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Glioblastomas (GBM) are heterogeneous highly vascular brain tumors exploiting the unique microenvironment in the brain to resist treatment and anti-tumor responses. Anti-angiogenic agents, immunotherapy, and targeted therapy have been studied extensively in GBM patients over a number of decades with minimal success. Despite maximal efforts, prognosis remains dismal with an overall survival of approximately 15 months. Bevacizumab, a humanized anti-vascular endothelial growth factor (VEGF) antibody, underwent accelerated approval by the U.S. Food and Drug Administration in 2009 for the treatment of recurrent GBM based on promising preclinical and early clinical studies. Unfortunately, subsequent clinical trials did not find overall survival benefit. Pursuing pleiotropic targets and leaning toward multitarget strategies may be a key to more effective therapeutic intervention in GBM, but preclinical evaluation requires careful consideration of model choices. In this study, we discuss bevacizumab resistance, dual targeting of pro-angiogenic modulators VEGF and YKL-40 in the context of brain tumor microenvironment, and how model choice impacts study conclusions and its translational significance.

Glioblastoma (GBM) is among the deadliest of solid tumors with median survival rates of approximately 12–15 months despite maximal therapeutic intervention. A rare population of self-renewing cells referred to as GBM cancer stem-like cells (GSCs) are believed to be the source of inevitable recurrence in GBM. GSCs exhibit preferential activation of the DNA damage response pathway (DDR) and evade ionizing radiation (IR) therapy by superior execution of DNA repair compared to their differentiated counterparts, differentiated GBM cells (DGCs). Replication Protein A (RPA) plays a central role in most of the DNA metabolic processes essential for genomic stability, including DNA repair. Here, we show that RPA is preferentially expressed by GSCs and high RPA expression informs poor glioma patient survival. RPA loss either by shRNA-mediated silencing or chemical inhibition impairs GSCs’ survival and self-renewal and most importantly, sensitizes these cells to IR. This newly uncovered role of RPA in GSCs supports its potential clinical significance as a druggable biomarker in GBM.