Fermented wheat germ proteins;mechanistic, immunologic and pre-clinical canine studies

在美国，大约33%的成年人使用了补充性健康方法（NHIS，CDC [4-6]）。 在这样做的过程中，5900万美国人每年花费302亿美元。最常用的 补充方法是天然产品（128亿美元，几乎是自付金额的四分之一 所有处方药的总支出）。此外，最近的研究发现，CAM的使用是非常重要的。 在这个国家和许多其他国家流行，36-52%的人口在某个时候使用CAM [29]。尽管 它们的频繁使用和对医疗保健资金的重大影响，科学研究提供的证据很少 用于癌症治疗的天然产品。 用酿酒酵母发酵的小麦胚芽的水提取物（FWGE）在美国出售。 作为膳食补充剂（商品名：爱维麦）。FWGE对几种人类癌细胞系具有细胞毒性[7-16]; 已经报道了对结肠直肠癌[17-21]、黑色素瘤[22]和鳞状细胞癌的体内疗效 [20]初步的临床数据是有希望的[17，22，23]。据报道，FWGE具有“免疫重建”功能 影响[17，22，24，30-32]。然而，这些结论大多是基于单一实验研究，缺乏 严格的后续行动。有人提出，FWGE活动的基础是其内容， 二甲氧基苯醌（DMBQ）[24-27]。然而，这还没有得到证实，事实上，早期的研究 表明DMBQ单独不能对FWGE的免疫刺激特性负责[24]，并且可能 实际上具有显著毒性[33-35]。 我们已经证实FWGE在体内NHL模型中具有显著的抗肿瘤活性，特别是当 与单克隆抗体（mAb）利妥昔单抗组合使用。FWGE的疗效与 而FWGE无明显毒副作用。我们公布的结果表明 来自发酵小麦胚芽（FWGP）的蛋白质组分，而不是DMBQ，负责这种活性， 至少部分地刺激体内自然杀伤（NK）细胞介导的肿瘤根除[28]。这是一个重大 因为在血液恶性肿瘤中描述了异常NK细胞溶解活性[36]。 本提案的总体目标是分离FWGP中的有源组件，并了解其 通过检查犬NHL体内和人类离体的活性/毒性， 人体临床试验 VA人群的显著性 我们已经证明FWGP在体外和体内均有效对抗NHL [28]。NHL是第六大 美国癌症相关死亡的常见原因[1-3]。增长最快的部分 患这种疾病的人群是老年男性（VA患者人群的很大一部分）。给定 这一点，以及NHL是一种与橙色相关的恶性肿瘤，对退伍军人的影响是巨大的。 我们也有大量的初步数据表明，FWGP是有效的，在临床前模型的非- 小细胞肺癌（NSCLC）。NK细胞在肺癌中的抗肿瘤活性越来越被人们所认识 作为一个可行的临床目标[44-47]。虽然这项建议的重点是NHL，我们的结果可能有 对NCSLC的治疗有重大影响。肺癌是世界上最常见的癌症死亡原因- #24489;，男女都有。NSCLC占所有肺癌的约85%。约2/3 的患者在初次就诊时患有晚期或转移性疾病[50]。存活率为2- 20%取决于阶段[51，52]。目前的化疗具有显著的毒性。检查点抑制具有 这是一个革命性的肿瘤学，但高达三分之二的NSCLC患者未能响应或最终复发。这 一项提案为开发新的、有效的、无毒的NHL治疗方法奠定了基础 和非小细胞肺癌，直接适用于VA患者人群。

Approximately 33% of adults in the U.S. have used complementary health approaches (NHIS, CDC [4-6]). In doing so, 59 million Americans spend $30.2 billion out-of-pocket/year. The most commonly used complementary approach are natural products ($12.8 billion-almost one fourth of the out-of-pocket amount spent on all prescription drugs combined). Moreover, recent studies have found that CAM use is highly prevalent in this and many other countries with 36-52% of the population using CAM at some time [29]. Despite their frequent use and significant impact in healthcare dollars, scientific research has provided scant evidence for benefit of natural products in cancer therapy. An aqueous extract of wheat germ fermented with Saccharomyces cerevisiae (FWGE) is sold in the U.S. as a dietary supplement (trade name: Avemar). FWGE is cytotoxic to several human cancer cell lines [7-16]; in vivo efficacy has been reported for colorectal carcinoma [17-21], melanoma [22] and squamous cell carcinoma [20] and preliminary clinical data is promising [17, 22, 23]. FWGE reportedly has “immune-reconstructive” effects [17, 22, 24, 30-32]. These conclusions, however, are mostly based on single-experiment studies devoid of rigorous follow-up. It has been proposed that FWGE activity is based on its content of dimethoxybenzoquinone (DMBQ) [24-27]. However, this has not been proven, and indeed early studies indicated that DMBQ alone cannot be responsible for the immunostimulatory properties of FWGE [24] and may in fact have significant toxicity [33-35]. We have confirmed that FWGE has remarkable anti-tumor activity in NHL models in vivo especially when used in combination with the monoclonal antibody (mAb) rituximab. The efficacy of FWGE was comparable to that of the aggressive R-CHOP regimen, but FWGE had no appreciable toxicity. Our published results suggest that a protein fraction from fermented wheat germ (FWGP), not DMBQ, is responsible for this activity by, at least in part, stimulating natural killer (NK) cell-mediated tumor eradication in vivo [28]. This is a significant observation since abnormal NK cytolytic activity has been described in hematological malignancies [36]. The overall goal of this proposal is to isolate active component(s) in FWGP and to understand its tumoricidal effects by examining activity/toxicity in vivo in canine NHL and ex vivo in humans in anticipation of human clinical trials. Significance for the VA population We have shown that FWGP is effective against NHL, both in vitro and in vivo [28]. NHL is the sixth most common cause of cancer-related death in the United States [1-3]. The fastest growing segment of the population acquiring this disease is elderly males (a substantial segment of the VA patient population). Given this, and the fact that NHL is an agent orange-associated malignancy, the impact on veterans is substantial. We also have substantial preliminary data suggesting that FWGP is effective in pre-clinical models of non- small cell lung carcinoma (NSCLC). NK cell anti-tumor activity in lung cancer is increasingly being recognized as an actionable clinical target [44-47]. While the focus of this proposal is on NHL, our results could have substantial impact in the treatment of NCSLC. Lung cancer is the most common cause of cancer-death world- wide world [48, 49] in both men and women. NSCLC represents ~85% of all lung cancers. Approximately 2/3 of the patients have advanced or metastatic disease at the time of initial presentation [50]. Survival rates are 2- 20% depending on stage [51, 52]. Current chemotherapy bears significant toxicity. Checkpoint inhibition has revolutionized oncology, but up to two thirds of NSCLC patients fail to respond or eventually relapse. This proposal lays the groundwork for development of new, effective, and non-toxic treatment approaches for NHL and NSCLC , which are directly applicable to the VA patient population.