Abstract
BackgroundHigh-grade gliomas are amongst the most deadly human tumors. Treatment results are disappointing. Still, in several trials around 20% of patients respond to therapy. To date, diagnostic strategies to identify patients that will profit from a specific therapy do not exist.MethodsIn this study, we used serum-free short-term treated in vitro cell cultures to predict treatment response in vitro. This approach allowed us (a) to enrich specimens for brain tumor initiating cells and (b) to confront cells with a therapeutic agent before expression profiling.ResultsAs a proof of principle we analyzed gene expression in 18 short-term serum-free cultures of high-grade gliomas enhanced for brain tumor initiating cells (BTIC) before and after in vitro treatment with the tyrosine kinase inhibitor Sunitinib. Profiles from treated progenitor cells allowed to predict therapy-induced impairment of proliferation in vitro.ConclusionFor the tyrosine kinase inhibitor Sunitinib used in this dataset, the approach revealed additional predictive information in comparison to the evaluation of classical signaling analysis.
Highlights
High-grade gliomas include the most frequent type of primary central nervous system (CNS) tumors, glioblastoma (GBM) [1]
Brain tumor initiating cells from high-grade glioma resections were starved in serum- and growth factor-free medium prior to treatment
VEGF/ PDGF, but not epidermal growth factor (EGF)/bFGF activated signaling was considerably abolished by Sunitinib
Summary
High-grade gliomas include the most frequent type of primary central nervous system (CNS) tumors, glioblastoma (GBM) [1]. The prevalent VEGF receptors 1–3 and platelet derived growth factor receptor (PDGFR) a/b are targets of Sunitinib [7]. Their role in GBM growth and neovascularisation has been widely studied [8,9]. In preclinical studies using in vitro models of primary CNS tumors Sunitinib inhibited proliferation and migration [10,11,12,13,14]. Clinical trials of Sunitinib and other smallmolecule inhibitors targeting RTKs have shown a clinical response only in subgroups [1,17,18] of GBM patients. Diagnostic strategies to identify patients that will profit from a specific therapy do not exist
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