TY - JOUR
T1 - Genetically engineered human pituitary corticotroph tumor organoids exhibit divergent responses to glucocorticoid receptor modulators
AU - Mallick, Saptarshi
AU - Chakrabarti, Jayati
AU - Eschbacher, Jennifer
AU - Moraitis, Andreas G.
AU - Greenstein, Andrew E.
AU - Churko, Jared
AU - Pond, Kelvin W.
AU - Livolsi, Antonia
AU - Thorne, Curtis A.
AU - Little, Andrew S.
AU - Yuen, Kevin C.J.
AU - Zavros, Yana
N1 - Funding Information: This research was supported by Department of Cellular and Molecular Medicine (University of Arizona College of Medicine) startup funds (Zavros). We acknowledge Maga Sanchez in the Tissue Acquisition and Cellular/Molecular Analysis Shared Resource (TACMASR University of Arizona Cancer Center) for assistance with embedding and sectioning of organoids. We would also like to acknowledge Patty Jansma (Marley Imaging Core, University Arizona) and, Douglas W Cromey (TACMASR imaging, University of Arizona Cancer Center) for assistance in microscopy. Research reported was partly supported by the National Cancer Institute of the National Institutes of Health under award number P30 CA023074 (Sweasy). We would like to acknowledge the assistance of Tina Schlafly (Corcept) for help with manuscript editing. Finally, the authors thank the patients who consented to donate tissues and blood for the development of the organoids. Without their willingness to participate in the study, this work would not be possible. Funding Information: This research was supported by Department of Cellular and Molecular Medicine (University of Arizona College of Medicine) startup funds (Zavros). We acknowledge Maga Sanchez in the Tissue Acquisition and Cellular/Molecular Analysis Shared Resource ( TACMASR University of Arizona Cancer Center ) for assistance with embedding and sectioning of organoids. We would also like to acknowledge Patty Jansma ( Marley Imaging Core, University Arizona ) and, Douglas W Cromey ( TACMASR imaging, University of Arizona Cancer Center ) for assistance in microscopy. Research reported was partly supported by the National Cancer Institute of the National Institutes of Health under award number P30 CA023074 (Sweasy). We would like to acknowledge the assistance of Tina Schlafly (Corcept) for help with manuscript editing. Finally, the authors thank the patients who consented to donate tissues and blood for the development of the organoids. Without their willingness to participate in the study, this work would not be possible. Publisher Copyright: © 2023 The Author(s)
PY - 2023/6
Y1 - 2023/6
N2 - 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 (iPSCUSP48) or USP8 (iPSCUSP8) 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 iPSCUSP48 and iPSCUSP8 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.
AB - 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 (iPSCUSP48) or USP8 (iPSCUSP8) 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 iPSCUSP48 and iPSCUSP8 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.
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U2 - 10.1016/j.trsl.2023.01.002
DO - 10.1016/j.trsl.2023.01.002
M3 - Article
C2 - 36640905
SN - 1931-5244
VL - 256
SP - 56
EP - 72
JO - Translational Research
JF - Translational Research
ER -