Molecular targets and targeted therapies in pheochromocytoma

Pheochromocytoma and paraganglioma are tumors of chromaffin cells occurring within the adrenal medulla or the sympathetic nervous system, respectively. About 15% of these tumors are malignant, especially in patients with mutations in the subunit B of the succinate dehydrogenase, who have a 40% probability of developing distant metastases. For these malignancies surgery is currently the treatment of choice, but, especially for advanced forms, treatment is unsatisfactory and prognosis is very poor. Thus, novel treatment options for these patients are urgently in need. Recent advances in our understanding of the molecular pathology of pheochromocytoma and paraganglioma have led to the identification of key oncogenic events. Several molecular pathways have been suggested to play a role in these tumors, including the RTKs/Ras/MAPK, PI3K/Akt/mTOR, HIF, HSP90 and mithocondrial proteins involved in energy-producing pathways. This increased knowledge can be matched by the increased number of novel compounds, including tyrosine kinase inhibitors and other novel targeted therapies already in clinical trial for other cancers, targeting signaling pathways important for tumor proliferation, survival and metastatic dissemination. The overarching objective of this research project was to identify mechanism-based, molecularly targeted therapeutic approaches to modulate cancer cell growth and metastatic growth in pheochromocytoma, promoting the translational development of more effective therapeutic options for these tumors. The lack of sensitive animal models of pheochromocytoma has hindered the study of this tumor and in vivo evaluation of antitumor agents.To this end, two in vivo models for the evaluation of efficacy of several molecular targeted therapies were developed: an experimental metastasis model to 3 monitor tumor spreading and a subcutaneous model to monitor tumor growth and spontaneous metastasis. These models offer a platform for sensitive, non-invasive and real-time monitoring of pheochromocytoma primary growth and metastatic burden to follow the course of tumor progression and for testing relevant antitumor treatments in metastatic pheochromocytoma. I then use in vitro experiments and the in vivo models above described to test the efficacy of selective ATP-competitive inhibitors targeting both mTORC1 and mTORC2 complexes, pointing out an important role for the mTOR signaling pathway in the development of pheochromocytoma. Moreover, I investigated also the 90 kDa heat shock protein (Hsp90) as a potential therapeutic target for advanced pheochromocytoma, using both first and second generation Hsp90 inhibitors. As an alternative approach to identify potential drugs that can more rapidly be implemented into clinical trials in patients with metastatic pheochromocytoma or paraganglioma, I used a drug repurposing/repositioning approach. With this strategy, several molecules with potential bioactivity in pheochromocytoma cells were identified, including an example of a combination with synergistic effect.