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

• 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
• 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

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已经实施了生活方式，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 癌变是在衰老的前列腺中存在与萎缩（PIA）相关的慢性炎症 男人。然而，围绕免疫反应在前列腺癌中的作用有一个悖论：“ 炎症悖论”。一方面，炎症可能是癌变的驱动力。另一方面 已知免疫系统会寻求和破坏癌细胞。大多数前列腺癌病变是“免疫 沙漠”，ICI在大多数情况下都无效。为什么在非 - PIA中的肿瘤区域，但是大多数前列腺癌中缺乏强大的免疫反应吗？我们假设 PIA中的慢性炎症代表了先天免疫反应的证据 致癌作用。但是，在这种炎症性的“证明地面”中，只能表观遗传的细胞 关闭这种反应可以出现，成为侵略性的肿瘤前体。我们假设这一点 免疫浸润和缺乏PD-L1的缺乏，证据表明前列腺癌细胞发展了许多 逃避抗肿瘤适应性免疫史的不同机制。我们假设其他细胞非 - 自主免疫抑制机制可实现疾病进展。我们提出3协同作用 研究项目（2个基本，1个翻译），以机械测试我们的“证明 地面“假设。 和慢性炎症，导致细胞损伤/细胞死亡和增殖。第二，在PIA细胞的子集中， 对免疫反应的刺痛的表观遗传沉默，使它们成为明显的前 肿瘤细胞。我们将在动物模型和翻译研究中对此进行测试，并采用注释和 分子表征前列腺切除术。 PTEN损失和MYC拷贝数的结合是一个 独立预测前列腺癌预后不良的指标。我们假设MYC和 PTEN刺激通过免疫的募集引起的非自主免疫进化机制 抑制髓样细胞和成纤维细胞激活蛋白（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检验这些假设。最近引入了成像技术 提出了一个假设，即PET/CT成像结果可能能够预测分子和肿瘤微型 侵略性前列腺癌的环境特征。使用PYL PET/CT的PSMA宠物成像具有 我们获得了FDA在前列腺切除术之前批准对高风险男性进行成像的批准。在Proj 3（翻译）中，我们采用 PET/CT扫描PSMA，并将其与mpMRI结合使用以解决这些假设。同样在Proj 3中，我们将 将新开发/开发的宠物成像剂应用于非侵入性和纵向研究 M2巨噬细胞和癌症与小鼠前列腺进展模型中的成纤维细胞相关。