Currently used and investigational drugs for Cushing´s disease

Figures & data

Table 1. Sites and mechanisms of action of the drugs tested in Cushing’s disease (CD).

	Site of action	Drug	Mechanism of action	Development status
Adrenal-directed therapy	Steroidogenesis	Ketoconazole	↓CYP17, ↓CYP11β	Clinical practice
		Levoketoconazole		Phase III
		Metyrapone	↓CYP11β	Off-label
		Aminoglutetimide	↓CYP11A1	Stopped
		Trilostane	↓CYP3B2	Stopped
		Etomidate	↓CYP11β	Off-label
		Mitotane	↓CYP11A1, ↓CYP11β	Off-label
		LCI699	↓CYP11β	Phase III
		ATR-101	↓ACAT 1	Preclinical
	Melanocortin-2 receptor	GPS1573, GPS1574	Block to the MC2R activated by ACTH	Preclinical
Cushing adenoma-directed therapy	Somatostatin receptor	Pasireotide	Stimulate SSTRs, with more affinity for SSTR5 (pasireotide) and 2,4, and 5 (DG-3173)	Clinical practice
		DG-3173		Phase I
	Dopamine receptor	Cabergoline	Stimulates D2 receptor	Off-label
	Somatostatin and dopamine receptor	BIM23A760	Stimulates SSTRs and D2 receptor	Stopped
	PPAR-γ agonists	Rosiglitazone	Inhibits the mRNA expression of POMC	Stopped
	Retinoic acid receptor	All-trans RA	Inhibit cell proliferation and secretion	Phase II
		9-cis RA
		13-cis RA
	EGFR	Gefitinib	Regulates POMC expression	Preclinical
	Cicline-dependent kinases	R-roscovitine	Effects on cell cycle, and inhibits ACTH secretion by targeting cyclin E/E2F1 pathway	Phase II
	HSP90C-terminal domain	Silibinin	Restores glucocorticoid sensitivity	Preclinical
Peripheral therapy	Glucocorticoid type II receptor	Mifepristone	Antagonist of GR	Clinical practice

CYP17: cytochrome P45017A1 (17 alfa-hydroxylase); CYP11β: cytochrome P45011β (11 beta-hydroxylase); CYP11A1: cytochrome P45011A1 (side-chain cleavage of cortisol biosynthesis); CYP3β2: cytochrome P4503β2 (3-β hydroxysteroid dehydrogenase/Δ5-Δ4 isomerase); ACAT 1: acetyl-coA acetyltransferase 1; MC2 R: melanocortin-2 receptor; ACTH: adrenocorticotrophic hormone; SSTR: somatostatin receptor; RA: retinoic acid; EGFR: epidermal growth factor receptor; POMC: proopiomelanocortin; HSP: heat shock protein; GR: glucocorticoid receptor.

Table 2. Overview on use, dose range, beneficial, and adverse effects of drugs currently used, tested, or under evaluation in clinical trials for CD.

Developmental status	Drug	Potential clinical positioning	Dose range tested	Beneficial effects reported	Most common side effects reported	References
Phase II	Retinoic acid receptor agonists	Persistent or recurrent hypercortisolism after trans-sphenoidal surgery	10–80 mg/day	Decrease of UFC	Severe adverse effects (potential teratogenicity, mucocutaneous toxicity, etc.) after long exposure to the efficacious concentrations	[9,10]
Phase III	Levoketoconazole	Pre-post surgery, if surgery is contraindicated, waiting for the effect of radiotherapy	150–600 mg/day	Higher effect than ketoconazole in decreasing enzymes in cortisol biosynthesis pathway	Diarrhea, dizziness, abdominal pain	[11–13]
	LCI699	Pre-post surgery	4–100 mg/day	Decrease of UFC	Gastrointestinal disturbances, headaches	[14–17]
	Ketoconazole	Pre-post surgery	200/1200 mg/day	Decrease of cortisol production	Hepatotoxicity, may lead to hypogonadism/gynecomastia (not advised in men)	[18]
Clinical practice	Mifepristone	For non-responders to multimodal therapies	300–1200 mg/day (for CS)	Decrease in body weight, waist circumference, and body fat, increased insulin sensitivity	Nausea, fatigue, headache, decreased blood potassium, arthralgia, vomiting, endometrial thickening, peripheral edema	[19]
	Pasireotide	After surgery or in patients not eligible for surgery	300–1200 µg/day	Decrease of UFC	Glucose-related adverse effects (not advised in patients with diabetes mellitus, impaired glucose tolerance)	[20–23]
Off-label	Cabergoline	Mainly effective in patients with D2 expression	0.5–7 mg/week	Suppression of ACTH levels	Generally well tolerated	[3,24]
	Etomidate	Pre-post surgery, for patients not able to take oral medication	0.2–0.6 mg/kg/h	Adrenal suppression after 30 min single dose application	Adrenal suppression, decrease in blood pressure, anaphylactic reactions, nausea, vomiting	[25–30]
	Metyrapone	Before surgery	500–6000 mg/day	Decrease of cortisol levels	Adrenal insufficiency, increased androgen levels (not recommended in women, increased deoxycortisone levels	[31]
	Mitotane	Pre-post surgery, need frequent monitoring	Up to 6 mg/day	Decrease of cortisol production	Gastrointestinal, neurological, and hepatic disturbances	[14,32,33]

