PSMA-based MR Imaging and Therapy of Prostate Cancer

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。雷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计划。具体来说，她将开发新一代的前列腺特异性膜抗原（PSMA）成像剂，将采用以前没有描述的方式和技术。PSMA通常是癌症成像和治疗的有吸引力的靶标，因为它不仅在前列腺癌中过表达，而且在大多数实体瘤新血管中过表达。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。她将获得进一步的，在癌症生物学，药理学和伦理学密切相关的进行临床前和转化研究的正式培训。该计划将在约翰霍普金斯大学的两名国际公认的科学家Martin Pomper和Zaver Bhujwalla博士的指导下，重点获得有关成像生物学和药理学的专业知识-特别是使用基于磁共振（MR）的方法。Ray博士将开发PSMA靶向多模态造影剂（CA），然后通过体外研究和相关动物模型的体内MR成像对这些化合物进行评价。这将使她能够评估体内结合特异性和药物动力学特征的先导化合物的路线，以人类研究。多模态成像平台与治疗剂的组合也将被探索用于靶向药物递送。ABCG 2多药耐药泵已成为克服化疗耐药性的重要靶点。通过RNA干扰靶组织选择性沉默ABCG 2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博士将专注于以下具体目标：1）开发靶向PSMA的多模态低分子量CA。2)开发针对PSMA的大分子CA。3)目的：开发PSMA靶向治疗前列腺癌的药物。该计划将提供一个很好的环境，其中申请人-在密切的指导下-可以深入参与癌症的磁共振成像。导师将更多地面向生物学问题，以提供一个全面的投资组合，因为她在生物医学成像研究的独立性的进展。

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.