Abstract
Medulloblastoma (MB) is one of the most common malignant pediatric brain tumors. Among the four molecular subgroups of MB (termed WNT, SHH, Group 3 and Group 4), patients with Group 3 MB associated with MYC amplification have the worst prognosis. Despite aggressive treatment including surgical resection followed by radiation and intensive chemotherapy, over 70% of patients develop tumor relapse and succumb to the disease. Moreover, surviving patients often suffer severe treatment-related side effects, including permanent cognitive and motor disabilities. Thus there is a critical need to develop novel, targeted therapies that not only improve survival but also limit damage to the healthy brain tissue. In preliminary studies, we discovered that a subpopulation of tumor cells in both mouse and human MYC-amplified MB strongly expressed oligodendrocyte lineage transcription factor 2 (Olig2). Radiation treatment eliminated most of the tumor cells, but a small number of tumor cells survived and eventually developed tumor relapse and distant metastases in forebrain and spinal cord. Olig2+ tumor cells comprised the majority of cells in the recurrent and metastatic tumors. Our studies demonstrated that a small molecule inhibitor CT-179 selectively reduced Olig2 expression and inhibited growth of Olig2+ tumor cells in MYC-amplified MB in vitro and in vivo. Olig2 antagonist therefore has the potential to provide monotherapy or adjuvant therapy for treatment of patients with MYC-amplified MB.