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Endocrine Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Breast, prostate, and neuroendocrine tumors are the main cancer types treated with hormonal-based therapies, and these are described below in Sections 8.2, 8.3, and 8.5, respectively. Estrogen and progesterone therapies can be used for several different tumor types, and these are described in the section on sex hormones (Section 8.6). The orphan drug mitotane for the treatment of adrenocortical carcinoma is described in Section 8.7. Although its mechanism of action is not fully established, it is a steroidogenesis inhibitor, modifying the peripheral metabolism of steroids and directly suppressing the adrenal cortex. Finally, sulfatase inhibitors which inhibit the sulfatase pathway of estrogen production are described in Section 8.8. Although no examples of this class of agent have been approved at the time of writing, a number have reached late-stage clinical trials but not progressed. It is noteworthy that cancers of the endometrium, ovaries, and testes do not respond well to endocrine agents, and so they are treated with surgery, radiotherapy, and chemotherapy, and more recently with some targeted small molecules and biological agents.
Neuroendocrine disease
Published in Philip E. Harris, Pierre-Marc G. Bouloux, Endocrinology in Clinical Practice, 2014
Pregnancy in patients with Cushing’s syndrome is very uncommon. The signs of Cushing’s syndrome can be difficult to detect because of the physiological changes that take place in pregnancy. The majority of cases are due to ACTH-independent adrenal disease. When it occurs, Cushing’s syndrome is associated with a high maternal and fetal morbidity, with an increased risk of spontaneous abortion. Surgical treatment should be considered whenever possible. Treatment with adrenal steroidogenesis inhibitors should be avoided if possible because of potential deleterious effects on the fetus. The role of pasireotide in the management of pregnant patients with Cushing’s disease remains to be established.240
Drug design strategies for Cushing’s syndrome
Published in Expert Opinion on Drug Discovery, 2019
S. A. Usanov, A. V. Kliuchenovich, N. V. Strushkevich
Steroidogenesis inhibitors block one or more of the enzymes in the steroidogenic pathway. This strategy was successfully used to reduce cortisol production, which is the last step in the conversion of cholesterol to cortisol (Figure 1). The most widely used drugs are ketoconazole and metyrapone (Figure 2). Ketoconazole was introduced in 1977 as an antifungal drug which targets CYP51 of pathogenic fungi [12]. It also inhibits the human CYP51 ortholog as well as human steroidogenic CYP11A1, CYP11B1, CYP17 and drug-metabolizing CYPs [13]. This finding has led to its application to treat CS [14]. However, oral administration of ketoconazole was restricted in 2013/2014 due to severe hepatotoxicity, while its hepatic safety is still being studied [15].
Osilodrostat for the treatment of Cushing’s disease
Published in Expert Opinion on Pharmacotherapy, 2021
Adrenal steroidogenesis inhibitors affect enzymes required for steroid production [32–34]. Ketoconazole is the most commonly utilized steroidogenesis inhibitor, inhibiting steroidogenic acute regulatory protein, CYP11A1, CYP11B1, and CYP17. It has a rapid onset with reported serum cortisol reduction in 70% of patients and normalization of UFC in up to 50% of patients, though failure may be attributable to the ‘escape phenomenon’ [5,14,25,33,35–42]. Although approved in the European Union (EU), ketoconazole is not FDA-approved for CD in the United States (US) and has a black box warning for potential hepatotoxicity [43].
New and emerging drug therapies for Cushing’s disease
Published in Expert Opinion on Pharmacotherapy, 2018
Sylvère Störmann, Jochen Schopohl
Medical progress abandons some treatment options as they are replaced by newer and more efficacious therapies. However, once in a while old pharmacological agents are resurrected and find a new place in the therapeutic armamentarium, as is the case for most steroidogenesis inhibitors in CD (see further below) [73]. Therefore, the following drugs deserve to be mentioned despite not commonly being part of current clinical applications [21,74,75].