PET TUMOR AND PROLIFERATION IMAGING VIA CATIONIC AMINO ACID TRANSPORT

通过阳离子氨基酸传输进行宠物肿瘤和增殖成像

• 批准号: 8712411
• 负责人: Jonathan Edward McConathy
• 金额: $ 15.77万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8712411
• 关键词: Address; Advisory Committees; Aftercare; Amino Acids; Animal Model; Animals; Applications Grants; Arginine; Award; Basic Amino Acid Transport Systems; Biodistribution; Biological Markers; Brain; Brain Neoplasms; Breast Adenocarcinoma; Breast Cancer Model; Cancer Patient; Cell Line; Cell Proliferation; Cell Survival; Cells; Clinical; Clinical Oncology; Clinical Research; Clinical Trials; Clinical Trials Design; Data; Development Plans; Doctor of Philosophy; Dose; Educational workshop; Environment; Faculty; Flow Cytometry; Funding; Future; Germany; Glioma; Goals; Grant; Human; Image; Implant; In Vitro; K-Series Research Career Programs; Kinetics; Label; Lead; Learning; Length; Lesion; Link; Location; Luciferases; Magnetic Resonance Imaging; Mammary Neoplasms; Measures; Mentors; Messenger RNA; Metabolism; Methodology; Modeling; Monitor; Mus; Muscle; Nitric Oxide; North America; Outcome; Patients; Pattern; Play; Polyamines; Positioning Attribute; Positron-Emission Tomography; Proliferating; Property; Proteins; Radiation necrosis; Radiation therapy; Radiation-Induced Change; Radioactive; Radiochemistry; Radiolabeled; Radiology Specialty; Rattus; Reaction; Research; Research Personnel; Research Project Grants; Research Training; Residencies; Residual Tumors; Residual state; Resources; Reverse Transcription; Rodent; Role; Rotation; Scientist; Secure; Series; Side; Societies; Specificity; Testing; Therapeutic; Time; Tracer; Training; Transcript; Translational Research; Triazoles; Tumor Biology; Tumor Cell Line; Tumor Tissue; Universities; Visit; Washington; Western Blotting; Work; angiogenesis; base; bioluminescence imaging; cancer imaging; career development; clinical application; design; experience; gliosarcoma; human subject; imaging modality; imaging probe; in vivo; in vivo imaging; knowledge base; meetings; molecular imaging; monoamine; mouse model; multimodality; neoplastic cell; neuro-oncology; novel; oncology; pre-clinical; preclinical evaluation; radiotracer; research and development; response; skills; treatment effect; tumor; tumor metabolism; uptake

DESCRIPTION (provided by applicant): The purpose of this K08 Mentored Clinical Scientist Research Career Development Award application is to provide additional critical mentored training and research experience to achieve my goal of becoming an independent investigator focused on molecular imaging for oncology. My training to date during my Ph.D. and research track radiology residency has focused on the design, synthesis and preliminary preclinical evaluation of PET tracers for brain monoamine transporters and 18F-labeled amino acids (AAs) for tumor imaging. Completion of the training and research plan in this proposal will provide additional key experiences in tumor biology, animal tumor models, kinetic analysis of PET tracers, and translational and clinical research using advanced magnetic resonance imaging (MRI) in conjunction with PET tracers. This additional training will provide me with the critical knowledge base and skill set needed to independently design and pursue translational research projects in cancer imaging. The research plan in this proposal focuses on developing novel 18F-triazole AAs synthesized via click the click reaction for in vivo PET imaging of cationic AA transport, tumor proliferation and response to radiation therapy. Cationic AA transport and metabolism play critical roles in tumor biology including cell proliferation through polyamine metabolism and in angiogenesis through nitric oxide synthesis. However, there are no 18F- labeled compounds available for imaging cationic AA transport. To address this unmet need in oncologic molecular imaging, we will perform the following Specific Aims: 1) Synthesize and characterize novel 18F-labeled 1,2,3-triazole substituted AAs optimized for cationic AA transport. 2) Validate the lead 18F-triazole AAs as in vivo imaging probes for cationic AA transport. 3) Measure in vivo tumor proliferation using the lead 18F-triazole AA in the mouse 66 breast cancer model and the human-in-mouse (HIM) breast cancer model. 4) Differentiate viable tumor from radiation-induced changes with the lead 18F-triazole AA in mice with intracranial DBT gliomas. Novel 18F-labeled triazole AAs will be synthesized, and their mechanisms of transport will be determined in vitro using rat 9L gliosarcoma, mouse DBT glioma and mouse mammary adenocarcinoma 66 cell lines. Biodistribution and microPET studies will be performed in rodents implanted with these tumors using the 18F- triazole AAs that are the best substrates for cationic AA transport. The in vivo uptake of these AAs in tumors will be correlated with mRNA and protein levels of cationic AA transporters. The in vivo uptake and kinetics of the lead 18F-triazole AA will also be correlated with in vivo tumor cell proliferation as measured with BrDU incorporation by mouse 66 tumors and human-derived breast tumors with and without functional p53 in the HIM model. The ability of the lead 18F-triazole AA to distinguish residual viable tumor from post-treatment effects including radiation necrosis will be assessed in mice with intracranial DBT tumors. The training and career development plan in this proposal includes didactic course work in tumor biology and clinical trial design. I will also have visiting rotations at the University of Washington in Seattle to gain additional experience with PET tumor proliferation imaging with [18F]FLT and at the J|lich Research Center in Germany to learn more about the clinical applications of PET-MRI using radiolabeled amino acids. I will also be actively involved in multimodality translational oncologic imaging through studies in human subjects with PET tracers as well as advanced MRI through the Center for Clinical Imaging Research (CCIR). My Mentor, Dr. Robert H. Mach, will provide expertise in radiotracer design, synthesis and tumor proliferation imaging, and my Co-Mentor Dr. Keith M. Rich will provide expertise in preclinical and clinical neuro-oncology and animal models of gliomas. I also will have an advisory committee who will meet semi-annually to provide guidance for my research and career development activities. The research environment at Washington University in St. Louis approaches the ideal for me, with outstanding faculty and resources in radiochemistry, basic, translational and clinical oncologic, and imaging research and clinical trials. My overall goal is to use the experience from the training component of this grant in conjunction with the data obtained through the research plan to successfully secure independent grant support including R01 funding to conduct human studies with these new PET tracers. We expect this research to provide novel PET tracers for imaging cationic AA transport, proliferation and response to radiation therapy with direct relevance to clinical oncology. Near the end of the award period, I will submit an application to the Clinical Trials Methodology Workshop sponsored by the Radiological Society of North America as well as a R21 or R01 grant application based on the tracers developed through the research component of this proposal. Completion of the research and training plan would position me to become an independent investigator at the conclusion of the award period.

