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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，他汀类药物与降胆固醇治疗之间有很强的相关性以及降低前列腺癌死亡风险。动物研究表明，降低胆固醇可以减少前列腺癌的发展降低前列腺癌患者胆固醇的生物效应是没有完全理解。很可能降低胆固醇可以直接抑制肿瘤的生长，转移的可能性然而，我们的初步数据表明另一个重要的机制：胆固醇- 降低可增强抗肿瘤免疫应答。在我们的动物模型中，通过免疫细胞中的mTOR通路进行信号传导。我们发现，同样的信号变化也出现在前列腺癌患者血液胆固醇降低时。我们的初步数据还表明，降低胆固醇可增强对长期癌症控制至关重要的免疫记忆细胞。我们的工作假设降低血清胆固醇（1）会降低淋巴细胞中的TORC 2信号传导，中枢记忆性CD 8 + T细胞的形成，（2）可以通过控制TcB来优化，以及（3）直接增加肿瘤免疫原性为了测试这一假设并将我们的小鼠模型的发现联系起来，我们提出了平行的小鼠和人类临床研究。因此，目的1评价了降低胆固醇对CD 8 + T细胞的影响。记忆细胞以及适应性免疫应答的其他关键成分，如调节性T细胞。我们的初步数据表明，降低胆固醇使肿瘤更“可见”的免疫系统，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这可能会改变免疫反应。我们还评估了肿瘤的影响，暴露在胆固醇中- 降低树突状细胞、巨噬细胞和中性粒细胞。目的2在一项前瞻性研究中评价胆固醇降低在低风险和中等风险前列腺癌男性中进行的临床试验，通过积极监测进行管理。这些男性癌症进展的风险很高，需要根治性手术或放射治疗，这往往使男性患有永久性尿失禁和勃起功能障碍在拟议的试验中，新诊断的前列腺患者癌症将经历最大的胆固醇降低或标准处理。前列腺活检组织并在开始治疗后进行比较，以确定胆固醇降低是否增加了CD 8 + T细胞。肿瘤，这是抗肿瘤免疫反应所需的。我们还将检查血液中的免疫细胞以识别和丰富最有可能应答的患者亚组。一项积极的研究将提供有力的理由一项3期多中心临床试验，以确定降低胆固醇是否可以防止形成或前列腺癌的发展它还将提供一种免疫机制，可以潜在地改善结果前列腺癌以外的其他癌症。