Novel targets for the treatment of ACTH-secreting tumors

Cushing's disease is an endocrine disorder caused by excessive production of ACTH. It represents a major challenge for the physician in terms of accurate diagnosis and efficient treatment. Unless treated, the disease is associated with high morbidity, and ultimately, mortality. In the absence of effective medical therapies, patients with Cushing's disease are usually treated by transsphenoidal pituitary surgery. However, surgery is associated with significant post-operative morbidities and not all patients can be cured by it. In addition to surgical procedures various drugs, such as dopamine agonists and somatostatin analogues, effective in only a limited number of cases, have been employed to treat ACTH-secreting tumors. The therapeutic potential of new generations of these drugs with more selective and long-lasting effects, such as cabergoline and SOM230, has been examined in recent studies. On the other hand, the identification of potential therapeutic targets in pituitary corticotroph tumors, such as the nuclear receptor peroxisome-proliferator-activated receptor -γ (PPARγ) and the retinoic acid receptors (RAR and RXR), provides novel approaches for the treatment of Cushing's disease. However, the ability of the PPARγ ligand rosiglitazone and retinoic acid to treat patients with Cushing's disease still needs to be validated in further clinical studies. Recently, a new study demonstrated the efficacy of the retinoic acid treatment in dogs with Cushing's disease. Since RAR and RXR might have synergistic inhibitory actions with PPARγ ligands, combination therapy with RXR and PPAR γ ligands might allow reduced concentrations of both ligands to be administered therapeutically. A recent in vitro and in vivo study demonstrated the potent antiproliferative and proapoptotic effects of doxazosin, an alpha1-adrenergic receptor antagonist, by mechanisms involving the down-regulation of nuclear factor-κB signalling. The efficiency of doxazosin treatment in patients with Cushing's disease still needs to be tested in clinical trials.