Endocrine Abstracts

Understanding of the molecular pathogenesis of adrenocortical neoplasias has been greatly advanced by exome sequencing demonstrating in Conn adenomas hot spot mutations in KCJN5, ATP1A1, ATP2B in a substantial subgroup of patients. Current work now demonstrates that constitutive activation of the cAMP – PKA pathway not only causes rare bilateral hyperplasias like PPNAD, but is also involved in a high percentage of cortisol producing adenomas. Intriguingly, this hot spot mutation is only seen in overt Cushing’s syndrome (CS), but not in subclinical CS or cortisol secreting adrenocortical cancer (ACC). Deep sequencing of ACC is currently performed by an international consortium and results are expected by the end of 2013. It is hoped that this analysis will reveal new targets for therapy, as current treatment options for advanced ACC remain unsatisfactory. The role of surgery for recurrent ACC has now been clarified by recent large retrospective studies indicating that surgery is most helpful in late recurrence and when complete resection of metastatic disease seems feasible. Mitotane remains the most important drug for ACC. However, due its strong induction of Cyp3A4 it impairs the activity of many new targeted therapies (e.g. sunitinib) making it a double edged sword. Current work, therefore, tries to better clarify the mechanism of action of mitotane with the goal to select useful drugs for combination therapy and to identify responders prior treatment.

Generously supported by Clinical Endocrinology Trust