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

在美国，大约33%的成年人使用过补充保健方法(NHIS、CDC[4-6])。 为此，5900万美国人每年自掏腰包花费302亿美元。最常用的 补充办法是天然产品(128亿美元-几乎是自付金额的四分之一 花在所有处方药上的费用加起来)。此外，最近的研究发现，CAM的使用率很高 在这个和许多其他国家流行，有时有36%-52%的人口使用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 为了天然产物在癌症治疗中的益处。 一种用酿酒酵母发酵的小麦胚芽的水提取物(FWGE)在美国销售。 作为膳食补充剂(商标：Avemar)。FWGE对几种人类癌细胞系有细胞毒性[7-16]； 已经报道了对结直肠癌、黑色素瘤和鳞状细胞癌的体内疗效。 [20]初步临床数据显示前景看好[17，22，23]。据报道，FWGE具有“免疫重建”功能 效果[17、22、24、30-32]。然而，这些结论大多基于缺乏单一实验研究。 严谨的后续行动。有人提出，FWGE活动是基于其以下内容 二甲氧基苯醌(DMBQ)[24-27]。然而，这一点还没有得到证实，甚至早期的研究也是如此 指出DMBQ本身不能对FWGE的免疫刺激特性负责[24]，并且可能 事实上具有显著的毒性[33-35]。 我们已经证实，FWGE在体内NHL模型中具有显着的抗肿瘤活性，尤其是当 与单抗(MAb)利妥昔单抗结合使用。FWGE的疗效与 侵袭性R-CHOP方案，但FWGE无明显毒性。我们公布的结果表明 来自发酵小麦胚芽的一种蛋白质组分(FWGP)，而不是DMBQ，通过，在 至少在体内，刺激自然杀伤(NK)细胞介导的肿瘤根除[28]。这是一个意义重大的 自从NK细胞溶解活性异常被描述为血液系统恶性肿瘤以来的观察[36]。 该方案的总体目标是分离FWGP中的活性成分(S)，并了解其 犬非霍奇金淋巴瘤体内活性/毒性检测及体外杀瘤作用的研究 人体临床试验。 对退伍军人管理局人口的意义 我们已经证明FWGP在体外和体内都对NHL有效[28]。NHL排在第六位 美国癌症相关死亡的常见原因[1-3]。增长最快的细分市场 感染这种疾病的人群是老年男性(VA患者人口的很大一部分)。vt.给出 这一点，以及NHL是一种与橙剂相关的恶性肿瘤，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在非临床前模型中是有效的 小细胞肺癌(NSCLC)。肺癌中NK细胞的抗肿瘤活性日益受到重视 作为一个可操作的临床靶点[44-47]。虽然这项提案的重点是NHL，但我们的结果可能是 对NCSLC的治疗有实质性影响。肺癌是癌症最常见的原因--死亡世界-- 男人和女人的世界都很广阔。非小细胞肺癌约占所有肺癌的85%。大约2/3 的患者在最初出现症状时已经是晚期或转移性疾病[50]。存活率是2- 20%取决于阶段[51，52]。目前的化疗具有明显的毒性。检查点抑制具有 肿瘤学发生了革命性的变化，但多达三分之二的非小细胞肺癌患者没有反应或最终复发。这 该提案为开发新的、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患者群体。

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.