PSMA-based MR Imaging and Therapy of Prostate Cancer

基于 PSMA 的前列腺癌 MR 成像和治疗

• 批准号: 8044425
• 负责人: Sangeeta Ray
• 金额: $ 11.6万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8044425
• 关键词: ABCG2 gene; Accounting; Address; Affinity; Age; Animal Model; Antigen Targeting; Area; Binding; Biological; Biological Assay; Biology; Bioluminescence; Biomedical Research; Cancer Biology; Cell surface; Cells; Cessation of life; Complement; Complex; Contrast Media; Death Rate; Dendrimers; Detection; Development; Diagnostic; Disease; Down-Regulation; Drug Delivery Systems; Drug Kinetics; Drug resistance pathway; Educational Activities; Enzymes; Ethics; Evaluation; Experimental Models; Family; Gadolinium; Generations; Glutamate Carboxypeptidase II; Goals; Hormones; Human; Image; In Vitro; Incidence; Indolent; Investments; Knowledge; Lead; Length; Lesion by Stage; Lysine; Magnetic Resonance; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of prostate; Mentors; Mentorship; Methods; Modality; Molecular; Molecular Weight; Multi-Drug Resistance; Neoplasm Metastasis; Optics; Pharmacology; Probability; Prostate; Prostate Cancer therapy; Proteins; Pump; RNA Interference; Radiation; Radiopharmaceuticals; Refractory; Research; Research Activity; Research Personnel; Resistance; Resolution; Route; Scientist; Series; Signal Transduction; Small Interfering RNA; Solid Neoplasm; Specificity; Spectrum Analysis; Structure of base of prostate; Techniques; Testing; Therapeutic; Therapeutic Agents; Tissues; Training; Translational Research; United States; Universities; Urea; Weight; Xenograft Model; anticancer research; antigen binding; arm; base; bioimaging; cancer cell; cancer imaging; cancer therapy; cellular imaging; chemotherapy; design; gadolinium oxide; image guided therapy; in vivo; information gathering; inhibitor/antagonist; male; metal chelator; molecular imaging; molecular/cellular imaging; multimodality; nanoparticle; neoplastic cell; neovasculature; pre-clinical; pre-clinical research; prognostic indicator; programs; radiotracer; receptor; scaffold; skills; tumor; uptake

DESCRIPTION (provided by applicant): This project is designed to customize the educational and research activities for Dr. Sangeeta Ray to achieve two major goals. The immediate goal is for Dr. Ray to expand her current research program in the targeted imaging of prostate cancer. Specifically, she will develop a new generation of imaging agents for the prostate- specific membrane antigen (PSMA) that will employ modalities and techniques not previously described. PSMA is an attractive target for the imaging and therapy of cancer in general, as it is over-expressed not only in prostate cancer, but in most solid tumor neovasculature. The long-term goal is for Dr. Ray to acquire advanced biomedical research skills and knowledge that complement her skills as an inorganic chemist. The ultimate goal is for her to develop into an independent, interdisciplinary researcher in the area of cellular and molecular imaging of cancer. She will obtain further, formal training in cancer biology, pharmacology and ethics germane to conducting preclinical and translational research. This program will be heavily weighted toward gaining expertise regarding the biology and pharmacology of imaging - particularly using magnetic resonance (MR)-based approaches under the mentorship of two internationally recognized scientists, Drs. Martin Pomper and Zaver Bhujwalla at Johns Hopkins University. Dr. Ray will develop PSMA-targeted multimodal contrast agents (CAs) followed by evaluation of these compounds through in vitro studies and in vivo MR imaging in relevant animal models. That will allow her to evaluate the in vivo binding specificity and pharmacokinetic profile of lead compounds en route to human studies. The combination of a multimodality imaging platform with therapeutic agents will also be explored for targeted drug delivery. The ABCG2 multi- drug resistance pump has become an important target in efforts to overcome chemotherapy resistance. Target tissue selective silencing of the ABCG2 gene via RNA interference could be a new, nontoxic strategy for treating prostate and other cancers. Accordingly, Dr. Ray will focus on the following specific aims: 1) to develop multimodality low molecular weight CAs that target PSMA. 2) To develop macromolecular CAs that target PSMA. 3) To develop PSMA targeted theranostic agents for PCa. This program will provide an excellent milieu in which the applicant - under close mentorship - can become deeply involved in MR imaging for cancer. Mentorship will be geared more toward biological issues to provide a well-rounded portfolio as she progresses toward independence in biomedical imaging research. PUBLIC HEALTH RELEVANCE: Prostate specific membrane antigen (PSMA) is an attractive target for the imaging and therapy of cancer in general, as it is over expressed not only in prostate cancer, but in most solid tumor neovasculature. In the research application PSMA-targeted multimodal MR contrast agents will be developed followed by evaluation of these compounds via in vitro cell imaging and in vivo MR imaging in suitable animal models. In addition, PSMA targeted compounds with therapeutic and diagnostic (theranostic) capabilities against prostate cancer will also be developed.

描述（由申请人提供）：该项目旨在为 Sangeeta Ray 博士定制教育和研究活动，以实现两个主要目标。 Ray 博士的近期目标是扩大她目前在前列腺癌靶向成像方面的研究项目。具体来说，她将开发新一代前列腺特异性膜抗原（PSMA）显像剂，该显像剂将采用以前未描述过的模式和技术。一般来说，PSMA 是癌症成像和治疗的一个有吸引力的靶点，因为它不仅在前列腺癌中过度表达，而且在大多数实体瘤新血管系统中过度表达。雷博士的长期目标是获得先进的生物医学研究技能和知识，以补充她作为无机化学家的技能。她的最终目标是发展成为癌症细胞和分子成像领域的独立、跨学科研究人员。她将获得与开展临床前和转化研究密切相关的癌症生物学、药理学和伦理学方面的进一步正式培训。该项目将重点关注获得成像生物学和药理学方面的专业知识，特别是在两位国际知名科学家 Drs. 的指导下使用基于磁共振 (MR) 的方法。约翰·霍普金斯大学的 Martin Pomper 和 Zaver Bhujwalla。 Ray 博士将开发 PSMA 靶向多模式造影剂 (CA)，然后通过体外研究和相关动物模型中的体内 MR 成像对这些化合物进行评估。这将使她能够在人体研究过程中评估先导化合物的体内结合特异性和药代动力学特征。还将探索多模态成像平台与治疗药物的结合用于靶向药物输送。 ABCG2多药耐药泵已成为克服化疗耐药的重要目标。通过 RNA 干扰选择性沉默靶组织 ABCG2 基因可能是治疗前列腺癌和其他癌症的一种新的无毒策略。因此，Ray 博士将重点关注以下具体目标：1）开发针对 PSMA 的多模态低分子量 CA。 2）开发针对PSMA的大分子CA。 3) 开发针对PCa的PSMA靶向治疗诊断剂。该项目将提供一个良好的环境，使申请人在密切指导下能够深入参与癌症的 MR 成像。随着她在生物医学成像研究方面的独立发展，指导将更多地针对生物学问题，以提供全面的投资组合。 公共健康相关性：前列腺特异性膜抗原 (PSMA) 是癌症成像和治疗的一个有吸引力的靶点，因为它不仅在前列腺癌中过度表达，而且在大多数实体瘤新血管系统中过度表达。在研究应用中，将开发 PSMA 靶向多模式 MR 造影剂，然后通过体外细胞成像和合适动物模型中的体内 MR 成像对这些化合物进行评估。此外，还将开发具有针对前列腺癌的治疗和诊断（治疗诊断）能力的 PSMA 靶向化合物。