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

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(申请人提供)：局部晚期非小细胞肺癌(NSCLC)和胰腺癌预后都很差，五年存活率在5-20%之间。最常见的治疗方法包括化疗、放射治疗的组合，如果可能的话，还包括手术。然而，鉴于结果不佳，改善结果的新的补充办法是非常可取的。生酮饮食(KD)是一种有希望的、创新的互补方法，它潜在地利用了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，多年来一直被安全用作癫痫的治疗方法。与蛋白质和碳水化合物相比，生酮饮食含有较高比例的脂肪，导致血酮水平升高，血糖指数下降，迫使细胞更多地依赖线粒体呼吸而不是糖酵解来产生能量。相对于正常细胞，癌细胞对葡萄糖的摄取增加，并被认为存在于慢性代谢氧化应激状态。已经提出，有重要的数据支持，癌细胞利用增加的葡萄糖代谢来产生还原当量，这是促进氢过氧化分解所必需的，作为对由癌细胞特有的线粒体O2代谢障碍引起的代谢氧化应激的适应性反应。如果生酮饮食限制了葡萄糖代谢，迫使细胞从线粒体代谢中获取能量，那么这些饮食也将选择性地增强癌细胞(相对于正常细胞)的氧化应激是合理的。最重要的假设是，生酮饮食(KD)在临床上耐受性良好，并通过氧化应激机制选择性地增强非小细胞肺癌(NSCLC)和胰腺癌对化疗放射增敏的反应。这是基于在患有人类NSCLC或胰腺癌的小鼠身上的初步数据，在放射治疗期间服用KD的小鼠显示出增强的治疗反应和指示氧化应激的参数增加，没有不良反应的证据。为了将这些令人兴奋的临床前观察转化为人体试验，目前的提议将确定局部晚期非小细胞肺癌和胰腺癌患者在接受同步标准放化疗的同时对延长(6.5-7.5周)KD的耐受性。此外，将对受试者的血液进行分析，以寻找指示酮病的参数(血清酮和血糖)以及氧化应激参数(脂质过氧化、DNA氧化和蛋白质氧化)增加的证据。这些研究的成功完成将证实受试者对KD合并化疗辐射的耐受性，以及评估饮食对新陈代谢和氧化应激指数的影响。这项研究的成功完成将使未来的试验能够评估KD作为癌症治疗的辅助剂的潜力，并有可能提高非小细胞肺癌和胰腺癌标准疗法的疗效。 公共卫生相关性：接受放化疗治疗的局部晚期非小细胞肺癌和胰腺癌患者的预后仍然很差；因此，非常希望有希望改善结果的易于实施、相对无毒的饮食干预措施。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来改善标准治疗结果的前景。因此，生酮饮食的发展，作为标准治疗的补充佐剂，可能会对改善标准癌症治疗产生重大影响。