USE OF INHIBITORS OF TGFB/ACTIVINB SIGNALING PATHWAY FOR THE TREATMENT OF PATIENTS SUFFERING FROM MEDULLOBLASTOMA GROUP 3

摘要

Medulloblastoma (MB) is a pediatric tumor of the cerebellum arising at a median age of 7 years. MB is a heterogeneous disease classified in four groups, with the poorly characterized Group 3 showing the worst prognosis. The inventors now show that a subset of Group 3 MBs displays activation of the TGFp/Activin pathway. In contrast to carcinomas where TGFPs are the main driver of activation of this pathway, the data established that this activation is mainly due to an autocrine stimulation involving ActivinB. These tumors express high levels of INHBB (encoding ActivinB) and display high expression of PMEPA1, a well-known target gene of this signaling pathway. Functionally, the pathway sustains cell proliferation by inducing the expression of PMEPA1. Importantly, treatment with Galunisertib, an inhibitor of this pathway currently tested in clinical trials for Glioblastoma patients, increases the survival of mice orthotopically grafted with Group 3 MB-PDX. Thus, the present invention relates to use of inhibitors of the TGFp/ ActivinB signaling pathway for the treatment of patients suffering from medulloblastoma group 3.