Intensive cholesterol-lowering intervention and anti-tumor immunity modeled in prostate cancer

以前列腺癌为模型的强化降胆固醇干预和抗肿瘤免疫

基本信息

批准号：
10802975
负责人：
HYUNG L KIM
金额：
$ 69.2万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-21 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10802975
关键词：
Aftercare Animal Model Animals Apoptosis Atherosclerosis Biological Biological Markers Biopsy Blood CD8-Positive T-Lymphocytes CD8B1 gene Cancer Control Cancer Patient Cancer cell line Cardiac health Cell physiology Cells Cessation of life Chemoprevention Cholesterol Clinical Research Clinical Trials Colon Carcinoma Combined Modality Therapy Data Dendritic Cells Diagnosis Disease Progression Drug Costs Enrollment Erectile dysfunction Experimental Models Exposure to FRAP1 gene Future Genetic Genetic study Goals Heat shock proteins Hepatic High-Risk Cancer Human Immune Immune response Immune system Immunologic Memory Immunologic Stimulation Immunologics In Vitro Incontinence Infiltration Intervention Knockout Mice Low-Density Lipoproteins Lymphocyte Lymphocytic Infiltrate Macrophage Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Measures Memory Meta-Analysis Modeling Monitor Multi-Institutional Clinical Trial Mus Neoplasm Metastasis Newly Diagnosed Operative Surgical Procedures Outcome Participant Pathway interactions Patients Peripheral Pharmaceutical Preparations Phase Phase III Clinical Trials Population Population Study Pre-Clinical Model Prevention strategy Primary Cancer Prevention Proliferating Prostate Prostatectomy Radiation Regulatory T-Lymphocyte Reporting Resources Risk Secondary Cancer Prevention Secondary Prevention Serum Signal Transduction Simvastatin Solid T memory cell Testing Tissues Tumor Immunity Tumor Tissue adaptive immune response anti-tumor immune response antitumor effect cancer type design epidemiology study ezetimibe high risk men immunogenic cell death immunogenicity immunoregulation improved outcome in vivo individual patient mTOR Signaling Pathway mTOR inhibition malignant breast neoplasm men mortality risk mouse model neutrophil patient response patient subsets pharmacologic phase change preclinical study prevent primary endpoint prospective prostate biopsy prostate cancer model prostate cancer progression prostate cancer risk rational design response trafficking trial design tumor tumor growth tumor progression

项目摘要

PROJECT SUMMARY In epidemiologic studies, a strong association has been noted between cholesterol-lowering therapy with statins and lower risk of death from prostate cancer. Animal studies suggest that cholesterol-lowering can decrease the progression of prostate cancer. The biologic effects of lowering-cholesterol in prostate cancer patients are not fully understood. It is very likely that lowering cholesterol can directly inhibit the growth of the tumor and its potential to metastasize. However, our preliminary data suggest another important mechanism: cholesterol- lowering enhances an antitumor immune response. In our animal models, cholesterol-lowering reduced signaling through the mTOR pathway in immune cells. We show that this same signaling change is seen in prostate cancer patients when their blood cholesterol is lowered. Our preliminary data also suggest that cholesterol-lowering enhances immune memory cells that are critical for long-term cancer control. Our working hypothesis is that lowering serum cholesterol (1) decreases TORC2 signaling in lymphocytes and enhances formation of central memory CD8+ T cell, (2) can be optimized by controlling Tregs, and (3) directly increases tumor immunogenicity. To test this hypothesis and to relate findings from our mouse models, we propose parallel mouse and human clinical studies. Therefore, Aim 1 evaluates the effects of cholesterol-lowering on CD8+ memory cells as well as other critical components of the adaptive immune response, such as regulatory T cells. Our preliminary data show that cholesterol-lowering makes the tumor more “visible” to the immune system by increasing the expression of heat shock proteins. We evaluate the effects of cholesterol-lowering on the tumor itself, which may then alter the immune response. We also assess the effects of tumor, exposed to cholesterol- lowering, on dendritic cells, macrophages and neutrophils. Aim 2 evaluates cholesterol-lowering in a prospective clinical trial in men with low and intermediate-risk prostate cancer being managed with active surveillance. These men are at high risk for cancer progression and needing radical surgery or radiation, which often leaves men with permanent incontinence and erectile dysfunction. In the proposed trial, men with newly diagnosed prostate cancer will undergo maximal cholesterol-lowering or standard management. The prostate biopsy tissue before and after starting treatment will be compared to determine if cholesterol lowering increases CD8+ T cells in the tumor, which are required for an antitumor immune response. We will also examine immune cells in the blood to identify and enrich for patient subgroups most likely to respond. A positive study will provide a strong rationale for a phase 3, multicenter clinical trial to determine if cholesterol-lowering can prevent the formation or progression of prostate cancer. It will also provide an immune mechanism that can potentially improve outcomes in other cancers beyond prostate cancer.

项目摘要在流行病学研究中，毒剂降低胆固醇的疗法之间已经注意到了很强的关联并降低了前列腺癌死亡的风险。动物研究表明，降胆固醇可以减少前列腺癌的进展。降低胆固醇在前列腺癌患者中的生物学作用是不完全理解。降低胆固醇很可能直接抑制肿瘤的生长及其生长转移的潜力。但是，我们的初步数据提出了另一种重要机制：胆固醇 - 降低会增强抗肿瘤免疫反应。在我们的动物模型中，降低胆固醇的降低通过免疫细胞中的MTOR途径传导。我们表明，在降低血液胆固醇时，前列腺癌患者。我们的初步数据也表明降低胆固醇可增强对长期控制癌症至关重要的免疫记忆细胞。我们的工作假设是降低血清胆固醇（1）会降低淋巴细胞中的Torc2信号传导并增强中央记忆CD8+ T细胞的形成，（2）可以通过控制Treg进行优化，（3）直接增加肿瘤免疫原性。为了检验这一假设并关联了我们的鼠标模型的发现，我们提出了并行的小鼠和人类临床研究。因此，AIM 1评估降胆固醇对CD8+的影响记忆细胞以及自适应免疫响应的其他关键成分，例如调节性T细胞。我们的初步数据表明，降低胆固醇使肿瘤通过增加热休克蛋白的表达。我们评估降低胆固醇对肿瘤的影响本身可能会改变免疫反应。我们还评估了暴露于胆固醇的肿瘤的作用在树突状细胞，巨噬细胞和中性粒细胞上降低。 AIM 2评估潜在的降胆固醇通过主动监测管理低和中等风险前列腺癌的男性的临床试验。这些男性面临癌症进展的高风险，需要进行根治性的手术或辐射，这常常会留下男性永久性尿失禁和勃起功能障碍。在拟议的试验中，新诊断为前列腺的男性癌症将经历最大的胆固醇或标准管理。前列腺活检组织在开始治疗后，将进行比较，以确定降低胆固醇是否会增加CD8+ T细胞肿瘤，这是抗毒液免疫反应所必需的。我们还将检查血液中的免疫细胞识别和丰富最有可能反应的患者子组。积极的研究将提供强大的理由对于第3阶段的多中心临床试验，以确定降低胆固醇是否可以防止形成或前列腺癌的进展。它还将提供一种可以改善预后的免疫力学在前列腺癌以外的其他癌症中。