Genetically engineered human pituitary corticotroph tumor organoids for drug testing
2023
University of Arizona College of Medicine, Tucson, USA
The Cushing's syndrome (CS) is a severe endocrine disorder attributed to an adrenocorticotropic hormone (ACTH)-secreting neuroendocrine pituitary tumor (PitNET), which subsequently leads to chronic hypercortisolism. Following treatment with the selective glucocorticoid receptor (GR) modulator Relacorilant, tumor regression has been reported, but the mechanisms behind this effect remain unknown.
In this study, human pituitary tumor models were generated in the laboratory, either from human stem cells or from tissue obtained from Cushing's syndrome patients. These models were utilized to mimic the development of these tumors. Some of these models exhibited specific genetic alterations typical of these tumors.
Organoids were treated with the GR antagonist Mifepriston or the GR modulator Relacorilant, with or without the somatostatin receptor (SSTR) agonists Pasireotid or Octreotid. Mifepriston led to increased production of a particular receptor called SSTR2 in the tumor cells, along with increased ACTH secretion, which stimulated tumor growth. Relacorilant primarily increased the production of SSTR5 and induced tumor cell death, with minimal ACTH release.
The Hedgehog signalling pathway mediated the induction of SSTR2 and SSTR5 in response to Mifepriston and Relacorilant. Relacorilant sensitized the PitNET organoids to treatment with Pasireotid.
Therefore, the study has highlighted the potential therapeutic benefit of Relacorilant in combination with somatostatin analogues and demonstrated the advantages of Relacorilant over Mifepriston, supporting its further development for the treatment of patients with Cushing's syndrome.
Genetically engineered human pituitary corticotroph tumor organoids exhibit divergent responses to glucocorticoid receptor modulators
Yana Zavros
Added on: 09-05-2023
[1] https://www.translationalres.com/article/S1931-5244(23)00002-6/fulltext
