Uncovering the Signaling Mechanisms Underlying Treatment Failure in Medulloblastoma

ABSTRACT Pediatric brain tumors are the leading cause of cancer-related deaths in children, with medulloblastoma (MB) being the most common type. Despite advances in MB treatment, tumors recur in approximately 30% of children. Virtually none of the patients with recurrent MB survive beyond one year, highlighting the need to better understand the mechanisms underlying treatment failure. In addition to changes in the mutational landscape at relapse, inherent tumor heterogeneity hinders the success of current therapeutic approaches for MB patients. In line with this concept, our data suggest that small populations of astrocyte and oligodendrocyte progenitor cells underlie the relapse of Sonic Hedgehog (SHH) subgroup MB when exposed to compounds acting on SHH signaling, as well as to chemotherapy. Despite their likely involvement in treatment failure and MB relapse, the signaling mechanisms allowing these glia-committed progenitor cells to propagate remain elusive. Here, we propose to uncover the mechanisms enabling these cells to expand in response to therapies, with the specific goal of identifying potential drug targets. Furthermore, we will assess the effectiveness of combining compounds that block bulk MB growth with those that control the propagation of glia-committed progenitor cells. Our studies will establish the mechanistic foundation for the development of future therapeutic approaches to enhance the efficacy of compounds attenuating MB growth, ultimately aiming to secure long-term remission.