Role of HSP90 and its co-chaperone FKBP51 in the pathogenesis of Cushing's syndrome

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Clinical signs and symptoms of Cushing syndrome are caused by endogenous hypercortisolism due to an ACTH secreting pituitary or ectopic source or autonomous production of cortisol by the adrenal gland. Unsuccessfully treated Cushing syndrome has a high burden of morbidity and mortality. The molecular chaperone Hsp90 (heat shock protein 90) folds and stabilizes many kinases and transcription factors that have oncogenic properties and are required for tumor growth. The alpha isoform of Hsp90 is over-expressed in many types of solid tumors thereby constituting a validated target for cancer therapy. In fact, currently, several Hsp90 inhibitors are being tested in clinical trials. Hsp90 is also essential for the proper folding and stabilization of the glucocorticoid receptor (GR). The interaction between Hsp90 and GR is strongly affected by the co-chaperone FKBP51 that acts as a binding partner, forming a functional complex. Furthermore, overexpression of Hsp90 has a negative influence on the transcriptional activity of GR. This inhibitory effect of Hsp90 on GR resembles the partial glucocorticoid resistance observed in ACTH-secreting adenomas of the pituitary and of tumors causing ectopic Cushing syndrome. We could recently show that C-terminal Hsp90 inhibitors can restore the sensitivity to glucocorticoids in models of Cushing disease and thereby normalize ACTH levels. Furthermore, there is good evidence that GR within the adrenal is tightly regulated by ACTH thereby forming a positive ultra-short regulatory loop exerted by GR supporting a complex intra-adrenal GR-mediated feedback. Within the proposed working program, we aim at in depth characterization of the complex interplay of Hsp90 dependent mechanisms within the pituitary-adrenal-axis. Specifically, the first aim of our project is to quantify Hsp90-alpha and FKBP51 expression in a large cohort of biopsies from pituitary and adrenal tumors from patients with Cushing syndrome in order to correlate them with clinical parameters including hormonal parameters, tumor characteristics and cardiovascular and metabolic endpoints. Our second aim is to characterize the biochemical interactions between Hsp90, FKBP51, and GR, as well as SREBP1 and CREB that control the production of ACTH and cortisol in corticotroph and adrenocortical cells. We will further investigate the impact of these mechanisms on oncoproteins and cell proliferation. In parallel, we will examine the in vivo effects of FKBP51 and Hsp90 inhibitors on mouse models with the prospect of using these results to design more potent and selective compounds for the treatment of Cushing syndrome and potentially other endocrine malignancies. Together, the results we expect from this project will constitute a full characterization of the mechanism of action of Hsp90 inhibitors on ACTH- and cortisol-secreting tumors.