Genetically engineered human pituitary corticotroph tumor organoids exhibit divergent responses to glucocorticoid receptor modulators.

Cushing's disease (CD) is a serious endocrine disorder attributed to an adrenocorticotropic hormone (ACTH)-secreting pituitary neuroendocrine tumor (PitNET) that that subsequently leads to chronic hypercortisolemia. PitNET regression has been reported following treatment with the investigational selective glucocorticoid receptor (GR) modulator relacorilant, but the mechanisms behind that effect remain unknown. Human PitNET organoid models were generated from induced human pluripotent stem cells (iPSCs) or fresh tissue obtained from CD patient PitNETs (hPITOs). Genetically engineered iPSC derived organoids were used to model the development of corticotroph PitNETs expressing USP48 (iPSC ^USP48 ) or USP8 (iPSC ^USP8 ) somatic mutations. Organoids were treated with the GR antagonist mifepristone or the GR modulator relacorilant with or without somatostatin receptor (SSTR) agonists pasireotide or octreotide. In iPSC ^USP48 and iPSC ^USP8 cultures, mifepristone induced a predominant expression of SSTR2 with a concomitant increase in ACTH secretion and tumor cell proliferation. Relacorilant predominantly induced SSTR5 expression and tumor cell apoptosis with minimal ACTH induction. Hedgehog signaling mediated the induction of SSTR2 and SSTR5 in response to mifepristone and relacorilant. Relacorilant sensitized PitNET organoid responsiveness to pasireotide. Therefore, our study identified the potential therapeutic use of relacorilant in combination with somatostatin analogs and demonstrated the advantages of relacorilant over mifepristone, supporting its further development for use in the treatment of Cushing's disease patients.
Competing Interests: Conflicts of Interest All authors have read the journal's policy on disclosure of potential conflicts of interest.. Dr. Andreas G. Moraitis and Dr. Andrew E.Greenstein are employees and stock holders of Corcept. Dr. Kevin CJ Yuen has received research grants to the Barrow Neurological Institute from Crinetics, Ascendis, Corcept, and Amryt. Dr. Yuen has served as an advisory board member for Novo Nordisk, Ipsen, Amryt, Crinetics, Recordati and Xeris, and served as a speaker for Recordati, Novo Nordisk and Corcept. All other authors have no potential conflicts of interest to declare.
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