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: 8333333
• 负责人: JOHN M. BUATTI
• 金额: $ 15.36万
• 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 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8333333
• 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.

描述（由申请人提供）：局部晚期非小细胞肺癌（NSCLC）和胰腺癌的预后均较差，五年生存率在 5-20% 之间。最常见的治疗方法包括化疗、放疗的组合，如果可能的话，还包括手术。然而，鉴于结果不佳，非常需要新的改善结果的补充方法。生酮饮食（KD）是一种有前途且创新的补充方法，它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，多年来一直安全地用于治疗癫痫。生酮饮食相对于蛋白质和碳水化合物含有较高比例的脂肪，导致血酮水平升高和血糖指数降低，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，癌细胞的葡萄糖摄取增加，并且被认为存在于慢性代谢氧化应激状态。有重要数据支持，有人提出，癌细胞利用增加的葡萄糖代谢来产生促进氢过氧化物分解所必需的还原当量，作为对癌细胞特异性线粒体 O2 代谢功能失调引起的代谢氧化应激的适应性反应。 如果生酮饮食限制葡萄糖代谢并迫使细胞从线粒体代谢中获取能量，那么有理由认为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）在临床上具有良好的耐受性，并通过氧化应激机制选择性增强非小细胞肺癌（NSCLC）和胰腺癌对化学放射增敏的反应。这是基于在放射治疗期间喂食 KD 的人类非小细胞肺癌或胰腺癌异种移植小鼠的初步数据，这些数据表明治疗反应增强，指示氧化应激的参数增加，但没有不良反应的证据。为了将这些令人兴奋的临床前观察结果转化为人体试验，当前的提案将确定患有局部晚期 NSCLC 和胰腺癌的受试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，将分析受试者血液以寻找指示酮症的参数（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耐受川崎病并发化疗放疗的能力，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使未来的试验能够评估 KD 作为癌症治疗佐剂的潜力，并有可能提高非小细胞肺癌和胰腺癌标准疗法的疗效。