(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: 10245004
• 负责人: Shiuan Chen
• 金额: $ 67.08万
• 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/10245004
• 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; Disease; 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; Knockout Mice; Lead; 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; 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; base; 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.

项目摘要 前列腺癌是男性最常见的癌症，也是与癌症相关的死亡的第二大原因。 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的二十年里有所增加，而且在早期发现癌症 阶段性更常见。从临床和临床前研究中积累的证据表明，怀特 纽扣蘑菇(WBM)对前列腺癌有有益的作用。因此，我们提出一种跨学科的 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？具体来说，我们将通过以下方式确定机制 服用哪种WBM可降低生化中的前列腺特异性抗原(PSA)水平 复发性前列腺癌(BRPC)患者和那些治疗天真、有良好风险和不活跃的患者 监视系统。我们先前的WBM第一阶段研究显示了生物活性和低毒性 BRPC患者。结果显示，36%的研究人群在~3岁后PSA水平有所下降 观察西医治疗数月，未观察到剂量限制毒性。我们对试验血样的分析 提示潜在的作用机制；完全应答患者的IL-15水平显著高于对照组， 大多数患者在治疗后髓系来源的抑制细胞(MDSCs)表现出与治疗相关的下降 心理治疗。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MDSCs通过释放精氨酸酶而发挥免疫抑制作用，这表明 WBM可能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，进而减少雄激素受体(AR)和 受AR调节的基因，如PSA，这表明WBM可能通过另一种机制发挥作用。基座 根据这些发现，我们假设前列腺癌的进展可以通过抑制 MDSCs和通过WBM消费调节其他免疫功能。我们提出了三个具体目标 为了验证这一假设：1.检验WBM对BRPC患者和 治疗天真，有利的风险，并通过2期临床试验进行积极监测。2.确定 WBM在血标本和前列腺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水平，并在我们建议的阶段与WBM反应相关 2个试验。3.明确西医结合治疗肿瘤相关疾病的细胞和分子机制 临床前同基因前列腺癌模型中的免疫细胞群，包括IL-15基因敲除和 转基因小鼠检测IL-15对WBM介导的免疫调节的影响。总体而言，我们 预计拟议的研究将导致新的饮食方案和其他方法，以减少或缓解 前列腺癌的进展或提高雄激素剥夺治疗的疗效。