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

发酵小麦胚芽蛋白；机制、免疫学和临床前犬研究

• 批准号: 10616508
• 负责人: JOSEPH M TUSCANO
• 金额: --
• 依托单位: VA NORTHERN CALIFORNIA HEALTH CARE SYS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-10-01 至 2025-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10616508
• 关键词: Adult; Affect; Alternative Medicine; American; Animal Model; Animals; Award; Biochemical; Biological Assay; Biology; Cancer Etiology; Cancer cell line; Canis familiaris; Cessation of life; Clinical Data; Clinical Research; Clinical Trials; Collaborations; Column Chromatography; Complementary Health; Complex; Country; Data; Development; Disease; Dose; Drug Combinations; Drug Prescriptions; Elderly; Environmental Risk Factor; Exposure to; Expression Profiling; Fermentation; Fractionation; Germ; Goals; Healthcare; Hematologic Neoplasms; Human; Immune; Immunity; Immunologics; Immunotherapy; In Vitro; Interferon Type II; Laboratory mice; Large Intestine Carcinoma; Legal patent; Ligands; Lymphoma; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Medicine; Monoclonal Antibodies; Names; Natural Killer Cells; Natural Products; Natural Source; Non-Hodgkin' s Lymphoma; Non-Small-Cell Lung Carcinoma; Oncologist; Oncology; Patients; Peptides; Persons; Phase; Phase II Clinical Trials; Population; Pre-Clinical Model; Production; Property; Protein Array; Proteins; Publishing; Regimen; Relapse; Reporting; Research; Resources; Role; Running; Saccharomyces cerevisiae; Squamous cell carcinoma; Survival Rate; Techniques; Therapeutic; Time; Toxic effect; Translating; United States; Veterans; Veterinary Medicine; Veterinary Schools; Wheat; Woman; Work; agent orange; anticancer activity; aqueous; cancer immunotherapy; cancer therapy; candidate identification; cell killing; checkpoint inhibition; chemotherapy; clinically actionable; commercialization; cytotoxic; cytotoxicity; dietary supplements; drug development; experience; experimental study; exposed human population; follow-up; human disease; human model; immunoregulation; in vitro activity; in vivo; in vivo Model; male; melanoma; men; mouse model; multidisciplinary; neoplastic cell; non-Hodgkin' s lymphoma patients; novel; patient population; pre-clinical; pre-clinical research; receptor; response; rituximab; standard of care; translational scientist; tumor; tumor eradication

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.

美国约有33％的成年人使用了完整的健康方法（NHIS，CDC [4-6]）。 这样一来，有5,900万美国人每年花费302亿美元。最常用的 完成的方法是天然产品（$ 128亿美元，几乎是自付费用的四分之一 花费所有处方药加在一起）。此外，最近的研究发现，CAM使用高度高 在这个和许多其他国家 /地区，在某个时候使用CAM的人口占36-52％[29]。尽管 科学研究经常使用和对医疗保健资金的重大影响，提供了很少的证据 对于天然产品在癌症治疗中的好处。 用酿酒酵母（FWGE）发酵的小麦种植水提取物在美国出售 作为饮食补充剂（商品名：Avemar）。 FWGE对几种人类癌细胞系具有细胞毒性[7-16]；在 已经报道了结直肠癌[17-21]，黑色素瘤[22]和鳞状细胞癌的体内效率 [20]和初步临床数据有望[17，22，23]。据报道，FWGE具有“免疫重建性” 效果[17，22，24，30-32]。但是，这些结论主要基于单示体研究 严格的随访。有人提出，FWGE活动基于其内容 二甲氧基苯甲酮（DMBQ）[24-27]。但是，这尚未得到证明，而且确实是早期的研究 表明单独的DMBQ不能对FWGE的免疫刺激特性负责[24]和5月 实际上，具有明显的毒性[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 与单克隆抗体（MAB）利妥昔单抗结合使用。 FWGE的效率与 侵略性的R-Chop方案是，但FWGE没有可欣赏的毒性。我们发表的结果表明 从发酵小麦胚芽（FWGP）而非DMBQ的蛋白质分数是由AT负责的 至少部分地，刺激体内刺激自然杀伤（NK）细胞介导的消除肿瘤[28]。这是重要的 观察发现，由于血液学恶性肿瘤中已经描述了异常NK胞溶活性[36]。 该提案的总体目标是隔离FWGP中的主动组件，并了解其 通过检查犬NHL体内的活性/毒性的肿瘤作用 人类临床试验。 对VA人口的意义 我们已经表明，FWGP在体外和体内都有效地针对NHL [28]。 NHL是第六位 美国与癌症相关死亡的常见原因[1-3]。增长最快的部分 该疾病的人口是男性（VA患者人群的大部分地区）。给出 这是NHL是与橙色相关的恶性肿瘤的事实，对退伍军人的影响很大。 我们还拥有大量的初步数据，表明FWGP在非 - 临床前模型中有效 小细胞肺癌（NSCLC）。肺癌中NK细胞抗肿瘤活性越来越多地被识别 作为可行的临床靶标[44-47]。尽管该提议的重点是NHL，但我们的结果可能已经 对NCSLC治疗的实质性影响。肺癌是癌症死亡世界的最常见原因 - 在男人和女人中，世界[48，49]。 NSCLC占所有肺癌的85％。大约2/3 在初次出现时，患者患有晚期或转移性疾病[50]。生存率为2- 20％取决于阶段[51，52]。当前的化学疗法具有明显的毒性。检查点抑制具有 彻底改变了肿瘤学，但多达三分之二的NSCLC患者未能反应或有时继电器。这 提案为NHL开发新，有效和无毒治疗方法开发了基础 和NSCLC，直接适用于VA患者人群。