The glucocorticoid receptor is a master regulator of normal physiology and its dysregulation is thought to drive the pathophysiology of many diseases, including mood disorders, metabolic diseases, and even cancer. Cell and genetically engineered animal models have been the mainstays for carefully articulating the abovementioned features of GR (patho)biology. Fully understanding GR’s role in human physiology and disease, as well as developing next generation therapeutics to more selectively modulate GR, requires new technologies that can safely probe GR signaling in living subjects. The lack of non-invasive biomarkers to interrogate GR signaling in humans has left the field to perform very suboptimal assays, for instance, analysis of GR and target gene expression levels from tissues collected at autopsy.
To better interrogate GR signaling dynamics in humans, we have developed a library of radiolabeled corticosteroids and synthetic agonists to measure GR expression levels in vivo. These tools have enabled an unprecedented view of GR expression dynamics to reveal aspects of GR biology that are only occurring in vivo. Moreover, we have demonstrated that GR PET can be used to reveal unexpected tissue specific drug-GR interactions, which establishes an entirely new paradigm for the development of selective GR modulators-a major unmet clinical need. Lastly, I supervise an ongoing clinical trial to translate one radioligand, 11C-YJH08, into humans to make the first non-invasive measurements of GR expression levels in healthy subjects and patients with mood disorders or prostate cancer.
Relevant Publications:
- Huang Y, Zhao N, Wang YH, Truillet C, Wei J, Blecha JE, VanBrocklin HF, Seo Y, Sayeed M, Feldman BJ, Aggarwal R, Behr SC, Shao H, Wilson DM, Villanueva-Meyer JE, Gestwicki JE, Evans MJ. A novel radioligand reveals tissue specific pharmacological modulation of glucocorticoid receptor expression with positron emission tomography. ACS Chem Biol. 2020 Apr 07. PMID: 32255605.
- Truillet C, Parker MFL, Huynh LT, Wei J, Jami KM, Wang YH, Shen YS, Sriram R, Wilson DM, Kurhanewicz J, Evans MJ. Measuring glucocorticoid receptor expression in vivo with PET. Oncotarget. 2018 Apr 17; 9(29):20399-20408. PMID: 29755660.
- In Vivo Profiling with 18F-YJH08 Reveals Diverse Tissue Patterns of Antagonist/Glucocorticoid Receptor Interactions. Mol Pharm. 2022 02 07; 19(2):704-709.Kim H, Huang Y, Zhao N, Wang YH, Sakhamuri S, Chopra S, Hooshdaran N, Sriram R, Aggarwal R, Evans MJ. PMID: 35049307.
- The Synthesis and Structural Requirements for Measuring Glucocorticoid Receptor Expression In Vivo with (±)-11C-YJH08 PET. J Nucl Med. 2021 05 10; 62(5):723-731.Huang Y, Zhao N, Wang YH, Truillet C, Wei J, Parker MFL, Blecha JE, Drake CR, VanBrocklin HF, Garrido-Ruiz D, Jacobson MP, Aggarwal R, Behr SC, Flavell RR, Wilson DM, Seo Y, Evans MJ. PMID: 32887758; PMCID: PMC8844266.