Oncolytic effects of parvovirus H-1 in medulloblastoma are associated with repression of master regulators of early neurogenesis

摘要

Based on extensive pre-ciinical. studies, the oncoiytic parvovirus H-l (H-1PV) is currently applied to patients with recurrent glioblastoma in a phase I/IIa clinical trial (ParvOryx01, NCT01301430). Cure rates of about 40% in pediatric high-risk meclulicblastoma (MB) patients also indicate the need of new therapeutic approaches, in order to prepare a future application of oncolytic parvovirotherapy to MB, the present study preclinicaily evaluates the cytotoxic efficacy of H-lPV on MB cells in vitro and characterizes cellular target genes involved in this effect. Six MB cell Lines were analyzed by whole genome oligonucleotide micro-srrays after treatment and the results were matched to known molecular and cytogenetic risk factors. In contrast to non-transformed infant astrocytes and neurons, in five out of six MB cell lines lytic H-IPV infection and efficient viral replication could be demonstrated. The cytotoxic effects induced by H-lPV were observed at LD50s below 0.05 p. f. u. per ceil indicating high susceptibility. Gene expression patterns in the responsive MB cell lines allowed the Identification of candidate target genes mediating the cytotoxic effects of H-lPV. H-lPV induced down-regulation of key regulators of early neurogenesis shown to confer poor prognosis in MB such as ZIC1, FQXG1B, MYC, and MFIA. In MB cell lines with genomic amplification of MYC, expression of MYC was the single gene most significantly repressed after H-1PV infection. H-lPV virotherapy may be a promising treatment approach for MB since it targets genes of functional relevance and induces cell death at very low titers of input virus.