Summary Medulloblastoma, the most common malignant pediatric brain tumour, is currently treated with non-specific cytotoxic therapies including surgery, whole brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, prior attempts to identify targets for therapy have been underpowered due to small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup enriched. The most common region of focal copy number gain is a tandem duplication of the Parkinson’s disease gene SNCAIP, which is exquisitely restricted to Group 4α. Recurrent translocations of PVT1, including PVT1-MYC and PVT1-NDRG1 that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGFβ signaling in Group 3, and NF-κB signaling in Group 4 suggest future avenues for rational, targeted therapy.

Purpose: Medulloblastoma, a malignant pediatric brain tumor, is incurable in about one third of patients despite multimodal treatments. In addition, current therapies can lead to long-term disabilities. Based on studies of the extensive tropism of neural stem cells (NSC) toward malignant gliomas and the secretion of growth factors common to glioma and medulloblastoma, we hypothesized that NSCs could target medulloblastoma and be used as a cellular therapeutic delivery system. Experimental Design: The migratory ability of HB1.F3 cells (an immortalized, clonal human NSC line) to medulloblastoma was studied both in vitro and in vivo. As proof-of-concept, we used HB1.F3 cells engineered to secrete the prodrug activating enzyme cytosine deaminase. We investigated the potential of human NSCs to deliver a therapeutic gene and reduce tumor growth. Results: The migratory capacity of HB1.F3 cells was confirmed by an in vitro migration assay, and corroborated in vivo by injecting chloromethylbenzamido-Dil^labeled HB1.F3 cells into the hemisphere contralateral to established medulloblastoma in nude mice. In vitro studies showed the therapeutic efficacy of HB1.F3-CD on Daoy cells in coculture experiments. In vitro therapeutic studies were conducted in which animals bearing intracranial medulloblastoma were injected ipsilaterally with HB1.F3-CD cells followed by systemic 5-flourocytosine treatment. Histologic analyses showed that human NSCs migrate to the tumor bed and its boundary, resulting in a 76% reduction of tumor volume in the treatment group (P < 0.01).Conclusion: These studies show for the first time the potential of human NSCs as an effective delivery system to target and disseminate therapeutic agents to medulloblastoma.Medulloblastoma is the most common childhood malignant brain tumor. Although multimodal treatments, including radical surgical resection followed by radiation and chemotherapy, have substantially improved the survival rate for this disease, it remains incurable in about one third of patients.These treatments are also toxic and can lead to long-term disabilities (1, 2). The main cause of death is recurrence associated with tumor dissemination, at which point current therapeutic options have little efficacy (3, 4). Consequently, there is substantial need for novel, effective, low-toxicity therapies for children with medulloblastoma.The discovery of the inherent tumor-tropic properties of neural stem cells (NSC) could serve as a novel adjuvant strategy to current medulloblastoma treatments. Recent studies have shown that NSCs have the capacity to target therapeutic genes to brain tumors, such as malignant glioma (5 -13) and melanoma brain metastasis (14). We have expanded these investigations to determine whether NSCs are capable of targeting medulloblastoma in an orthotopic xenograft animal model. Therapeutic proof-of-concept studies were done using cytosine deaminase (CD) -producing NSCs and systemic 5-fluorocytosine (5-FC) prodrug administration. Our results show for the first time the pote...

Our results indicate that an early diagnosis and active intervention before establishment of irreversible hemodynamic change are essential to achieve a favorable clinical outcome in children with MMD.

There were distinctive expression patterns of matrixins, cytokines and angiogenic factors in MMD patients, which seemed to correlate with disease pathogenesis. The balance between MMPs and TIMPs was disrupted in MMD and correlated with disease pathogenesis. Increased plasma levels of MCP-1 and VEGF in MMD patients may play a role in the recruitment of vascular progenitor cells and in the formation of collateral vessels.