Translational imaging biomarkers of the tumor microenvironment in early prostate cancer

项目摘要 这个翻译项目的目标是连接的遗传和细胞特征的总体，试验场 [癌症允许的肿瘤微环境（TME）]这种U 54应用于成像生物标志物的假设 可以在临床上用来检测并最终阻断前列腺癌。人们对细胞 参与前列腺癌中上皮-基质相互作用的亚型，或关于其发生的时间， 在进展过程中出现。我们已经开发了一系列翻译成像剂， 测量TME内的癌上皮和特定细胞。我们将利用这些代理的一个子集， 定量了解前列腺癌中的TME，以便在治疗过程中早期检测和重新编程。 恶性转化在目标1中，我们将前瞻性地对原发性前列腺癌患者进行多功能成像， 参数磁共振成像（mpMRI）和18F-DCFPyL（PyL）正电子发射 前列腺特异性膜抗原（PSMA）是前列腺断层扫描/计算机断层扫描（PET/CT）的靶向抗原。 我们将对中高危前列腺癌患者进行标准治疗PyL PET/CT成像 在前列腺切除术之前。我们将量化和相关的成像和病理的假设， 在其他高级别肿瘤中，PSMA低区域与直肠癌切除术中的不良病理学相关， 更好地了解原发病的异质性。我们还将比较PyL PET/CT与细胞 前列腺癌TME的免疫和基质区室的组成和空间结构。我们将 还回顾性地使用了同意进行基因组研究的同一患者的脑切除术， 项目2.我们将检验PyL PET/CT测量的PSMA水平与MYC直接相关的假设。 表达、MYC拷贝数增加、PTEN丢失和TP 53突变。我们还将以公正的方式确定 基因表达、基因组和表观基因组改变与PSMA PET成像最相关的方式 功能.我们还将采用放射组学和机器学习方法，不仅对患有 前列腺癌分为预后组，正如我们以前所做的那样，而且还可以预测谁可能具有侵袭性。 疾病的初始PyL PET/CT分期。为此，我们不仅需要合并mpMRI和PyL PET/CT 数据，但也组织病理学，相关基因组学，和现有的受保护的历史信息。目标2和 3涉及BMPC小鼠模型的纵向研究，我们已经开发并重现了人类 前列腺癌的发病时间表我们将确定巨噬细胞和癌症的程度- BMPC肿瘤中和周围的相关成纤维细胞随着时间的推移而发展， 通过小动物PET/MR成像，我们将使用我们开发的新型成像剂， CSF 1 R（巨噬细胞）和FAP（CAFs），并将结果与免疫组织化学和基因组学相关联。 通过仔细的放射学-病理学相关性，该项目将为未来的临床研究提供理论基础， 更好地了解前列腺癌中的TME，以及如何重新编程以对抗这种疾病。

Project Summary The goal of this translational project is to link the genetic and cellular features of the overarching, proving ground [cancer-permissive tumor microenvironment (TME)] hypothesis of this U54 application to imaging biomarkers that can be used clinically to detect and ultimately intercept prostate cancer. Little is known about the cellular subtypes that participate in the epithelial-stromal interactions in prostate cancer, or about the timing of their appearance during progression. We have developed a series of translational imaging agents designed to measure cancer epithelium and specific cells within the TME. We will leverage a subset of those agents to understand quantitatively the TME in prostate cancer so that it can be detected and reprogrammed early during malignant transformation. In Aim 1 we will image patients with primary prostate cancer prospectively with multi- parametric magnetic resonance imaging (mpMRI) and 18F-DCFPyL (PyL) positron emission tomography/computed tomography (PET/CT), which targets the prostate-specific membrane antigen (PSMA). We will perform standard-of-care PyL PET/CT imaging on patients with intermediate to high-risk prostate cancer prior to prostatectomy. We will quantify and correlate between imaging and pathology with the hypothesis that PSMA-low regions in otherwise high-grade tumors correlate with adverse pathology at prostatectomy in an effort to understand better the heterogeneity of primary disease. We will also compare PyL PET/CT with the cellular composition and spatial architecture of immune and stromal compartments of the prostate cancer TME. We will also retrospectively use prostatectomies from the same patients that were consented for genomic studies in Project 2. We will test the hypothesis that PyL PET/CT measured PSMA levels will directly correlate with MYC expression, MYC copy number gain, PTEN loss, and TP53 mutation. We will also determine in an unbiased manner which gene expression, genomic and epigenomic alterations best correlate with PSMA PET imaging features. We will also employ radiomic and machine-learning approaches not only to subtype patients with prostate cancer into prognostic groups, as we have done before, but also to predict who may have aggressive disease on initial PyL PET/CT staging. For this we will require merging not only the mpMRI and PyL PET/CT data, but also the histopathology, relevant genomics, and available protected historical information. Aims 2 and 3 involve longitudinal studies in the BMPC murine model, which we have developed and recapitulates human prostate cancer according to a specific timetable. We will determine the extent of macrophages and cancer- associated fibroblasts in and around the BMPC tumors as they develop over time and correlate their presence with imaging by small animal PET/MR. We will use novel imaging agents that we have developed, which target CSF1R (macrophages) and FAP (CAFs), and correlate the results with immunohistochemistry and genomics. Through careful radiologic-pathologic correlation, this project will provide rationale for future clinical studies to understand better the TME in prostate cancer, and how it can be reprogrammed to combat this disease.