Abstract
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.
Highlights
The glucocorticoid receptor (GR) is a nuclear hormone receptor that regulates many cellular processes, including catabolism and apoptosis [1, 2]
The silyl ether group on 2 was removed with tetra-butyl ammonium fluoride (TBAF) to confer 3, and the C24 primary alcohol was activated by reaction with methane sulfonyl chloride (MsCl) to confer 4
The precursor synthesis was high yielding, the radiochemistry can be automated, and the preparation of 18F-GR02 utilizes radiochemistry that is safe for human translation [23]
Summary
The glucocorticoid receptor (GR) is a nuclear hormone receptor that regulates many cellular processes, including catabolism and apoptosis [1, 2]. The transcriptional activity of GR in peripheral tissues is activated by binding to corticosteroids, which are synthesized and secreted by the adrenal cortex. A pulse of high corticosteroid production and secretion typically occurs transiently after periods of stress, whereupon homeostasis is restored by corticosteroid metabolism in peripheral tissues [2]. Early stage prostate cancer does not express GR, upregulation of GR in castration resistant prostate cancer was recently identified as mechanism of resistance to the antiandrogen enzalutamide (Xtandi) [8,9,10], as GR can transcriptionally activate direct androgen receptor (AR) target genes, but enzalutamide cannot bind and inactivate GR. In concert with GR expression, deficient corticosteroid metabolism in castration resistant prostate www.oncotarget.com cancer cells can override the antitumor activity of enzalutamide [10]
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