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: 8294527
• 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/8294527
• 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.

描述（由申请人提供）：该项目旨在自定义Sangeeta Ray博士的教育和研究活动，以实现两个主要目标。直接的目标是Ray博士在前列腺癌的有针对性成像中扩展她当前的研究计划。具体而言，她将为前列腺特异性膜抗原（PSMA）开发新一代的成像剂，该成像剂将采用先前未描述的方式和技术。 PSMA通常是对癌症进行成像和治疗的有吸引力的靶标，因为它不仅在前列腺癌中，而且在大多数实体瘤新生血管中都过表达。长期的目标是让雷博士获得高级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。最终目标是让她发展成为癌症细胞和分子成像领域的独立的跨学科研究人员。她将在进行临床前和转化研究中进一步的癌症生物学，药理学和伦理学的正式培训。该程序将在获得成像的生物学和药理学方面的专业知识，尤其是在两位国际认可的科学家Drs的指导下使用基于磁共振（MR）的方法。约翰·霍普金斯大学（Johns Hopkins University）的Martin Pomper和Zaver Bhujwalla。 Ray博士将通过体外研究和相关动物模型中的体内MR成像来开发以PSMA为目标的多模式对比剂（CAS），然后通过体外研究和体内MR成像评估这些化合物。这将使她能够评估人类研究途径的铅化合物的体内结合特异性和药代动力学特征。还将探索多模式成像平台与治疗剂的组合，以供靶向药物递送。 ABCG2多耐药性泵已成为克服化学疗法耐药性的努力的重要目标。通过RNA干扰对ABCG2基因的目标组织选择性沉默可能是治疗前列腺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特定目的：1）开发靶向PSMA的多模态低分子量CA。 2）开发靶向PSMA的大分子CA。 3）开发PCA的PSMA靶向疗法剂。该计划将提供一个极好的环境，在该环境中，申请人（在密切指导下）可以深入参与MR成像的癌症。随着生物医学成像研究的独立性，指导将更加针对生物学问题提供全面的投资组合。