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.
Positron emission tomography (PET) is an imaging method that uses radioactive compounds to provide information to scientists and doctors about the location and metabolism of tumors. The research in this proposal will develop new radioactive compounds that are transported into cells like the natural amino acid L- arginine to detect tumors. Using animal models, we will test the ability of these new PET tracers to measure how rapidly tumors are growing and to measure the response of brain tumors to radiation therapy. The long term goal of this research is to provide doctors with a new way to detect and characterize tumors using PET that will provide better treatment options and outcomes for cancer patients.
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