Mechanistic and translational studies to improve cisplatin sensitivity of testicular cancer

Testicular cancer (TC) is one of the most common solid tumors in men between 20-40 years of age. While cisplatin-based chemotherapy is highly effective in TC patients, cisplatin resistance is still an important issue and refractory testicular cancer is a significant cause of death in this relatively young age group. Therefore, we aimed to identify new therapeutic targets and treatment strategies to overcome cisplatin resistance. To assist in pre-clinical validation of novel therapeutic strategies, we established and characterized three testicular cancer patient-derived xenograft (PDX) models which we showed to faithfully reflect the patient tumor it originated from at a histological, molecular and chemosensitivity level. Furthermore, we investigated different resistance mechanisms and novel combination therapies. First, we showed that TC cell lines are characterized by a highly active PI3K/AKT/mTOR pathway, and that inhibition of this pathway, especially mTORC1/2 inhibition, is an effective therapeutic strategy to sensitize TC cell lines and TC PDX models to cisplatin treatment. Second, we investigated therapeutic strategies based on MDM2 inhibition, showing that MDM2 inhibitors sensitized TC cells to both mTORC1/2 inhibitors and cisplatin. Addition of BH3 mimetics, mimicking pro-apoptotic proteins, to these two drug combinations further enhanced treatment efficacy. Furthermore, pre-clinical efficacy of MDM2 inhibitors combined with cisplatin was demonstrated in TC mouse models. In conclusion, this thesis provides new leads for patients with refractory or cisplatin resistant testicular cancer for future combination therapies involving targeted drugs against mTORC1/2, MDM2 and the chemotherapeutic cisplatin.