Herein, using the SmoA1Tg mouse model and primary human MB patient xenograft tumor samples (PDXs), we observed that tumor-propagating capacity of CD15+ TPCs in SHH-driven MB is regulated at least in part by the PTEN-PI-3K signaling pathways, and that targeting this axis using PI-3K inhibitors may block the in vivo propagation of TPCs and induce apoptosis. This evidence concerns the gene PIK3CA and neoplasm.