PSMA-based MR Imaging and Therapy of Prostate Cancer

描述(由申请者提供)：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项目。具体地说，她将开发新一代前列腺特异性膜抗原(PSMA)显像剂，这种显像剂将采用以前没有描述过的模式和技术。PSMA不仅在前列腺癌中过度表达，而且在大多数实体瘤新生血管中都有过度表达，因此是癌症成像和治疗的一个有吸引力的靶点。长期目标是让雷博士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、跨学科的研究人员。她将获得癌症生物学、药理学和伦理学方面的进一步正式培训，这与进行临床前和翻译研究密切相关。该项目将侧重于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的指导下使用基于磁共振(MR)的方法，这两位科学家是约翰·霍普金斯大学的马丁·庞珀博士和扎弗·布杰瓦拉博士。Ray博士将开发以PSMA为靶点的多模式造影剂(CA)，然后通过体外研究和相关动物模型的体内磁共振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。还将探索将多模式成像平台与治疗剂相结合，以实现靶向药物输送。ABCG2多药耐药泵已成为克服化疗耐药的重要靶点。通过RNA干扰靶向组织选择性沉默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博士将专注于以下具体目标：1)开发以PSMA为目标的多模低分子CA。2)开发以PSMA为靶点的大分子CA。3)研制以PSMA为靶点的前列腺癌治疗药物。这项计划将提供一个很好的环境，申请者-在密切的指导下-可以深入参与癌症的磁共振成像。随着她在生物医学成像研究方面走向独立，导师将更多地面向生物学问题，提供一个全面的投资组合。

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.