Measuring glucocorticoid receptor expression in vivo with PET
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Charles Truillet1,*, Matthew F.L. Parker1,*, Loc T. Huynh1, Junnian Wei1, Khaled M. Jami1, Yung-Hua Wang1, Yuqin S. Shen1, Renuka Sriram1, David M. Wilson1, John Kurhanewicz1,2,3 and Michael J. Evans1,2,3
1Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA 94143, USA
2Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94143, USA
3Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94143, USA
*These authors contributed equally to this work
Michael J. Evans, email: [email protected]
Keywords: cancer; glucocorticoid receptor; precision medicine; positron emission tomography; pharmacodynamics
Received: November 30, 2017 Accepted: March 06, 2018 Published: April 17, 2018
The glucocorticoid receptor (GR) is an emerging drug target for several common and deadly solid tumors like breast and prostate cancer, and clinical trials studying the antitumor effects of GR antagonists are beginning. Since GR expression can be variable in tumor cells, and virtually all normal mammalian tissues express some GR, we hypothesized that an imaging tool capable of detecting GR positive tumors and/or measuring GR occupancy by drug in tumor and normal tissues could improve the precision application of anti-GR therapies in the clinic. To this end, we developed a fluorine-18 labeled corticosteroid termed GR02 that potently binds the endogenous ligand binding pocket on full length GR. Binding of 18F-GR02 was suppressed in many normal tissues by co-treatment with mifepristone, a GR antagonist in human use, and was elevated in many normal tissues among mice lacking circulating corticosteroids due to adrenalectomy. 18F-GR02 also accumulated in GR positive subcutaneous and subrenal capsule prostate cancer models, and uptake in tumors was competed by mifepristone. Combined with a straightforward and high yielding radiosynthesis, these data establish the foundation for near-term clinical translation of 18F-GR02.
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