Targeting c-met in sonic hedgehog medulloblastomas

Medulloblastoma (MB), a cerebellar tumour primarily diagnosed in children, is the most common malignant brain tumour consisting of four molecular subgroups: Wingless (WNT), Sonic Hedgehog (SHH), Group 3 and Group 4. Although the 70-75% of MB patients survive the disease, the current therapeutic regimen, which comprises surgical resection, chemotherapy and cranial irradiation, is worryingly associated with severe side effects in these young patients. Thus, identifying new and more precise therapeutic strategies is needed to overcome medulloblastoma progression and dissemination as well as the eradication of the disease. Over the last few years, various tyrosine kinase signalling pathways have been identified to play important roles in medulloblastoma tumorigenesis. Active c-MET kinase has been detected as a marker of SHH-driven MB and several inhibitors provided pre-clinical evidence for an effective therapy for SHH-MB patients.In this PhD project, we firstly confirmed that c-MET is highly expressed in SHH MBs; next, the efficacy of multiple commercially available c-MET kinase inhibitors against several in vitro SHH-MB cell lines was evaluated to identify the most potent in the MB cells context and to provide a detailed explanation of how they induce cell death in MB cells. We showed that the highly selective c-MET inhibitor tivantinib outperformed the c-MET inhibitors foretinib and crizotinib in impairing cell viability in both 2D and 3D cell models by inducing a strong apoptotic response, which was more prominent in TP53-/- MB SHH cells compared to TP53wt cells, where it showed primarily mitotic delay. We observed a complex and diverse pharmacological response to c-MET inhibitors; while tivantinib strongly induce mitotic cell death, through downregulation of MCL-1 protein, foretinib and crizotinib causes mitotic slippage, phenomenon frequently correlated to aneuploidy and drug-resistance. However, we demonstrated that use of BH-3 mimetics can reverse this effect and cause cell death. Taken together, this first set of data substantiate the rational use of c-MET inhibitors for SHH-driven MB but the pharmacological heterogeneity in response to c-MET inhibitors should be highly considered when designing novel effective therapies for MBs. Finally, we demonstrated that tivantinib had synergistic anti-proliferative in vitro SHH-MB cells effects, when combined with either first-line chemotherapy for MB or small-molecule, supporting the possibility of new therapeutic approaches aimed to lower doses of drugs and to limit drug toxicities as well as side effects