Identification of target genes of Parvovirus H-1 (H-1PV) induced cytopathic effects in medulloblastoma

Medulloblastoma patients with poor prognosis have been identified either as suffering from metastasizing disease at the time of intitial diagnosis or by the detection of cytogenetic rearrangements or distinct gene expression signatures within the primary tumor. In these patients survival rates are below 30% implicating the need for new treatment modalities such as oncolytic virotherapy. The rodent parvovirus H-1PV is a non-recombinant oncolytic virus, which is non-pathogenic in humans. Intratumoral H-1PV application had been shown to induce complete long-term regression in vivo in an orthotopic high-grade glioma model.

In order to determine the oncolytic potential of H-1PV on medullo-blastoma we analysed its cytotoxicity to medulloblastoma cell lines (n=7), and to non-transformed primary brain cells. Non-neoplastic infant astrocytes and neuronal cells in short term culture were unaffected in viability and morphology after H-1PV infection. In contrast, all medullo-blastoma cell lines were efficiently infectable with H-1PV. Efficient viral replication could be shown in five medulloblastoma cell lines which displayed a dose-dependent cytotoxicity with LD50s below 1p.f.u/cell. Here, H-1PV induced G2 arrest and subsequent apoptosis.

After H-1PV treatment differenzially regulated genes were identified within the responsive cell lines, among them MYC, FOXG1B and NF1A. Three of the most responsive cell lines were MYC amplified (D425, D458, Med8A) based on aCGH and showed down-regulation of c-myc on mRNA and protein level. Thus, application of oncolytic H-1PV may be a promising treatment option for high-risk medulloblastoma targeting functionally relevant genes in these cells.