Prostate inflammatory lesions as a proving ground for development of aggressive prostate cancer

前列腺炎性病变是侵袭性前列腺癌发展的试验场

基本信息

批准号：
10518913
负责人：
ANGELO Michael DE MARZO
金额：
$ 155.89万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-15 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10518913
关键词：
Acute Address Aging Animal Model Atrophic Basic Science Cancer Etiology Cancer Model Carcinoma Cell Death Cell Proliferation Cells Characteristics Chronic Clinical DNA Sequence Alteration Development Disease Disease Outcome Disease Progression Environmental Risk Factor Epidemiology Epigenetic Process FDA approved FOLH1 gene Fibroblasts Genes Genetic Genome Genomics Gleason Grade for Prostate Cancer Growth Heterogeneity Image Imaging technology Immune Immune Evasion Immune checkpoint inhibitor Immune response Immune system Immunologic Surveillance Immunotherapy Inflammation Inflammatory Innate Immune Response Intercept Lesion Life Style Link Localized Disease Longitudinal Studies Magnetic Resonance Imaging Malignant Neoplasms Malignant neoplasm of prostate Metastatic Neoplasm to Lymph Nodes Metastatic Prostate Cancer Molecular Mus Mutation Myeloid-derived suppressor cells Neoplasm Metastasis Noninfiltrating Intraductal Carcinoma Outcome PET/CT scan PTEN gene Pathologic Phase Population Positron-Emission Tomography Process Prostate Prostate carcinoma Prostatectomy Prostatic Research Research Project Grants Resource Sharing Risk Role Signal Transduction TP53 gene Testing Therapeutic Tissue Sample Tissues Tumor-infiltrating immune cells United States Up-Regulation X-Ray Computed Tomography adaptive immune response adaptive immunity anti-cancer base cancer cell cancer diagnosis cancer initiation carcinogenesis carcinogenicity cell injury disorder control epigenetic silencing epigenomics fibroblast-activating factor high risk men human tissue imaging agent immunoreaction improved innovation macrophage men microbial molecular imaging mortality mouse model neoplastic neoplastic cell preneoplastic cell prevent prognostic programmed cell death ligand 1 prospective prostate cancer cell prostate cancer progression prostate carcinogenesis recruit response stem synergism translational study tumor tumor microenvironment

项目摘要

Project Summary: Epidemiological and pathological studies have implicated lifestyle, microbial, and environmental factors in prostate cancer etiology/risk. A potential link between these factors and prostate carcinogenesis is the presence of chronic inflammation associated with atrophy (PIA) in prostates of aging men. Yet, there is a paradox surrounding the role of the immune response in prostate cancer: “the inflammation paradox”. On one hand, inflammation may be a driver of carcinogenesis. On the other, the immune system is known to seek and destroy cancer cells. The majority prostate cancer lesions are “immune deserts”, and ICIs are ineffective in most cases. Why is there an evidently strong immune reaction in non- neoplastic regions in PIA, but a lack of a robust immune response in most prostate cancers? We hypothesize that chronic inflammation in PIA represents evidence of an innate immune response that drives carcinogenesis. However, in this inflammatory “proving ground”, only cells that can epigenetically switch off this response can emerge to become aggressive neoplastic precursors. We hypothesize that the paucity of immune infiltrates and lack of PD-L1, is evidence that prostate cancer cells develop a number of different mechanisms that evade anti-tumor adaptive immunity. We postulate that additional cell non- autonomous immune suppressive mechanisms enable disease progression. We propose 3 synergistic Research Projects (2 basic,1 translational) to mechanistically test key questions stemming from our “proving ground” hypothesis. In Proj 1 (Basic Science) we hypothesize that the STING induction in PIA drives acute and chronic inflammation, leading to cell injury/cell death and proliferation. Second, in a subset of PIA cells, epigenetic silencing of STING dampens of the immune response, allowing them to emerge as overt pre- neoplastic cells. We will test this in animal models and in translational studies employing annotated and molecularly characterized prostatectomies. The combination of PTEN loss and MYC copy number gain is an independent predictor of poor outcome in prostate cancer. We hypothesize that the combination of MYC and PTEN stimulates a cell non-autonomous immune evasion mechanism induced by the recruitment of immuno- suppressive myeloid cells, and fibroblast activation protein (FAP)-positive fibroblasts. Proj 2 (Basic Science) will test these hypotheses in animal models and in human tissues. Recently introduced imaging technologies have raised the hypothesis that PET/CT imaging results may be able to predict molecular and tumoral micro- environmental characteristics of aggressive prostate cancer. PET imaging for PSMA using PyL PET/CT has been FDA approved for imaging high risk men prior to prostatectomy. In Proj 3 (Translational) we employ PET/CT scanning for PSMA and combine this with mpMRI to address these hypotheses. Also in Proj 3 we will apply newly developed/developing PET imaging agents to non-invasively and longitudinally study the extent of M2 macrophages and cancer associated fibroblasts in our mouse prostate progression cancer models.

项目摘要：流行病学和病理学研究表明生活方式、微生物和前列腺癌病因/风险中的环境因素这些因素与前列腺之间的潜在联系。致癌是指衰老的前列腺中存在与萎缩相关的慢性炎症（PIA）然而，围绕免疫反应在前列腺癌中的作用存在一个悖论：“ 炎症悖论”。一方面，炎症可能是致癌的驱动因素。众所周知，免疫系统会寻找并消灭癌细胞，大多数前列腺癌病变都是“免疫”的。为什么非免疫反应明显强烈？ PIA 中的肿瘤区域，但大多数前列腺癌缺乏强大的免疫反应？ PIA 中的慢性炎症代表了先天免疫反应的证据然而，在这个炎症“试验场”中，只有能够表观遗传的细胞。关闭这种反应可能会成为侵袭性肿瘤的前体。免疫浸润的缺乏和 PD-L1 的缺乏，证明前列腺癌细胞会发展出许多我们假设额外的细胞非-逃避抗肿瘤适应性免疫的不同机制。我们提出了 3 种协同作用的自主免疫抑制机制。研究项目（2 个基础项目，1 个转化项目）机械地测试源于我们的“证明”的关键问题在项目 1（基础科学）中，我们发现 PIA 中的 STING 感应会导致急性发作。其次，在 PIA 细胞的子集中， STING 的表观遗传沉默会抑制免疫反应，使它们成为明显的预免疫反应。我们将在动物模型和使用注释的转化研究中对此进行测试。 PTEN 缺失和 MYC 拷贝数增加的结合是分子特征前列腺切除术的一个重要组成部分。我们发现 MYC 和 MYC 的组合是前列腺癌不良结果的独立预测因子。 PTEN 刺激由免疫招募诱导的细胞非自主免疫逃避机制抑制性骨髓细胞和成纤维细胞活化蛋白 (FAP) 阳性成纤维细胞 Proj 2（基础科学）。将在动物模型和人体组织中测试这些假设。提出了这样的假设：PET/CT 成像结果可能能够预测分子和肿瘤微使用 PyL PET/CT 进行 PSMA 的侵袭性前列腺癌 PET 成像的环境特征。已获 FDA 批准用于在前列腺切除术之前对高危男性进行成像。在 Proj 3（转化）中，我们采用了该技术。对 PSMA 进行 PET/CT 扫描，并将其与 mpMRI 相结合来解决这些假设。应用新开发/正在开发的 PET 显像剂进行非侵入性纵向研究我们的小鼠前列腺癌进展模型中的 M2 巨噬细胞和癌症相关成纤维细胞。