Enhanced imaging and treatment of aggressive subtypes of prostate cancer

前列腺癌侵袭性亚型的增强成像和治疗

• 批准号: 10450131
• 负责人: MARTIN G POMPER
• 金额: $ 44.36万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10450131
• 关键词: Active Sites; Address; Adenocarcinoma; Affinity; Androgens; Antiandrogen Therapy; Antigen Targeting; Attention; Biological; CAR T cell therapy; CEACAM5 gene; Categories; Cell membrane; Clinical; Clinical Data; Clinical Management; Complement; Data; Data Set; Detection; Development; Discipline of Nuclear Medicine; Disease; Engineering; FOLH1 gene; Funding; Genes; Gleason Grade for Prostate Cancer; Goals; Human; Image; Image Enhancement; Immunotherapy; Indolent; Interleukin-12; Laboratories; Lesion; Machine Learning; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Methods; Modernization; Monitor; Morbidity - disease rate; Nanotechnology; Neoplasm Metastasis; Neuroendocrine Prostate Cancer; Neurosecretory Systems; Normal tissue morphology; Output; Patients; Pharmaceutical Preparations; Positioning Attribute; Positron-Emission Tomography; Productivity; Prostate; Prostate Cancer therapy; Radiation therapy; Reagent; Recycling; Reporter Genes; Scientist; Signal Transduction; Solid Neoplasm; Specificity; Specimen; System; T-Lymphocyte; Targeted Radiotherapy; Techniques; Technology; Therapeutic Studies; Tissues; Training; Translations; Unnecessary Surgery; Urea; Work; X-Ray Computed Tomography; antigen test; base; cancer biomarkers; cancer cell; chimeric antigen receptor T cells; design; detection method; imaging agent; imaging study; improved; in vivo; machine learning method; molecular imaging; multimodality; optical sensor; photoacoustic imaging; prevent; prognostic significance; programs; promoter; scaffold; small molecule; spatial relationship; synthetic antibodies; targeted agent; targeted imaging; theranostics; tumor; tumor microenvironment

Targeting the prostate-specific membrane antigen (PSMA) with small molecules for imaging and therapy of prostate cancer (PC) has revitalized the field of nuclear medicine. Few targets have its combination of salutary attributes, namely, high concentration in malignant with restricted expression in normal tissues, easy access with recycling to and from the plasma membrane, an enzymatic active site toward which small molecules of high affinity and specificity can be designed, and biological relevance – an inverse relationship with androgen signaling while being directly related to degree of malignancy. The ureas that we initially described for imaging PSMA in 2002 have inspired a wide variety of cancer targeting species from radiotherapeutics to synthetic antibody mimics. Our goal is to use what we have learned from PSMA-targeted detection, imaging and treatment of PC to focus on highly aggressive disease, including that which does not express PSMA. We will deploy this prolific cancer target here by beginning with a project that leverages the considerable clinical data obtained during the last funding period to refine and simplify PSMA-targeted imaging with positron emission tomography (PET) – in a way agnostic to imaging agent employed. Complementing PET we will explore sensitive new PSMA- targeted agents and methods for photoacoustic (PA) imaging, which can characterize primary disease in new ways in an effort to uncover signatures that could separate aggressive from indolent cancer to prevent unnecessary surgery and its attendant morbidity. Because PC is a heterogeneous disease, in the second half of the project we will move from detection and characterization of PSMA-expressing PC to address highly aggressive, PSMA-negative adenocarcinoma and especially neuroendocrine PC (NEPC), a lethal and increasingly prevalent subtype with the proliferation of modern anti-androgen therapies. First, we will use a PSMA reporter gene strategy to track NEPC-targeted chimeric antigen receptor (CAR) T cells in order to gauge their spatial relationship to tumor, measure their expansion in vivo, and sense their microenvironment, with a view to improving this case of solid tumor CAR T cell therapy. Finally, we will use cancer cell specific promoter (CCSP) technology, which we developed for imaging and treating metastases, to enhance PSMA expression specifically within NEPC tissue so that it may become susceptible to the detection and treatment of its PSMA- expressing adenocarcinoma counterpart. In addition to using existing PSMA-targeted radiotherapy we will show how a new urea-drug conjugate we have developed can kill NEPC once it is re-programmed to express PSMA. To achieve these goals, we take the approach of beginning with a more sophisticated analysis of our clinical PSMA PET data then work toward more laboratory-based imaging and therapeutic studies also designed for translation. The team we have assembled is comprised of clinicians and scientists with a track record of high productivity and impact working together.

用小分子靶向前列腺特异性膜抗原（PSMA），用于成像和治疗 前列腺癌（PC）振兴了核医学领域。很少有目标是有益的 属性，即在正常组织中表达受限的恶性肿瘤高浓度，轻松访问 从质膜回收往返质膜，这是一个酶促活性位点，高的分子高 可以设计亲和力和特异性，并且生物学相关性 - 与雄激素的反比关系 信号传导与恶性肿瘤直接相关。我们最初描述的成像的尿液 2002年的PSMA启发了从放射治疗到合成的各种癌症靶向物种 抗体模仿。我们的目标是利用我们从PSMA靶向检测，成像和治疗中学到的知识 PC专注于高度侵略性疾病，包括不表达PSMA的疾病。我们将部署此 从一个利用可获得的大量临床数据的项目开始，这里的多产癌症目标是 在最后的资金期间，通过正电子发射断层扫描来完善和简化PSMA靶向成像 （PET） - 以某种方式对成像剂的不可知论。补充宠物，我们将探索敏感的新PSMA- 光声（PA）成像的靶向剂和方法，可以表征新的原发性疾病 努力发现可以将侵略性与懒惰癌区分开以防止的签名的方法 不必要的手术及其随之而来的发病率。因为PC是一种异质性疾病，所以 我们将从表达PSMA的PC的检测和表征转变为高度解决的项目 侵略性，PSMA阴性腺癌，尤其是神经内分泌PC（NEPC），致死和 随着现代抗雄激素疗法的增殖，增长了盛行的亚型。首先，我们将使用 PSMA报告基因策略以跟踪靶向NEPC靶向的嵌合抗原受体（CAR）T细胞以衡量 他们与肿瘤的空间关系，测量其体内扩张并感知其微环境，并用 考虑改善这种实体瘤CAR T细胞疗法的情况。最后，我们将使用癌细胞特异性启动子 （CCSP）我们开发用于成像和处理转移酶的技术，以增强PSMA表达 特别是在NEPC组织中，因此它可能容易受到检测和处理其PSMA- 表达腺癌对应物。除了使用现有的PSMA靶向放射疗法外，我们还将显示 一旦对NEPC进行了重新编程以表达PSMA，我们开发的新尿素毒物结合物如何杀死NEPC。 为了实现这些目标，我们以对临床的更复杂的分析开始采取一种方法 然后，PSMA PET数据随后用于更基于实验室的成像和治疗研究，也是为此设计的 翻译。我们组装的团队由临床医生和科学家组成，并有高级记录 生产力和影响力共同努力。