ET-57TOPOISOMERASE II IN PRONEURAL GLIOMAS, A MODULATOR OF TRANSCRIPTION AND A THERAPEUTIC TARGET

Topoisomerase II (TOP2) is highly expressed on proneural gliomas, but its specific function on these tumors is unknown. We found that TOP2 is expressed in gliomas from early stages, increases during progression, and is elevated in radiographically localized non-enhancing regions of human glioblastoma, an area that is challenging to target systemically, and a common source of recurrence. TOP2A is highly expressed by infiltrating tumor cells, in the tumor center and at the edges, and low on surrounding brain. TOP2 enzymatic activity was detected on proneural glioma cell lines. TOP2 poison etoposide and 3 TOP2 inhibitors showed significant cytotoxicity on a proneural glioma cells (IC50 0.3-4 mM). Moreover, intracranial etoposide convection-enhanced delivery (CED) (80 mM) was tolerated and led to a significant survival benefit in mouse proneural gliomas. In contrast, etoposide CED (4 mM) showed transient decrease in tumor growth but failed to prolong survival, consistent with ineffective tumoral concentrations in trials of systemic etoposide for recurrent gliomas. TOP2 transcriptional modulation on proneural gliomas was suggested as the activity of many key transcription factors correlates with TOP2 levels across glioblastoma patients. TOP2 pharmacological targeting is a promising treatment target for some gliomas. Refining patient selection and drug delivery is key for optimizing this therapy.