(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: 10005252
• 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/10005252
• 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; Diet; 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; 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。 鉴于人口老龄化的比例增加以及前列腺癌筛查的常见应用， 在过去的二十年中，前列腺癌的事件有所增加，并在早期发现癌症 阶段更为普遍。从临床和临床前研究中积累的证据表明白人 纽扣蘑菇（WBM）对前列腺癌具有有益的影响。因此，我们提出了一个跨学科的 解决挑衅性问题11：通过饮食和营养的哪些机制 干预措施会影响对癌症治疗的反应？具体而言，我们将通过 哪种WBM的消耗导致生物化学中前列腺特异性抗原（PSA）水平降低 复发性前列腺癌（BRPC）患者和那些幼稚，有利风险且活跃的患者 监视。我们先前对WBM的1阶段研究表明生物学活性和低毒性特征 BRPC患者。结果表明，36％的研究人群在〜3之后的PSA水平有所下降 几个月的WBM治疗和未观察到剂量限制毒性。我们对试验血液样本的分析 提出的潜在作用机制；完全反应的患者的IL-15水平明显更高， 大多数患者在髓样衍生的抑制细胞（MDSC）中暴露了与治疗相关的下降 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，所以这表明可能 WBM可能影响免疫功能的机制。另外，通过WBM抑制精氨酸酶 导致多胺水平降低，进而降低了雄激素受体（AR）的表达 AR调节的基因（例如PSA）提出了WBM可能作用的另一种机制。基于 在这些发现中，我们假设前列腺癌的进展可能会通过抑制来减弱 MDSC和通过WBM消耗调节其他免疫功能。我们提出了三个具体目标 检验此假设：1。检查WBM对BRPC患者的PSA抑制作用 通过第二阶段临床试验，治疗幼稚，有利的风险以及在主动监测下。 2。确定 WBM在血液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的水平，并对应于我们提出的阶段的WBM响应 2审判。 3。定义WBM对肿瘤相关的效应的细胞和分子机制 临床前促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 期望拟议的研究会导致新的饮食方案和其他减少或减轻的方法 前列腺癌的进展或提高雄激素剥夺疗法的效率。