Editorial: Cushing's disease and stereotactic radiosurgery

Pandey

Churko

et al. 2022

Cells

(1) Background: Cushing’s disease (CD) is a serious endocrine disorder caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary neuroendocrine tumor (PitNET) that stimulates the adrenal glands to overproduce cortisol. Chronic exposure to excess cortisol has detrimental effects on health, including increased stroke rates, diabetes, obesity, cognitive impairment, anxiety, depression, and death. The first-line treatment for CD is pituitary surgery. Current surgical remission rates reported in only 56% of patients depending on several criteria. The lack of specificity, poor tolerability, and low efficacy of the subsequent second-line medical therapies make CD a medical therapeutic challenge. One major limitation that hinders the development of specific medical therapies is the lack of relevant human model systems that recapitulate the cellular composition of PitNET microenvironment. (2) Methods: human pituitary tumor tissue was harvested during transsphenoidal surgery from CD patients to generate organoids (hPITOs). (3) Results: hPITOs generated from corticotroph, lactotroph, gonadotroph, and somatotroph tumors exhibited morphological diversity among the organoid lines between individual patients and amongst subtypes. The similarity in cell lineages between the organoid line and the patient’s tumor was validated by comparing the neuropathology report to the expression pattern of PitNET specific markers, using spectral flow cytometry and exome sequencing. A high-throughput drug screen demonstrated patient-specific drug responses of hPITOs amongst each tumor subtype. Generation of induced pluripotent stem cells (iPSCs) from a CD patient carrying germline mutation CDH23 exhibited dysregulated cell lineage commitment. (4) Conclusions: The human pituitary neuroendocrine tumor organoids represent a novel approach in how we model complex pathologies in CD patients, which will enable effective personalized medicine for these patients.

Section: Introductionmentioning

confidence: 99%

Development of Human Pituitary Neuroendocrine Tumor Organoids to Facilitate Effective Targeted Treatments of Cushing’s Disease

Pandey

Churko

et al. 2022

Cells

“…Hence, medical therapy is often considered in the following situations: when surgery is contraindicated or fails to achieve remission, or when recurrence occurs after apparent surgical remission. While stereotactic radiosurgery treats incompletely resected or recurrent pituitary adenomas, the main drawbacks include the longer time to remission (12-60 months) and the risk of hypopituitarism 3,11,12 . There is an inverse relationship between disease duration and reversibility of complications associated with the disease thus emphasizing the importance of identifying an effective medical strategy to rapidly normalize cortisol production by targeting the pituitary adenoma 4,6,10 .…”

Section: Introductionmentioning

confidence: 99%

Development of Human Pituitary Adenoma Organoids to Facilitate Effective Targeted Treatments of Cushing's Disease.

Zavros

Pandey

et al. 2022

Preprint

Cushing's disease (CD) is a serious endocrine disorder caused by dysregulated adrenocorticotropic hormone (ACTH)-secreting pituitary tumor that stimulates the adrenal glands to overproduce cortisol. Chronic exposure to excess cortisol has detrimental effects on health, including increased stroke rates, diabetes, obesity, cognitive impairment, anxiety, depression, and death. The first-line treatment for CD is pituitary surgery, which is followed by disease remission. Current surgical remission rates reported range from 47–85% depending on several remission criteria. The lack of specificity, poor tolerability, and low efficacy of the subsequent second-line medical therapies makes CD a medical therapeutic challenge. One major limitation that hinders the development of specific medical therapies is the lack of human relevant model systems that recapitulate the cellular composition of pituitary adenomas. Human pituitary adenoma tissue was harvested during transsphenoidal surgery from CD patients to generate organoids (hPITOs). hPITOs generated from corticotroph, lactotroph, gonadotroph and somatotroph adenomas exhibited morphological diversity among the organoid lines between individual patients and amongst subtypes. The similarity in cell lineages between the organoid line and the patient’s tumor was validated by comparing the neuropathology report to the expression pattern of pituitary adenoma specific markers using spectral flow cytometry and exome sequencing. A high-throughput drug screen demonstrated patient-specific drug responses of hPITOs amongst each adenoma subtype. Generation of induced pluripotent stem cells (iPSCs) from patients carrying germline mutations relevant to CD exhibited dysregulated cell lineage commitment. The human pituitary adenoma organoids represent a novel approach in how we model complex pathologies in CD patients that may enable more effective personalized medicine for these patients.

“…Medical therapy is often considered when initial surgery fails to achieve remission, or when the tumor recurs after apparent surgical remission. Approved treatments include pituitary-targeted drugs, adrenal steroidogenic inhibitors, and a non-selective glucocorticoid receptor (GR) antagonist [3, 11, 12]. There is an inverse relationship between disease duration and reversibility of complications associated with the disease, thus emphasizing the importance of identifying an effective medical strategy to rapidly normalize hypercortisolemia/cortisol activity by directly targeting the pituitary adenoma [4, 7, 10].…”

Section: Introductionmentioning

confidence: 99%

Genetically Engineered Human Pituitary Corticotroph Tumor Organoids Exhibit Divergent Responses To Glucocorticoid Receptor Modulators

Mallick

Eschbacher

et al. 2022

Preprint

Cushings disease (CD) is a serious endocrine disorder attributed to an ACTH-secreting pituitary neuroendocrine tumor (PitNET) that subsequently causes 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 the 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 CD patients.