This project will continue work on imaging therapeutic targets to choose appropriate cancer therapy and image the effect of the chosen drug on the therapeutic targets. During the previous funding period we made progress in imaging estrogen receptors (ER) in breast cancer, using [18]F-fluoroestradiol (FES) PET. The renewal will use FES PET to measure regional ER as a pharmaco-dynamic response of breast cancer endocrine therapy and FDG PET to localize active tumor sites and to identify early effects of drug therapy on growth factor pathways including HER2 and ER. We will also extend our imaging of receptor targets to prostate cancer.
Aim 1 : We will test the use of FES PET to help choose therapy in patients with a history of ER+ breast cancer who have failed prior regimens and are being considered for salvage endocrine therapy. This is a group where our prior experience showed that low FES uptake strongly predicted a lack of response to endocrine therapy. In this same group, we will test whether the use of FES as a predictive marker results in an increased response rate compared to historical data from similar patients where FES imaging was purely observational.
Aim 2 : Use FES PET and FDG PET to predict response to endocrine treatment combined with other targeted agents. Serial FES/FDG PET will be used to measure the pharmacodynamics (PD) of combined therapy. For patients with ER+ and HER2 over-expressing tumors, imaging will be used to assess the effect of anti-HER2 treatment on ER expression (FES PET) and early response to combined therapy (FDG PET). We will also explore therapy to re-express ER in breast cancer tumors refractory to endocrine therapy using a histone deacetylase (HDAC) inhibitor. FES and FDG PET will be performed prior to therapy and after 14 days of HDAC inhibitor therapy alone, followed by combined HDAC inhibitor/aromatase inhibitor therapy to test the hypothesis that successful therapy can be measured by an increase in ER expression.
Aim 3 : Develop methods to image hormonal function in prostate cancer. Endocrine therapy continues to be an important first line in prostate cancer patients. We will evaluate androgen receptor-targeted imaging agents, starting with FDHT, but continuing to new agents from project 5 if preclinical trials are encouraging. As in our early studies of ER imaging in breast cancer, the initial focus will be on refining the approaches to image acquisition and analysis, including metabolism and protein binding, and on hormone-refractory disease.

Public Health Relevance

If our pilot study shows that FES PET provides a tool to direct salvage endocrine therapy in patients with breast cancer, it will pave the way for future multi-center trials. This will be one of the first uses of PET imaging of therapy targets to direct treatment. The pharmacodynamic studies are a unique use of imaging to verify re-expression of a receptor after an inhibition therapy, and providing evidence that the target can be to re-challenge with targeted therapy that the patient had previously failed. Extension of this targeted imaging paradigm to prostate cancer, specifically AR expression, should identify heterogeneous disease and be helpful in directing further targeted treatment.

Agency
National Institute of Health (NIH)
Type
Research Program Projects (P01)
Project #
5P01CA042045-25
Application #
8722454
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
Budget End
Support Year
25
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Washington
Department
Type
DUNS #
City
Seattle
State
WA
Country
United States
Zip Code
98195
Huang, Jian; O'Sullivan, Finbarr (2014) An analysis of whole body tracer kinetics in dynamic PET studies with application to image-based blood input function extraction. IEEE Trans Med Imaging 33:1093-108
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
Eary, Janet F; Krohn, Kenneth A (2013) Standards for reporting PET clinical trials. J Nucl Med 54:1516-7
Eary, Janet F; Link, Jeanne M; Muzi, Mark et al. (2011) Multiagent PET for risk characterization in sarcoma. J Nucl Med 52:541-6
Peterson, Lanell M; Kurland, Brenda F; Link, Jeanne M et al. (2011) Factors influencing the uptake of 18F-fluoroestradiol in patients with estrogen receptor positive breast cancer. Nucl Med Biol 38:969-78
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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