ABSTRACT
Medulloblastoma (MB) is the most frequent malignant pediatric brain tumor, representing 20% of newly diagnosed childhood central nervous system malignancies. Although advances in multimodal therapy yielded a 5-year survivorship of 80%, MB still accounts for the leading cause of childhood cancer mortality. In this work, we describe the epigenetic regulator BMI1 as a novel therapeutic target for the treatment of recurrent human Group 3 MB, a childhood brain tumor for which there is virtually no treatment option beyond palliation. Current clinical trials for recurrent MB patients based on genomic profiles of primary, treatment-naive tumors will provide limited clinical benefit since recurrent metastatic MBs are highly genetically divergent from their primary tumor. Using a small molecule inhibitor against BMI1, PTC-028, we were able to demonstrate complete ablation of self-renewal of MB stem cells in vitro. When administered to mice xenografted with patient tumors, we observed significant reduction in tumor burden in both local and metastatic compartments and subsequent increased survival, without neurotoxicity. Strikingly, serial in vivo re-transplantation assays demonstrated a marked reduction in tumor initiation ability of recurrent MB cells upon re-transplantation of PTC-028-treated cells into secondary recipient mouse brains. As Group 3 MB is often metastatic and uniformly fatal at recurrence, with no current or planned trials of targeted therapy, an efficacious targeted agent would be rapidly transitioned to clinical trials.
Subject(s)
Cerebellar Neoplasms/drug therapy , Medulloblastoma/drug therapy , Neoplastic Stem Cells/drug effects , Polycomb Repressive Complex 1/antagonists & inhibitors , Small Molecule Libraries/administration & dosage , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Cerebellar Neoplasms/genetics , Cerebellar Neoplasms/metabolism , Child , Epigenesis, Genetic , Gene Expression Regulation, Neoplastic/drug effects , Humans , Medulloblastoma/genetics , Medulloblastoma/metabolism , Mice , Neoplastic Stem Cells/cytology , Neoplastic Stem Cells/metabolism , Polycomb Repressive Complex 1/genetics , Small Molecule Libraries/pharmacology , Treatment Outcome , Up-Regulation/drug effects , Xenograft Model Antitumor AssaysABSTRACT
Pilomyxoid astrocytomas (PMAs) are low-grade (WHO Grade II) tumors for which the imaging features are similar to pilocytic astrocytomas (PAs), but for which histological features and the clinical course differ. They are classified as a variant of PA. They have only been recently recognized, and they behave more aggressively than PAs. Most cases occur in the hypothalamic-chiasmatic area, although they may be located in any part of the neuraxis. Posterior fossa PMAs are very rare. The authors report a case of a 2-year-old girl with cerebellar PMA.