描述（由申请人提供）：本 K08 指导临床科学家研究职业发展奖申请的目的是提供额外的关键指导培训和研究经验，以实现我成为专注于肿瘤学分子成像的独立研究者的目标。我在博士期间迄今为止的培训。放射学住院医师培训的研究重点是脑单胺转运蛋白 PET 示踪剂和用于肿瘤成像的 18F 标记氨基酸 (AA) 的设计、合成和初步临床前评估。完成本提案中的培训和研究计划将为肿瘤生物学、动物肿瘤模型、PET示踪剂的动力学分析以及使用先进的磁共振成像（MRI）与PET示踪剂相结合的转化和临床研究提供额外的关键经验。这些额外的培训将为我提供独立设计和开展癌症成像转化研究项目所需的关键知识基础和技能。该提案中的研究计划重点是开发通过点击反应合成的新型 18F-三唑 AA，用于阳离子 AA 转运、肿瘤增殖和放射治疗反应的体内 PET 成像。阳离子 AA 转运和代谢在肿瘤生物学中发挥着关键作用，包括通过多胺代谢进行细胞增殖，以及通过一氧化氮合成进行血管生成。然而，没有 18F 标记的化合物可用于对阳离子 AA 传输进行成像。为了解决肿瘤分子成像中这一未满足的需求，我们将实现以下具体目标：1) 合成并表征针对阳离子 AA 传输优化的新型 18F 标记的 1,2,3-三唑取代 AA。 2) 验证先导 18F-三唑 AA 作为阳离子 AA 转运的体内成像探针。 3) 在小鼠 66 乳腺癌模型和人鼠 (HIM) 乳腺癌模型中使用铅 18F-三唑 AA 测量体内肿瘤增殖。 4) 在患有颅内 DBT 神经胶质瘤的小鼠中，用 18F-三唑 AA 铅区分活肿瘤和辐射引起的变化。将合成新型 18F 标记的三唑 AA，并使用大鼠 9L 神经胶质肉瘤、小鼠 DBT 神经胶质瘤和小鼠乳腺癌 66 细胞系在体外确定其转运机制。将使用 18F-三唑 AA 在植入这些肿瘤的啮齿动物中进行生物分布和 microPET 研究，18F-三唑 AA 是阳离子 AA 转运的最佳底物。肿瘤中这些 AA 的体内摄取将与阳离子 AA 转运蛋白的 mRNA 和蛋白质水平相关。先导 18F-三唑 AA 的体内摄取和动力学也与体内肿瘤细胞增殖相关，如在 HIM 模型中使用或不使用功能性 p53 的小鼠 66 肿瘤和人源性乳腺肿瘤通过 BrDU 掺入进行测量。将在患有颅内 DBT 肿瘤的小鼠中评估先导 18F-三唑 AA 区分残余存活肿瘤与治疗后效应（包括放射性坏死）的能力。该提案中的培训和职业发展计划包括肿瘤生物学和临床试验设计的教学课程。我还将在西雅图的华盛顿大学轮流访问，以获得使用 [18F]FLT 进行 PET 肿瘤增殖成像的更多经验，并在德国的 J|lich 研究中心了解更多有关使用放射性标记的 PET-MRI 的临床应用的信息氨基酸。我还将通过临床影像研究中心 (CCIR) 使用 PET 示踪剂和先进 MRI 对人体进行研究，积极参与多模态转化肿瘤成像。我的导师 Robert H. Mach 博士将提供放射性示踪剂设计、合成和肿瘤增殖成像方面的专业知识，我的共同导师 Keith M. Rich 博士将提供临床前和临床神经肿瘤学以及神经胶质瘤动物模型方面的专业知识。我还将设立一个咨询委员会，该委员会每半年举行一次会议，为我的研究和职业发展活动提供指导。圣路易斯华盛顿大学的研究环境对我来说非常理想，在放射化学、基础、转化和临床肿瘤学、影像研究和临床试验方面拥有出色的师资和资源。我的总体目标是利用本次资助的培训部分的经验以及通过研究计划获得的数据，成功获得独立资助支持，包括 R01 资金，以利用这些新的 PET 示踪剂进行人体研究。我们期望这项研究能够提供新型 PET 示踪剂，用于对与临床肿瘤学直接相关的阳离子 AA 运输、增殖和放射治疗反应进行成像。在奖励期即将结束时，我将向北美放射学会主办的临床试验方法研讨会提交申请，以及基于通过本提案的研究部分开发的示踪剂的 R21 或 R01 拨款申请。完成研究和培训计划将使我在奖励期结束时成为一名独立调查员。