Targeting HDAC And PI3K Inhibits MYC-Driven Medulloblastoma Growth

Patients with medulloblastoma (MB), a highly malignant pediatric brain tumor, currently undergo a therapeutic regimen involving surgery followed by radiation and chemotherapy, which often results in devastating long-term effects. In particular, patients with Group 3 (G3) MB, which represents one of the most aggressive molecular MB subtypes and is characterized by MYC amplification or overexpression, are more likely to exhibit a poor clinical outcome. To identify efficacious compounds that target G3 MBs, Pei, Liu, and colleagues performed a high-throughput screen of 3,642 small-molecule compounds representing diverse drug classes. The initial screen used tumor cells freshly isolated from a genetically engineered mouse model of G3 MB (generated by orthotopic transplantation of neural stem cells expressing Myc and dominant-negative Trp53). The screen identified 142 compounds that killed tumor cells, 23 of which also exhibited efficacy against human MYC-driven MB cells and were nontoxic to normal neurons and astrocytes. Histone deacetylase (HDAC) inhibitors, which accounted for four of the 23 hits, were among the most potent inhibitors of murine Myc-driven MB, and were also effective against patient-derived xenograft lines representing G3 and subtypes of MB. Mechanistically, HDAC inhibitors induced the expression of forkhead box O1 (FOXO1), a tumor suppressor gene that the authors found to be inversely correlated with the expression of MYC in murine and human MB. Expression of FOXO1, which is thought to oppose the transforming effects of MYC, inhibited MYC-driven MB growth in vitro and in vivo. Inhibitors of PI3K, which regulates FOXO1 activity via the PI3K/AKT signaling axis, synergized with HDAC inhibitors to activate FOXO1 and inhibit murine and human MYC-driven MB growth in vitro and in vivo. Together, these results show that screening freshly isolated murine MB tumor cells can identify inhibitors of MB and that the combination of HDAC inhibitors and PI3K inhibitors can potently activate FOXO1 to inhibit MYC-driven MB growth.

Pei Y, Liu K-W, Wang J, Garancher A, Tao R, Esparza LA, et al. HDAC and PI3K antagonists cooperate to inhibit growth of MYC-driven medulloblastoma. Cancer Cell 2016;29:311–23.