Pecori Giraldi F, Ambrogio AG, Andrioli M, et al. Potential role for retinoic acid in patients with Cushing’s disease. J Clin Endocrinol Metab. 2012;97(10):3577–3583.

 PubMed Web of Science ®Google Scholar

Vilar L, Albuquerque JL, Lyra R, et al. The role of isotretinoin therapy for Cushing’s disease: results of a prospective study. Int J Endocrinol. 2016; 2016:8173182.

 PubMed Web of Science ®Google Scholar

GlobalData.com [Internet]. Cortendo’s Normocort: a Cushing’s syndrome newcomer entersphase III. [cited 2014 Aug 18]. Available from: https://healthcare.globaldata.com/resources/expert-insights/pharmaceuticals/cortendos-normocort-a-cushings-syndrome-newcomer-enters-phase-iii.html

 Google Scholar

MarketResearch.com [Internet]. Cushing’s Syndrome-opportunity analysis and forecast to 2018. GlobalData. [cited 2015 Dec 12]. Available from: http://www.marketresearch.com/product/sample-8941833.pdf

 Google Scholar

Morris D, Grossman A. The medical management of Cushing’s syndrome. Ann N Y Acad Sci. 2002;970(1):119–133.

 PubMed Web of Science ®Google Scholar

ClinicalTrials.gov [Internet]. Safety and efficacy of LCI699 for the treatment of patients withCushing’s disease. [cited 2015 Nov 26]. Available from https://clinicaltrials.gov/ct2/show/NCT02180217

 Google Scholar

Feelders RA, Hofland LJ. Medical treatment of Cushing’s disease. J Clin Endocrinol Metab. 2013;98(2):425–438.

 PubMed Web of Science ®Google Scholar

Fleseriu M, Biller BM, Findling JW, et al. Mifepristone, a glucocorticoid receptor antagonist produces clinical and metabolic benefits in patients with Cushing’s Syndrome. J Clin Endocrinol Metab. 2012;97(6):2039–2049.

 PubMed Web of Science ®Google Scholar

Boscaro M, Ludlam WH, Atkinson B, et al. Treatment of pituitary-dependent Cushing’s disease with the multireceptor ligand somatostatin analog pasireotide (SOM230): a multicenter, phase II trial. J Clin Endocrinol Metab. 2009;94(1):115–122.

 PubMed Web of Science ®Google Scholar

Stalla GK, Brockmeier SJ, Renner U, et al. Octreotide exerts different effects in vivo and in vitro in Cushing’s disease. Eur J of Endocrinol. 1994;130(2):125–131.

 PubMed Web of Science ®Google Scholar

Pivonello R, De Leo M, Cozzolino A, et al. The treatment of Cushing’s disease. Endocr Rev. 2015;36(Aug):385–486.

 PubMed Web of Science ®Google Scholar

Lamberts S, McLoad R. Regulation of prolactin secretion at the level of the lactotroph. Physiol Rev. 1990;70:279–318.

 PubMed Web of Science ®Google Scholar

Igaz P, Tombol Z, Szabo PM, et al. Steroid biosynthesis inhibitors in the therapy of hypercortisolism: theory and practice. Curr Med Chem. 2008;15(26):2734–2747.

 PubMed Web of Science ®Google Scholar

Greening JE, Brain CE, Perry LA, et al. Efficient short-term control of hypercortisolaemia by low-dose etomidate in severe paediatric Cushing’s disease. Horm Res. 2005;64(3):140–143.

 PubMed Web of Science ®Google Scholar

Fleseriu M, Petersenn S. Medical management of Cushing’s disease: what is the future? Pituitary. 2012;15(3):330–341.

 PubMed Web of Science ®Google Scholar

Feelders RA, Hofland LJ, de Herder WW. Medical treatment of Cushing’s syndrome: adrenal-blocking drugs and ketaconazole. Neuroendocrinology. 2010;92(1):111–115.

 PubMed Web of Science ®Google Scholar

Eckstein N, Haas B, Hass MD, et al. Systemic therapy of Cushing’s syndrome. Orphanet J Rare Dis. 2014;9:122.

 PubMed Web of Science ®Google Scholar