(PQ11) Immune modulatory effects of white button mushroom in prostate cancer - A translational research

(PQ11) 白蘑菇对前列腺癌的免疫调节作用 - 转化研究

• 批准号: 10689092
• 负责人: Shiuan Chen
• 金额: $ 64.42万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10689092
• 关键词: Address; Affect; Androgen Receptor; Anti-Inflammatory Agents; Attenuated; Biochemical; Biological; Biopsy; Blood specimen; Cancer Cell Growth; Cancer Detection; Cancer Etiology; Cancer Patient; Cells; Cessation of life; Clinical Research; Clinical Trials; Consumption; Correlative Study; Dietary Intervention; Dose Limiting; Effectiveness; Eligibility Determination; Exhibits; Feedback; Future; Genes; Hormones; Human; Immune; Immune response; Immunosuppression; In complete remission; Incidence; Infiltration; Inflammation Mediators; Intake; Interleukin-15; Knock-out; Localized Disease; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Molecular; Mus; Myeloid-derived suppressor cells; Outcome; PSA level; Patients; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Polyamines; Population; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Radiation; Radical Prostatectomy; Randomized; Recurrence; Recurrent disease; Regimen; Risk; Screening for Prostate Cancer; Testing; Tissues; Toxic effect; Transgenic Mice; Translational Research; Treatment Protocols; Tumor-infiltrating immune cells; Work; aging population; androgen deprivation therapy; antitumor effect; arginase; arm; cancer therapy; cancer type; cohort; dietary; experience; experimental study; immune function; immunoregulation; improved; men; novel; partial response; patient population; patient response; phase 1 study; phase II trial; pre-clinical; preclinical study; profiles in patients; prostate cancer cell; prostate cancer model; prostate cancer progression; response; side effect; study population; tumor

Project Summary Prostate cancer is the most common cancer and the second leading cause of cancer-related deaths in men. Given the increasing proportion of the aging population and common application of prostate cancer screening, the incidence of prostate cancer has increased over the last two decades and detection of cancer at early phases is more common. Accumulating evidence from clinical and preclinical studies demonstrates that white button mushroom (WBM) has beneficial effects on prostate cancer. Therefore, we propose a transdisciplinary approach to address Provocative Question 11: Through what mechanisms do diet and nutritional interventions affect the response to cancer treatment? Specifically, we will determine the mechanisms through which consumption of WBM leads to reduction of prostate-specific antigen (PSA) levels in biochemically recurrent prostate cancer (BRPC) patients and those who are therapy naïve, favorable risk, and under active surveillance. Our previous Phase 1 study of WBM demonstrated biological activity and a low toxicity profile in BRPC patients. Results showed that 36% of the study population had some decline in PSA levels after ~3 months of WBM treatment and no dose limiting toxicities were observed. Our analysis of trial blood samples suggested potential mechanisms of action; complete response patients had significantly higher levels of IL-15, and most patients exhibited therapy-associated declines in myeloid-derived suppressor cells (MDSCs) after therapy. Our preliminary studies and the work of others further suggest that WBM inhibits arginase activity. Because MDSCs exert an immunosuppressive activity through release of arginase, this suggests a possible mechanism through which WBM may affect immune function. In addition, inhibition of arginase by WBM can lead to decreased polyamine levels, which in turn decreases expression of the androgen receptor (AR) and AR-regulated genes such as PSA, suggesting an additional mechanism through which WBM may act. Based on these findings, we hypothesize that the progression of prostate cancer may be attenuated by inhibiting MDSCs and modulating other immune functions through WBM consumption. We propose three specific aims to test this hypothesis: 1. To examine the PSA suppressing effect of WBM in patients with BRPC and who are therapy naïve, favorable risk, and under active surveillance through a Phase 2 clinical trial. 2. To determine the direct and immune-mediated antitumor effects of WBM in blood specimens and biopsy tissue from prostate cancer patients. We will also assess the levels of IL-15 and correlate to WBM response in our proposed Phase 2 trial. 3. To define the cellular and molecular mechanisms underlying WBM effects on the tumor-associated immune cell populations in preclinical syngeneic prostate tumor models, including IL-15 knockout and transgenic mice for determining the effect of IL-15 on WBM-mediated immune modulations. Collectively, we expect the proposed studies to lead to new dietary regimens and other approaches to reduce or mitigate the progression of prostate cancer or improve the efficacy of androgen deprivation therapy.

项目概要 前列腺癌是最常见的癌症，也是男性癌症相关死亡的第二大原因。 鉴于人口老龄化比例不断增加以及前列腺癌筛查的普遍应用， 前列腺癌的发病率在过去二十年中有所增加，并且早期发现癌症 阶段更为常见。临床和临床前研究积累的证据表明，白色 蘑菇（WBM）对前列腺癌有有益作用。因此，我们提出一个跨学科的 解决挑衅性问题 11 的方法：饮食和营养通过什么机制发挥作用？ 干预措施会影响癌症治疗的反应吗？具体来说，我们将通过以下方式确定机制： 消耗 WBM 会导致生化指标中前列腺特异性抗原 (PSA) 水平的降低 复发性前列腺癌 (BRPC) 患者以及未接受治疗、高风险且活动不足的患者 监视。我们之前的 WBM 一期研究证明了其生物活性和低毒性 BRPC 患者。结果显示，36% 的研究人群在约 3 年后 PSA 水平有所下降 经过数月的 WBM 治疗，未观察到剂量限制性毒性。我们对试验血液样本的分析 建议的潜在作用机制；完全缓解患者的 IL-15 水平显着升高， 大多数患者在治疗后表现出与治疗相关的骨髓源性抑制细胞 (MDSC) 下降 治疗。我们的初步研究和其他人的工作进一步表明 WBM 抑制精氨酸酶活性。 由于 MDSC 通过释放精氨酸酶发挥免疫抑制活性，这表明可能 WBM 影响免疫功能的机制。此外，WBM 对精氨酸酶的抑制可以 导致多胺水平降低，进而降低雄激素受体（AR）的表达， AR 调节的基因，如 PSA，表明 WBM 可能通过另一种机制发挥作用。基于 根据这些发现，我们假设前列腺癌的进展可能通过抑制 MDSC 并通过 WBM 消耗调节其他免疫功能。我们提出三个具体目标 为了检验这一假设： 1. 检验 WBM 对 BRPC 患者和患有以下疾病的患者的 PSA 抑制作用： 未经治疗，风险良好，并通过 2 期临床试验进行积极监测。 2. 确定 WBM 在前列腺血液样本和活检组织中的直接和免疫介导的抗肿瘤作用 癌症患者。我们还将评估 IL-15 的水平并与我们提议的阶段中的 WBM 反应相关联 2 审判。 3. 明确WBM对肿瘤相关细胞影响的细胞和分子机制 临床前同基因前列腺肿瘤模型中的免疫细胞群，包括 IL-15 敲除和 转基因小鼠用于确定 IL-15 对 WBM 介导的免疫调节的影响。总的来说，我们 期望拟议的研究能够带来新的饮食方案和其他方法来减少或减轻 前列腺癌的进展或提高雄激素剥夺疗法的疗效。