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.

项目概要流行病学研究发现，他汀类药物降低胆固醇治疗之间存在密切关联动物研究表明，降低胆固醇可以降低前列腺癌的死亡风险。前列腺癌患者降低胆固醇的生物学效应是尚不完全清楚，降低胆固醇很可能可以直接抑制肿瘤及其生长。然而，我们的初步数据表明了另一个重要机制：胆固醇- 在我们的动物模型中，降低胆固醇可以增强抗肿瘤免疫反应。我们发现，免疫细胞中通过 mTOR 通路的信号传导也存在同样的信号变化。我们的初步数据还表明，前列腺癌患者的血液胆固醇降低。降低胆固醇可增强免疫记忆细胞，这对于长期癌症控制至关重要。假设是降低血清胆固醇 (1) 会减少淋巴细胞中的 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 Tregs 来优化，(3) 直接增加为了检验这一假设以及我们的小鼠模型的相关发现，我们提出了平行的建议。因此，目标 1 评估了降低胆固醇对 CD8+ 的影响。记忆细胞以及适应性免疫反应的其他关键成分，例如调节性 T 细胞。我们的初步数据表明，降低胆固醇使肿瘤对免疫系统更加“可见” 我们评估了降低胆固醇对肿瘤的影响。其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影响。目标 2 前瞻性地评估胆固醇降低作用。对患有低风险和中风险前列腺癌的男性进行的临床试验，通过主动监测进行管理。男性癌症进展的风险很高，需要进行根治性手术或放射治疗，这通常会使男性在拟议的试验中，患有永久性失禁和勃起功能障碍的男性新诊断出前列腺癌。癌症之前将接受最大限度的胆固醇降低或标准的前列腺活检组织管理。并在开始治疗后进行比较，以确定降低胆固醇是否会增加 CD8+ T 细胞肿瘤，这是抗肿瘤免疫反应所必需的。我们还将检查血液中的免疫细胞。识别和丰富最有可能做出反应的患者亚组一项积极的研究将提供强有力的理由。进行第 3 阶段、多中心临床试验，以确定降低胆固醇是否可以预防胆固醇的形成或它还将提供一种可能改善结果的免疫机制。前列腺癌以外的其他癌症。