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

项目摘要 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。 鉴于老龄化人口比例的增加和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， 阶段比较常见。来自临床和临床前研究的累积证据表明，白色 蘑菇（WBM）对前列腺癌有有益的作用。因此，我们提出了一个跨学科的 解决挑衅性问题11的方法：饮食和营养通过什么机制 干预措施会影响癌症治疗的反应吗？具体而言，我们将通过以下方式确定机制： 其中WBM的消耗导致生物化学中前列腺特异性抗原（PSA）水平的降低， 复发性前列腺癌（BRPC）患者和未接受过治疗、风险有利和活性不足的患者 监视我们之前的WBM 1期研究证明了WBM的生物活性和低毒性特征， 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。 WBM治疗3个月，未观察到剂量限制性毒性。我们对试验血样的分析 提示了潜在的作用机制;完全反应患者的IL-15水平显著较高， 大多数患者在治疗后表现出与治疗相关的髓源性抑制细胞（MDSC）下降。 疗法我们的初步研究和其他人的工作进一步表明，WBM抑制酶活性。 由于MDSC通过释放β-淀粉酶发挥免疫抑制活性，这表明MDSC可能是一种免疫抑制剂。 WBM可能影响免疫功能的机制。此外，WBM对酶的抑制作用可 导致多胺水平降低，从而降低雄激素受体（AR）的表达， AR调节基因如PSA，表明WBM可能通过另一种机制起作用。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和通过WBM消耗调节其他免疫功能。我们提出三个具体目标 为了验证这个假设：1。为了检查WBM在BRPC患者中的PSA抑制作用， 未经治疗，风险有利，并通过II期临床试验进行积极监测。2.确定 WBM在前列腺血液标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，并将其与WBM反应相关联， 2次试验。3.为了明确WBM对肿瘤相关细胞的影响的细胞和分子机制， 临床前同源前列腺肿瘤模型中的免疫细胞群，包括IL-15敲除和 转基因小鼠用于测定IL-15对WBM介导的免疫调节的作用。我们共同 预计拟议的研究将导致新的饮食方案和其他方法，以减少或减轻 前列腺癌的进展或提高雄激素剥夺治疗的疗效。

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.