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: 9779443
• 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 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9779443
• 关键词: Adult; Affect; Alternative Medicine; American; Animal Model; Animals; Award; Biochemical; Biological Assay; Biology; Cancer Etiology; Cancer cell line; Canis familiaris; Centers for Disease Control and Prevention (U.S.); Cessation of life; Clinical Data; Clinical Research; Clinical Trials; Collaborations; Column Chromatography; Complementary Health; Complex; Country; Data; Development; Disease; Dose; Drug Prescriptions; Elderly; Environmental Risk Factor; Exposure to; Expression Profiling; 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; Non-Hodgkin' s Lymphoma; Non-Small-Cell Lung Carcinoma; Oncologist; Oncology; Patients; Peptides; Phase; Phase II Clinical Trials; Population; Pre-Clinical Model; Production; Property; Protein Array; Proteins; Publishing; Regimen; Relapse; Reporting; Research; Resources; Role; Running; Saccharomyces cerevisiae; Source; Squamous cell carcinoma; Survival Rate; Techniques; Therapeutic; Time; Toxic effect; Translating; United States; Ursidae Family; Veterans; Veterinary Medicine; Veterinary Schools; Wheat; Woman; Work; agent orange; anticancer activity; aqueous; base; 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; reconstruction; research and development; 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.

大约 33% 的美国成年人使用了补充健康方法（NHIS、CDC [4-6]）。 为此，5900 万美国人每年自掏腰包支出 302 亿美元，这是最常用的。 补充方法是天然产品（128 亿美元——几乎是自付费用的四分之一 此外，最近的研究发现 CAM 的使用率很高。 在这个国家和许多其他国家很流行，有 36-52% 的人口在某个时候使用 CAM [29]。 它们的频繁使用和对医疗保健费用的重大影响，科学研究提供的证据很少 天然产物在癌症治疗中的益处。 用酿酒酵母 (FWGE) 发酵的小麦胚芽的水提取物在美国销售。 作为膳食补充剂（商品名：Avemar），FWGE 对多种人类癌细胞系具有细胞毒性 [7-16]； 已报道结直肠癌 [17-21]、黑色素瘤 [22] 和鳞状细胞癌的体内疗效 [20] 初步临床数据令人鼓舞 [17,22,23] 据报道，FWGE 具有“免疫重建作用”。 然而，这些结论大多基于缺乏单一实验的研究。 有人提出，FWGE 活动是基于其内容的。 二甲氧基苯醌（DMBQ）[24-27] 然而，这尚未得到证实，而且早期研究确实如此。 表明单独的 DMBQ 不能对 FWGE 的免疫刺激特性负责 [24]，并且可能 事实上具有显着的毒性[33-35]。 我们已证实 FWGE 在体内 NHL 模型中具有显着的抗肿瘤活性，尤其是当 与单克隆抗体（mAb）利妥昔单抗联合使用 FWGE 的功效与此相当。 与积极的 R-CHOP 方案相比，但 FWGE 没有明显的毒性。 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， 至少在某种程度上，刺激自然杀伤（NK）细胞介导的体内肿瘤根除[28]。 自从在血液恶性肿瘤中发现了异常的 NK 溶细胞活性以来，我们就进行了观察[36]。 该提案的总体目标是分离 FWGP 中的活性成分并了解其 通过检查犬 NHL 的体内活性/毒性和人类的离体活性/毒性来预测杀肿瘤作用 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 在体外和体内均能有效对抗 NHL [28]。 在美国，癌症相关死亡的常见原因[1-3]。 患有这种疾病的人群是老年男性（退伍军人事务部患者群体的很大一部分）。 事实上，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。 我们还有大量初步数据表明 FWGP 在非临床前模型中有效 小细胞肺癌 (NSCLC) 中 NK 细胞的抗肿瘤活性日益得到认可。 作为一个可行的临床目标 [44-47] 虽然该提案的重点是 NHL，但我们的结果可能会有所不同。 肺癌是世界上最常见的癌症死亡原因。 全世界 [48, 49] 男性和女性 NSCLC 约占所有肺癌的 2/3。 的患者在初次就诊时患有晚期或转移性疾病[50]。 20%，取决于阶段[51, 52]。检查点抑制具有显着的毒性。 彻底改变了肿瘤学，但多达三分之二的非小细胞肺癌患者未能做出反应或最终复发。 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 NSCLC，直接适用于 VA 患者群体。