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。在前列腺癌（PCA）的情况下，它是重要的预后标记，其表达预示着早期的生化复发。 PCA实验模型中的成像PSMA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靶向疗法正在诊所中出现。例如，Openics Pharmaceuticals，Inc。具有PSMA靶向抗体 - 药物结合物，在其I期试验中证明了功效，导致了II期三亚菌。用多西他赛浸渍，靶向PSMA靶向的聚（乳酸 - 乙醇酸）纳米颗粒的治疗导致转移性胆管癌患者的肺部病变消退。同时，PSMA的各种成像剂开始循环。在过去的一年中，出现了使用低分子量剂进行成像PSMA的前三篇临床论文。美国开发的第一个这样的代理[18F] DCFBC正在国家癌症研究所的分子成像计划中进行在线。我们打算使用我们正在开发的正电子发射断层扫描（PET）的几种PSMA靶向成像剂中的第二代DCFPYL [18F] DCFPYL，并将转移到NCI中，并在转移性，castrate-Castrate-Castrate-eneration-enerant-enerant-enerant-enerant-cpa（CRPC）中进行验证。我们还将使用该药物检查是否在这种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，以便在支持患有PCA患者的现有和新兴疗法方面充分利用它。我们还将将成像发现与源自活检标本的PCA中的可能改变的信号通路相关联。这将发生在四个特定目标中：（1）[18F] DCFPYL与[18F] DCFBC的性能比较，通过对前者的首次人类研究，以决定在随后的目标中可以继续前进； （2）使用dcfpyl-pet/磁共振成像（假设第二代化合物的卓越性能），具有局部局部晚期初级PCA的对象治疗患者，并将信号与同时获得的MR以及肿瘤等级，PSMA表达和Androgen受体（AR）的信号（AR）信号（AR）发出的NeoAdAdjulant和Readjuveant（AR）相关联（AR）。 （3）使用dcfpyl- PET/MR对CRPC的患者进行成像，并将发现与骨和软组织活检相关联； （4）对患有DCFPY-PET/MR的CRPC患者成像，并与基于99mTC的标准骨扫描相关，以指导寡聚疾病患者的立体定向身体辐射治疗（SBRT）。该项目将是约翰·霍普金斯大学，NCI分子成像计划和NIH临床中心的分子成像研究人员与医学和辐射肿瘤学家之间的新的跨学科合作。