Novel preclinical models, therapies and biomarkers for testicular cancer

Abstract

Testicular cancer (TC) is the most common solid tumor among young men. The prognosis of TC patients with metastatic disease is good; however, 20% of them will need second-line treatment as consequence of relapse or refractory disease. Whenever resistance to cisplatin-based chemotherapy occurs there are limited options for these patients. The aim of this thesis was to study response to chemotherapy in TC from different perspectives. Firstly, we evaluated novel tumor markers in patients’ serum, specifically miRNAs, using qPCR to detect relapse or refractory disease early in the course of treatment. We established that miRNA levels increased earlier than classical tumor markers in TC patients with relapse and refractory disease. Additionally, we developed and characterized TC Patient Derived Xenografts (PDX) to study therapies that sensitize TC tumors towards chemotherapy. PDX models were found to preserve TC tumor characteristics, like histology and cisplatin sensitivity even at later mouse generations. The same PDX models were used to test the best combinatorial strategy found in the lab, cisplatin in combination with mTOR inhibitors, showing a higher effect on tumor volume than cisplatin or mTOR inhibitors alone. Finally, APF and β-HCG serum levels were evaluated in PDX models showing no correlation of the patient’s tumor marker production and the expression of AFP and β-HCG in mice. In conclusion, we characterized novel tumor markers in sensitive and resistant TC patients and found therapies that hold the potential to improve clinical outcome of TC.