This project will develop new radiopharmaceutical probes and new applications for established imaging agents to maintain a pipeline of new PET imaging strategies for assessing cancer and its response to therapy These are four projects that could complement our overall goal of imaging important characteristics of the tumor phenotype and move toward translation to human studies within five years. Our first objective is to develop imaging of HER2/neu, an important target for therapy of breast cancer. W( will compare two approaches. The first involves labeling of trastuzumab, the antibody that has therapeutic value in some patients with breast cancer, with a long-lived positron emitter, Zr. We will also label a low M Antibody to the same target with F following two methods and compare these imaging agents in human cell lines and mouse models that express HER2, including some control studies. One the challenges of imaging androgen receptor (AR) expression through its ligands Is the enzymatic metabolism and catabolism of these steroids.
This aim will combine the pre-clinical expertise and animal models of prostate researchers at UW and chemistry expertise of J Katzenellenbogen to develop and test better imaging agents for testing of AR activity in the prostate. Cu]ATSM is an alternative hypoxia imaging agent that we will compare with FMISO through chemistry cell culture and animal studies designed to distinguish the copper reduction reaction in tissues from the basic coordination chemistry of copper with ATSM. The literature mechanism is incomplete in that it fails to account for variability of uptake with tumor type and does not reconcile an observed paradoxical increase in CuATSM uptake as PO2 is returned to normal after an episode of hypoxia;FMISO appropriately decreases when PO2 i normal. We will test the hypothesis that CuATSM retention is reflecting thiol redox and, as such, is complementary to FMISO. This project will also evaluate a brain PET radiopharmaceuticals from the literature that might be applied to unique cancer studies locally. The Prostate SPORE is interested in a new therapy directed at monoamine oxidase A for which there is a known imaging agent, C]clorgyline. We will use cellular and small animal studies to evaluate its potential for imaging prostate cancer to eventually test whether inhibiting this enzyme will synergize with chemotherapy.
This research project is important to replenish the pipeline of new imaging agents selected in collaboration with our cancer colleagues for their potential to answer important clinical questions. PET agents for imaging HER2, an important target in breast cancer, will be developed and tested. Another collaboration will provide a unique opportunity to develop better AR imaging agents. Some critical tests comparing two potential hypoxia imaging agents are planned and an established PET agent for imaging the brain will be evaluated for selecting subjects for a new targeted therapy for prostate cancer. All of these radiopharmaceuticals would provide valuable imaging tools to support translational cancer research.
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|O'Sullivan, Finbarr; Muzi, Mark; Mankoff, David A et al. (2014) VOXEL-LEVEL MAPPING OF TRACER KINETICS IN PET STUDIES: A STATISTICAL APPROACH EMPHASIZING TISSUE LIFE TABLES. Ann Appl Stat 8:1065-1094|
|Zhou, Dong; Lin, Mai; Yasui, Norio et al. (2014) Optimization of the preparation of fluorine-18-labeled steroid receptor ligands 16alpha-[18F]fluoroestradiol (FES), [18F]fluoro furanyl norprogesterone (FFNP), and 16beta-[18F]fluoro-5alpha-dihydrotestosterone (FDHT) as radiopharmaceuticals. J Labelled Comp Radiopharm 57:371-7|
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|Kurland, Brenda F; Peterson, Lanell M; Lee, Jean H et al. (2011) Between-patient and within-patient (site-to-site) variability in estrogen receptor binding, measured in vivo by 18F-fluoroestradiol PET. J Nucl Med 52:1541-9|
|Hendrickson, Kristi; Phillips, Mark; Smith, Wade et al. (2011) Hypoxia imaging with [F-18] FMISO-PET in head and neck cancer: potential for guiding intensity modulated radiation therapy in overcoming hypoxia-induced treatment resistance. Radiother Oncol 101:369-75|
|Linden, Hannah M; Kurland, Brenda F; Peterson, Lanell M et al. (2011) Fluoroestradiol positron emission tomography reveals differences in pharmacodynamics of aromatase inhibitors, tamoxifen, and fulvestrant in patients with metastatic breast cancer. Clin Cancer Res 17:4799-805|
|Dunnwald, Lisa K; Doot, Robert K; Specht, Jennifer M et al. (2011) PET tumor metabolism in locally advanced breast cancer patients undergoing neoadjuvant chemotherapy: value of static versus kinetic measures of fluorodeoxyglucose uptake. Clin Cancer Res 17:2400-9|
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