Novel Insights into Diagnosis and Treatment of Adrenocortical Tumors

Adrenocortical tumors can cause two distinct clinical problems, with in some cases a combination of both:
1) hormonal overproduction, and
2) malignant tumor growth.
The first clinical problem includes Cushing’s syndrome, due to chronic exposure to high levels of cortisol. Despite the fact that surgery is the first treatment approach, medical treatment is indicated in several settings, but is associated with limited efficacy and toxicity. In the first part of this dissertation, we aim to investigate the in vitro effects of two novel steroidogenesis inhibitors currently investigated in clinical trials, i.e. levoketoconazole and osilodrostat, on adrenocortical steroidogenesis and pituitary adenoma cells. We conclude that both steroidogenesis inhibitors are potential novel compounds for the treatment of Cushing’s syndrome.
The second part of this dissertation focuses on adrenocortical carcinoma, of which diagnosis and monitoring is currently challenging. Therefore, we propose a novel diagnostic test to discriminate adrenocortical carcinomas from adenomas, and also show for the first time the possibility to detect circulating cell-free tumor DNA in a patient with adrenocortical carcinoma. Furthermore, efficacy of treatment of adrenocortical carcinoma has limited efficacy and is associated with severe toxicity. We provide novel insights into the currently used medical treatments like mitotane and chemotherapy. We also present potential ways to improve sensitivity of treatment, by targeting the multidrug resistance 1 gene or by using a compound not previously tested in adrenocortical carcinoma, i.e. temozolomide.