tretinoin and pasireotide

Cushing's syndrome is associated with multisystem morbidity and, when suboptimally treated, increased mortality. Medical therapy is an option for patients if surgery is not successful and can be classified into pituitary-directed drugs, steroid synthesis inhibitors, and glucocorticoid receptor antagonists. In the last decade there have been new developments in each drug category. Targeting dopamine and somatostatin receptors on corticotroph adenomas with cabergoline or pasireotide, or both, controls cortisol production in up to 40% of patients. Potential new targets in corticotroph adenomas include the epidermal growth factor receptor, cyclin-dependent kinases, and heat shock protein 90. Osilodrostat and levoketoconazole are new inhibitors of steroidogenesis and are currently being evaluated in multicentre trials. CORT125134 is a new selective glucocorticoid receptor antagonist under investigation. We summarise the drug therapies for various forms of Cushing's syndrome and focus on emerging drugs and drug targets that have the potential for new and effective tailor-made pharmacotherapy for patients with Cushing's syndrome.

Topics: ACTH Syndrome, Ectopic; ACTH-Secreting Pituitary Adenoma; Adenoma; Adrenal Gland Neoplasms; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Cabergoline; Cushing Syndrome; Dopamine Agonists; ErbB Receptors; Gefitinib; Hormones; Humans; Imidazoles; Isoquinolines; Molecular Targeted Therapy; Pituitary ACTH Hypersecretion; Pyrazoles; Pyridines; Receptors, Glucocorticoid; Roscovitine; Somatostatin; Temozolomide; Tretinoin

The most frequent cause of endogenous hypercortisolism is Cushing disease (CD), a devastating condition associated with severe comorbidities and high mortality. Effective tumor-targeting therapeutics are limited.. Search in PubMed with key words "corticotroph" and "Cushing's disease" plus the name of the mentioned therapeutic agent and in associated references of the obtained papers. Additionally, potential therapeutics were obtained from ClinicalTrials.gov with a search for "Cushing disease.". At present, the tumor-targeted pharmacological therapy of CD is concentrated on dopamine agonists (cabergoline) and somatostatin analogs (pasireotide) with varying efficacy, escape from response, and considerable side effects. Preclinical studies on corticotroph pathophysiology have brought forward potential drugs such as retinoic acid, silibinin, and roscovitine, whose efficacy and safety remain to be determined.. For many patients with CD, effective tumor-targeted pharmacological therapy is still lacking. Coordinated efforts are pivotal in establishing efficacy and safety of novel therapeutics in this rare but devastating disease.

Topics: ACTH-Secreting Pituitary Adenoma; Adenoma; Antineoplastic Agents; Cabergoline; Clinical Trials as Topic; Corticotrophs; Humans; Pituitary ACTH Hypersecretion; Roscovitine; Silybin; Somatostatin; Treatment Outcome; Tretinoin

Hypercortisolism induced by Cushing disease causes high morbidity and mortality. The treatment of choice is pituitary surgery, but it often fails to achieve cure, and other treatment modalities (radiotherapy, bilateral adrenalectomy) may therefore be required. If these treatments are not effective or while waiting for their results, hypercortisolism should be controlled with drugs. The classical drug treatments are those that act by inhibiting cortisol secretion by the adrenal gland (ketoconazole, metyrapone, mitotane, etomidate). The preliminary results of a new drug (LCI699) which is a potent enzyme inhibitor of cortisol secretion have been reported. A clinical trial of the safety and efficacy of mifepristone, a glucocorticoid receptor antagonist, has just been published. The drugs deserving more attention today are those with a direct action on the tumor by inhibiting ACTH secretion: somatostatin analogues (pasireotide), dopamine agonists (cabergoline), PPAR-γ, and retinoic acid. A special review is made of the available clinical trials with pasireotide and cabergoline.

Topics: Adenoma; Adrenocorticotropic Hormone; Animals; Cabergoline; Clinical Trials as Topic; Clinical Trials, Phase III as Topic; Drug Evaluation, Preclinical; Ergolines; Etomidate; Humans; Hydrocortisone; Imidazoles; Ketoconazole; Metyrapone; Mice; Mifepristone; Mitotane; Multicenter Studies as Topic; Pituitary ACTH Hypersecretion; Pituitary Neoplasms; PPAR gamma; Pyridines; Rats; Somatostatin; Therapies, Investigational; Tretinoin

Despite considerable progress, there is still no medical treatment available for some kinds of pituitary tumors, in particular hormone inactive adenomas and corticotroph pituitary tumors. Surgical removal or at least debulking of the tumor is the only option to treat these kinds of tumors apart from rarely applied radiotherapy. Moreover, treatment resistance is present in a considerable proportion of patients bearing pituitary tumors, for which medical treatment regimens are already available (prolactinomas, somatotroph adenomas). Thus, novel or improved medical treatment strategies would be desirable. Here, we summarize preclinical and clinical findings about the hormone and growth-suppressive action of various drugs, which will probably lead to novel future medical treatment concepts for pituitary tumors.

Topics: Dopamine; Dopamine Agonists; Humans; Interferon-gamma; Pituitary Neoplasms; Somatostatin; Tretinoin