PSMA Directed Imaging of Prostate Cancer Focus on Androgen Receptor Dynamics

描述（由申请人提供）：前列腺特异性膜抗原（PSMA）越来越被认为是癌症成像和治疗的重要靶点。它是前列腺癌（PCa）的重要预后标志物，其表达预示着更早的生化复发。前列腺癌实验模型中的PSMA成像已用于报告雄激素信号传导和对紫杉烷治疗的反应。新的PSMA靶向治疗正在临床上出现。例如，Progenics Pharmaceuticals，Inc.具有PSMA靶向抗体-药物偶联物，在其I期试验中证明了有效性，导致II期试验。用紫杉醇浸渍的PSMA靶向聚（乳酸-羟基乙酸共聚物）纳米颗粒治疗转移性胆管癌患者可使肺病变消退。同时，多种用于PSMA的成像剂开始流通。在过去的一年中，出现了前三篇使用低分子量药物进行PSMA成像的临床论文。第一个这样的代理，[18 F]DCFBC，由我们开发，即将在国家癌症研究所的分子成像计划中上线。我们打算使用药物动力学优化的第二代化合物[18 F]DCFPyL作为我们正在开发的用于正电子发射断层扫描（PET）的几种PSMA靶向成像剂中的第二种，并将转移到NCI以在转移性去势抵抗性PCa（CRPC）患者中进行验证。我们还将使用这种药物来检查前列腺内病变，以验证在这种情况下以及在抗雄激素治疗和最终生化复发治疗的情况下。总体目标是在临床上验证[18 F]DCFPyL，以便其可用于充分支持现有和新兴治疗方法，用于一系列患有PCa的患者。我们还将相关的影像学检查结果与潜在的改变信号通路的前列腺癌来自活检标本。这将发生在四个特定目标中：（1）通过对前者的首次人体研究比较[18 F]DCFPyL与[18 F]DCFBC的性能，以决定在后续目标中前进;（2）使用DCFPyL-PET/磁共振成像对未经治疗的局限性-局部晚期原发性PCa患者进行成像（假设第二代化合物的上级性能），并将信号与同时获得的MR信号以及肿瘤分级相关联，新辅助雄激素剥夺（ADT）前后PSMA表达和雄激素受体（AR）信号传导：（3）使用DCFPyL-PET/MR对CRPC患者进行成像，并将结果与骨和软组织活检相关联;（4）对CRPC患者进行DCFPyL-PET/MR显像，并与标准99 mTc骨扫描相结合，指导少转移性疾病患者的立体定向体部放射治疗（SBRT）。该项目将是约翰霍普金斯大学、NCI分子成像项目和NIH临床中心的分子成像研究人员与医学和放射肿瘤学家之间的一项新的跨学科合作。

DESCRIPTION (provided by applicant): The prostate-specific membrane antigen (PSMA) is increasingly recognized as an important target for cancer imaging and therapy. It is an important prognostic marker in the case of prostate cancer (PCa), where its expression portends an earlier biochemical relapse. Imaging PSMA in experimental models of PCa has been used to report on androgen signaling and response to taxane therapy. New PSMA- targeted therapies are appearing in the clinic. For example, Progenics Pharmaceuticals, Inc. has a PSMA- targeted antibody-drug conjugate that demonstrated efficacy in its phase I trial, leading to a phase II tria. Treatment with docetaxel-impregnated, PSMA-targeted poly(lactic-co-glycolic acid) nanoparticles caused regression of lung lesions in patients with metastatic cholangiocarcinoma. Concurrently a wide variety of imaging agents for PSMA is beginning to circulate. In the past year year the first three clinical papers that employ low molecular weight agents for imaging PSMA have appeared. The first such agent, [18F]DCFBC, developed by us, is coming online within the Molecular Imaging Program at the National Cancer Institute. We intend to use a pharmacokinetically optimized second generation compound, [18F]DCFPyL, as the second of several PSMA-targeted imaging agents for positron emission tomography (PET) that we are developing and will transfer to NCI to be validated in patients with metastatic, castrate-resistant PCa (CRPC). We will also use this agent to check for intra-prostatic lesions for validation in that setting as well as in the setting of treatment with anti-androgen therapy and eventual biochemical recurrence. The overall goal is to validate [18F]DCFPyL clinically so that it can be used to full advantage in supporting existing and emerging therapies for a spectrum of patients suffering from PCa. We will also correlate imaging findings with potentially altered signaling pathways in PCa derived from biopsy specimens. That will occur across four Specific Aims: (1) performance comparison of [18F]DCFPyL to [18F]DCFBC through a first-in-human study of the former to decide with which to move forward in subsequent aims; (2) To image treatment-naive patients with localized-locally advanced primary PCa using DCFPyL-PET/magnetic resonance imaging (hypothesizing superior performance of the second generation compound), and correlate signal with that on MR concurrently obtained, as well as with tumor grade, PSMA expression and androgen receptor (AR) signaling before and after two months of neoadjuvant androgen deprivation (ADT); (3) To image patients with CRPC using DCFPyL- PET/MR and correlate findings with bone and soft tissue biopsy; (4) To image patients with CRPC with DCFPyL-PET/MR and correlate with standard 99mTc-based bone scan to guide stereotactic body radiation treatment (SBRT) in patients with oligometastatic disease. This project will be a new, transdisciplinary collaboration between molecular imaging researchers and medical and radiation oncologists at Johns Hopkins University, the NCI Molecular Imaging Program and the NIH Clinical Center.