Steroidogenic factor-1 inverse agonists as a treatment option for canine hypercortisolism: in vitro study

Sanders, Karin; Mol, Jan A.; Slob, Adri; Kooistra, Hans S.; Galac, Sara

doi:10.1016/j.domaniend.2017.11.001

Cited by 7 publications

(8 citation statements)

References 56 publications

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“…Compounds that can target SF‐1 activity, called SF‐1 inverse agonists, have been identified and inhibited cell proliferation and steroid hormone production in vitro in human ACC cells . We showed in a previous study that one SF‐1 inverse agonist, compound #31, effectively inhibited cortisol production and SF‐1 target gene expression in canine adrenocortical cells in vitro . If SF‐1 inverse agonists will be further developed for clinical use, this may have much potential to improve the prognosis of dogs with an ACC with high SF‐1 expression.…”

Section: Discussionmentioning

confidence: 99%

Molecular markers of prognosis in canine cortisol‐secreting adrenocortical tumours

Sanders

Staalduinen

Uijens

et al. 2019

Vet Comparative Oncology

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Hypercortisolism is caused by a cortisol-secreting adrenocortical tumour (ACT) in approximately 15%-20% of cases in dogs. Little is known about which molecular markers are associated with malignant behaviour of canine ACTs. The objective of this study was to identify molecular markers of prognosis, which could be useful to refine prognostic prediction and to identify potential treatment targets. Cortisol-secreting ACTs were included from 40 dogs, of which follow-up information was available. The ACTs were classified as low risk of recurrence tumours (LRT; n = 14) or moderate-high risk of recurrence tumours (MHRT; n = 26), based on the novel histopathological Utrecht score. Normal adrenals (NAs) were included from 11 healthy dogs as reference material. The mRNA expression of 14 candidate genes was analysed in the 40 ACTs and in 11 NAs with quantitative RT-PCR. The genes' expression levels were statistically compared between NAs, LRTs and MHRTs. Univariate and multivariate analyses were performed to determine the association of the genes' expression levels with survival. Seven genes were differentially expressed between NAs and ACTs, of which pituitary tumour-transforming gene-1 (PTTG1) and topoisomerase II alpha (TOP2A) were also differentially expressed between LRTs and MHRTs. In survival analyses, high expression levels of Steroidogenic factor-1 (SF-1), PTTG1 and TOP2A were significantly associated with poor survival. In conclusion, we have identified several genes that are part of the molecular signature of malignancy in canine ACTs. These findings can be used to refine prognostic prediction, but also offer insights for future studies on druggable targets. K E Y W O R D S adrenocortical adenoma, adrenocortical carcinoma, cancer, canine, Cushing syndrome, prognostic, treatment targets

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Section: Discussionmentioning

confidence: 99%

Molecular markers of prognosis in canine cortisol‐secreting adrenocortical tumours

Sanders

Staalduinen

Uijens

et al. 2019

Vet Comparative Oncology

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“…The adrenocortical cell suspensions were prepared as described previously (Sanders et al 2018 ). In short, the adrenal cortices were digested in a collagenase solution, then filtered and washed.…”

Section: Methodsmentioning

confidence: 99%

Melanocortin 2 receptor antagonists in canine pituitary-dependent hypercortisolism: in vitro studies

et al. 2018

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Canine hypercortisolism is most often caused by an ACTH-secreting pituitary adenoma (pituitary-dependent hypercortisolism; PDH). An interesting target for a selective medical treatment of PDH would be the receptor for ACTH: the melanocortin 2 receptor (MC2R). In this study we investigated whether two peptide compounds, BIM-22776 (#776) and BIM-22A299 (#299), are effective MC2R antagonists in vitro. Their effects on cortisol production and mRNA expression of steroidogenic enzymes, MC2R and melanocortin 2 receptor accessory protein (MRAP) were evaluated in primary adrenocortical cell cultures (n = 8) of normal canine adrenal glands. Cortisol production stimulated by 50 nM ACTH was dose-dependently inhibited by #299 (inhibition 90.7 ± 2.3% at 5 μM) and by #776 (inhibition 38.0 ± 5.2% at 5 μM). The ACTH-stimulated mRNA expression of steroidogenic enzymes, MC2R and MRAP was significantly inhibited by both compounds, but most potently by #299. These results indicate that canine primary cell culture is a valuable in vitro system to test MC2R antagonists, and that these compounds, but especially #299, are effective MC2R antagonists in vitro. To determine its efficacy in vivo, further studies are warranted. Antagonism of the MC2R is a promising potential treatment approach in canine PDH.

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“…None offer any advantages on conventional medical therapy, but studies are ongoing into using some of them as part of combination therapies. Also, recent studies have reported novel medical treatment options that could be used for HAC in the future (De Wit and others 2018, Sanders and others 2018); however, further research into these is required.…”

Section: Medical Options For Hyperadrenocorticismmentioning

confidence: 99%

Update on the treatment options for canine hyperadrenocorticism

Schofield¹,

Geddes²,

Fenn³

et al. 2020

In Practice

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Background: Canine hyperadrenocorticism (or Cushing’s syndrome) occurs due to a functional pituitary or adrenal tumour, resulting in excessive circulatory glucocorticoids, which produce the classical clinical signs in affected dogs. Although management of the disease traditionally focuses on treating these endocrine consequences, the pathology reflects an oncological disease with the possibility of progression of the underlying neoplasia. Surgical options for these tumours are now becoming increasingly available and successful.Aim of the article: This article covers how to distinguish between pituitary and adrenal hyperadrenocorticism as well as outlining the treatment options for this important disease in dogs.

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Steroidogenic factor-1 inverse agonists as a treatment option for canine hypercortisolism: in vitro study

Cited by 7 publications

References 56 publications

Molecular markers of prognosis in canine cortisol‐secreting adrenocortical tumours

Molecular markers of prognosis in canine cortisol‐secreting adrenocortical tumours

Melanocortin 2 receptor antagonists in canine pituitary-dependent hypercortisolism: in vitro studies

Update on the treatment options for canine hyperadrenocorticism

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