萄糖摄取增加，据信以慢性代谢氧化应激状态存在。已经提出，有了重要的支持数据，癌细胞利用增加的葡萄糖代谢来产生减少等效物，这是促进氢过氧化物的分解所必需的，作为对由癌细胞特异性功能功能性功能功能性的官能体性O2 O2代谢的适应性反应。 如果生酮饮食限制葡萄糖代谢和迫使细胞从线粒体代谢中得出能量，则可以合理地提出，这些饮食还将选择性地增强癌细胞（相对于正常细胞）的氧化应激。总体假设是，生酮饮食（KD）在临床上的耐受性良好，并有选择地增强了非小细胞肺癌（NSCLC）（NSCLC）和胰腺癌对化学降低敏感性通过氧化应激机制的反应。这是基于人类NSCLC或胰腺癌异种移植物在放射治疗期间喂养KD的小鼠的初步数据，表明治疗反应增强，并且参数的增加表示氧化应激的参数，没有不良影响的证据。为了将这些令人兴奋的临床前观察转化为人类试验，目前的提案将确定局部晚期NSCLC和胰腺癌受试者的容忍度，以在接受并发标准化学放射治疗的同时长时间（6.5-7.5周）KD。此外，将分析受试者的血液，以表明参数增加的证据，指示酮（血清酮和血糖）以及氧化应激的参数（脂质过氧化，DNA氧化和蛋白质氧化）。这些研究的成功完成将证实受试者与同时化学辐射耐受KD的能力，并评估饮食对代谢和氧化应激指数的影响。这项研究的成功完成将允许将来的试验评估KD用作癌症治疗的辅助药物的潜力，从而有可能增加标准疗法对NSCLC和NSCLC和胰腺癌的疗效。 公共卫生相关性：接受无线电化疗治疗的患者的预后治疗局部晚期NSCLC和胰腺癌的预后仍然很差；因此，非常需要实施相对无毒的饮食干预措施，这些干预措施非常需要改善预后。此外，生酮饮食显示出利用癌细胞和正常细胞之间固有的氧化代谢差异以改善标准治疗结果的有望。因此，作为标准疗法的补充辅助饮食的开发可能会对改善标准癌症护理产生重大影响。