The role of mTOR as target for treatment of adrenal tumors

Adrenal tumors (AT) include benign and malignant cortical tumors, named adrenocortical adenomas (ACAs) and adrenocortical carcinomas (ACCs), respectively and benign and malignant pheochromocytomas (PCCs). The malignant ATs are aggressive tumors with a poor prognosis, for which additional treatments are required. The mTOR pathway has been suggested to play a role in AT pathogenesis.

The main aim of the present thesis was to explore the role of mTOR pathway as a potential target for new treatment option in ATs.
The results of the studies included in the present thesis describe expression of the main components of the mTOR pathway in normal adrenal, adrenal hyperplasia, ACAs and ACCs, and the effects of the mTOR-inhibitors on ACC cell proliferation and cortisol production and on PCC cell proliferation. The effects of mTOR inhibitors alone or in combination with other drugs were also explored in ACC (in combination with mitotane or OSI-906) and PCC (in combination with OSI-906) cell lines, demonstrating that these drugs, or a combination of drugs, might represent new treatment options for a subset of patients with these adrenal tumors. In addition to the mTOR and IGF pathway, the presence of molecular events potentially targetable with currently developed targeted drugs in a large series of ACC samples, were investigated, which demonstrated that no simple targetable molecular event emerged. Moreover, based on genomic alterations, the cell cycle appeared to be the most relevant new potential therapeutic target for patients with advanced ACC.

In conclusion, the results of these studies support the role of the mTOR pathway as a potential target for the treatment of patients with ACCs or malignant PCCs, but they underline that better results are expected by combining treatments and by selecting patients. A need to move into the direction of a more personalized approach for the treatment of patients with malignant ATs is emphasized.