Convection-enhanced delivery of etoposide is effective against murine proneural glioblastoma

Traditionally, the World Health Organization classification of gliomas is based on tumor histology. Recently, major efforts in characterizing the global expression profiles and genetic alterations in glioblastoma have led to significantly improved understanding of this disease.1–6 Of all these efforts, it is evident that one of the most robust and identifiable gene expression patterns in gliomas is the proneural (PN) subtype.7,8 Differences in glioblastoma molecular phenotypes can have differences in clinical response to therapies. The PN subgroup in particular has been found to be associated with younger patient age at diagnosis and a phenotype that is unresponsive to aggressive traditional therapies that do reduce mortality for the other subgroups.9 Therefore, there is a pressing need to identify proper therapeutic interventions that can benefit PN glioblastoma patients. Our group previously described a murine glioma model that is phenotypically classifiable with human PN glioblastoma based on its gene expression profile.10 In this model, PN murine tumors are generated in vivo by retrovirally induced overexpression of platelet derived growth factor (PDGF) and deletion of phosphatase and tensin homolog (PTEN) with or without additional p53 deletion in glial progenitor cells using the Cre-lox system in transgenic mouse strains. More recently, we showed that cell lines derived from these murine glioma models retain their PN phenotype in vitro and can be utilized for in vitro and in vivo experimentation, providing a reasonable PN glioma model.11 We looked for potential therapeutic targets among PN-specific genes, hoping to find genes that are overexpressed in this group of patients. Topoisomerase II (TOP2) was previously identified as a PN-specific gene based on its high expression levels.9 Thus, in this current study we explored the therapeutic effects of TOP2 inhibition as a therapeutic strategy in a murine PN glioma model. Poisons that act on TOP2, such as etoposide, have been used in combination therapies for the treatment of malignant gliomas. Unfortunately these trials have shown limited antitumoral activity and poor response rates for chemotherapy regimens involving systemic delivery of etoposide.12–14 It is likely that factors such as poor penetration across the blood–brain barrier and systemic toxicities limit the therapeutic efficacy of etoposide following systemic delivery. Moreover, as seen in expression data of The Cancer Genome Atlas (TCGA; http://tcga-data.nci.nih.gov/tcga/), TOP2 expression is variable across glioblastoma samples, suggesting that clearly defined inclusion criteria restricted to those patients with high expression of this enzyme might lead to better therapeutic results of targeting TOP2. In this study, we explore the efficacy of etoposide in a preclinical model of PN glioma. To maximize the efficacy of this agent and overcome the challenging pharmacokinetics of systemic administration for brain tumors, we tested the use of convection-enhanced delivery (CED) for this agent. CED involves the use of catheters surgically implanted into the tumor and surrounding brain parenchyma, allowing for a continuous delivery of chemotherapy directly into the tumor through positive pressure microperfusion.15 This delivery method provides an advantage over systemic administration in bypassing the blood–brain barrier and reducing toxicities to other organs. In the context of this background, here we present preclinical data suggestive of the efficacy of etoposide treatment for the PN subgroup of glioblastoma.