PSMA Directed Imaging of Prostate Cancer Focus on Androgen Receptor Dynamics

描述(申请人提供)：前列腺特异性膜抗原(PSMA)日益被认为是癌症成像和治疗的重要靶点。在前列腺癌(PCa)中，它是一个重要的预后标记物，它的表达预示着早期的生化复发。前列腺癌实验模型中的PSMA成像已被用于报道雄激素信号和紫杉烷治疗的反应。新的PSMA靶向疗法正在临床上出现。例如，Progenics制药公司有一种PSMA靶向抗体-药物结合物，它在第一阶段试验中证明了有效性，导致了第二阶段试验。用多西紫杉醇浸渍、PSMA靶向的聚(乳酸-乙醇酸)纳米粒治疗可使转移性胆管癌患者的肺部病变消退。与此同时，各种用于PSMA的显像剂开始流通。在过去的一年里，使用低分子试剂进行PSMA成像的前三篇临床论文已经出现。第一个这样的试剂，[18F]DCFBC，由我们开发，在国家癌症研究所的分子成像计划中即将上线。我们打算使用药代动力学优化的第二代化合物[18F]DCFPyL，作为我们正在开发的几种PSMA靶向成像试剂中的第二种，用于正电子发射断层扫描(PET)，并将转移到NCI，用于转移性、去势耐药前列腺癌(CRPC)患者的验证。我们还将使用该试剂检查前列腺内病变，以验证在该环境下以及在抗雄激素治疗和最终生化复发的治疗环境中的有效性。总的目标是在临床上验证[18F]DCFPyL，这样它就可以在支持一系列前列腺癌患者的现有和新兴疗法方面发挥充分的优势。我们还将把成像结果与来自活检标本的前列腺癌中可能改变的信号通路联系起来。这将跨越四个具体目标：(1)通过对[18F]DCFPyL和[18F]DCFBC的首次人类研究来比较[18F]DCFPyL和[18F]DCFBC的性能，以确定在随后的目标中前进的方向；(2)使用DCFPyL-PET/磁共振成像(假设第二代化合物具有优越的性能)对局部晚期原发PCa患者进行成像治疗，并将信号与同时获得的MR上的信号以及肿瘤分级、PSMA表达和雄激素受体(AR)信号在新辅助雄激素剥夺(ADT)前后进行关联；(3)使用DCFPyL-PET/MR对CRPC患者进行成像，并与骨和软组织活检对照：(4)对CRPC患者进行DCFPyL-PET/MR成像，并与标准的99mTc骨显像对照，指导少转移瘤患者的立体定向全身放射治疗(SBRT)。该项目将是分子成像研究人员与约翰·霍普金斯大学、NCI分子成像计划和NIH临床中心的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.