PSMA Directed Imaging of Prostate Cancer Focus on Androgen Receptor Dynamics

PSMA 定向前列腺癌成像重点关注雄激素受体动态

• 批准号: 8825596
• 负责人: THEODORE L DEWEESE
• 金额: $ 41.02万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-14 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8825596
• 关键词: Androgen Receptor; Androgens; Antiandrogen Therapy; Antibodies; Antigen Targeting; Biochemical; Biopsy; Biopsy Specimen; Blood; Bone Tissue; Cholangiocarcinoma; Clinic; Clinical; Data; Detection; Disease; Disease Resistance; Disease-Free Survival; Drug Kinetics; Experimental Models; Gene Expression; Generations; Gland; Glutamate Carboxypeptidase II; Glycolates; Goals; Health; Image; Image Guided Biopsy; Lesion; Lung; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of prostate; Medical Oncologist; Metastatic Neoplasm to the Bone; Molecular Weight; National Cancer Institute; Neoadjuvant Therapy; Neoplasm Metastasis; Operative Surgical Procedures; Paper; Patients; Performance; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Pilot Projects; Positron; Positron-Emission Tomography; Pre-Clinical Model; Prognostic Marker; Prostatic; Radiation Oncologist; Radiation therapy; Radiosurgery; Receptor Signaling; Recurrence; Relapse; Relative (related person); Reporting; Research; Research Personnel; Resistance; Sampling; Signal Pathway; Signal Transduction; Site; Taxane Compound; Techniques; Technology; Testing; Text; Tissues; United States National Institutes of Health; Universities; Validation; X-Ray Computed Tomography; arm; base; bone; bone imaging; cancer imaging; cancer therapy; deprivation; docetaxel; human study; image guided; imaging agent; interdisciplinary collaboration; molecular imaging; nanoparticle; phase I trial; phase II trial; programs; response; scaffold; soft tissue; targeted imaging; targeted treatment; taxane; therapeutic target; tumor

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.

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标。它是前列腺癌 (PCa) 的重要预后标志物，其表达预示着较早的生化复发。 PCa 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 靶向疗法正在临床上出现。例如，Progenics Pharmaceuticals, Inc. 的 PSMA 靶向抗体药物缀合物在其 I 期试验中证明了功效，并进入了 II 期试验。使用多西紫杉醇浸渍的 PSMA 靶向聚（乳酸-乙醇酸）纳米颗粒进行治疗可使转移性胆管癌患者的肺部病变消退。同时，多种 PSMA 显像剂开始流通。在过去的一年中，出现了前三篇使用低分子量试剂对 PSMA 进行成像的临床论文。我们开发的第一个此类试剂 [18F]DCFBC 即将在国家癌症研究所的分子成像项目中上线。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前列腺癌 (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，以便在该情况下以及在抗雄激素治疗和最终生化复发的情况下进行验证。总体目标是在临床上验证 [18F]DCFPyL，以便充分利用它来支持针对一系列 PCa 患者的现有和新兴疗法。我们还将把影像学结果与活检标本中 PCa 中可能改变的信号通路联系起来。这将在四个具体目标中实现：(1) 通过对[18F]DCFPyL 与[18F]DCFBC 的首次人体研究进行性能比较，以决定在后续目标中推进哪个目标； (2) 使用 DCFPyL-PET/磁共振成像对未接受过治疗的局部晚期原发性 PCa 患者进行成像（假设第二代化合物具有优越的性能），并将信号与同时获得的 MR 信号以及新辅助雄激素剥夺 (ADT) 前后两个月的肿瘤分级、PSMA 表达和雄激素受体 (AR) 信号相关联； (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) 使用 DCFPyL-PET/MR 对 CRPC 患者进行成像，并与基于标准 99mTc 的骨扫描相关联，以指导寡转移性疾病患者的立体定向全身放射治疗 (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。