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

描述（由申请人提供）：局部晚期非小细胞肺癌（NSCLC）和胰腺癌的预后都很差，5年生存率在5- 20%之间。最常见的治疗包括化疗，放射治疗的组合，如果可能的话，手术。然而，鉴于结果不佳，非常需要改进结果的新的补充方法。一种有希望的和创新的补充方法，可能利用癌细胞和正常细胞之间的基本代谢差异是生酮饮食（KD）。 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高比例的脂肪，并导致血酮水平升高和血糖指数降低，这迫使细胞更严重地依赖于线粒体呼吸而不是糖酵解来产生能量。相对于正常细胞，癌细胞具有增加的葡萄糖摄取，并且被认为存在于慢性代谢氧化应激状态中。已经提出，具有重要的支持数据，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，作为对由癌细胞特异性功能失调的线粒体O2代谢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得能量，则有理由提出这些饮食也会选择性地增强癌细胞中的氧化应激（相对于正常细胞）。总体假设是生酮饮食（KD）将具有良好的临床耐受性，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NSCLC或胰腺癌异种移植物小鼠的初步数据，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结果转化为人体试验，目前的提案将确定局部晚期NSCLC和胰腺癌受试者在接受同步标准化放疗的同时对长期（6.5-7.5周）KD的耐受性。此外，将分析受试者血液中指示酮症的参数（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KD与同步化疗-放疗的能力，并评估饮食对代谢和氧化应激指数的影响。本研究的成功完成将使未来的试验能够评估KD用作癌症治疗辅助治疗的潜力，以及增加NSCLC和胰腺癌标准治疗疗效的潜力。

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.