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Perspective: targeting VEGF-A and YKL-40 in glioblastoma - matter matters
Camilla Bjørnbak Holst1,2,3,4,5, Henriette Pedersen3, Elisabeth Anne Adanma Obara3
1Department of Medicine, Herlev and Gentofte Hospital, Herlev, Denmark.
Abstract:
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.
Insights
Bevacizumab, an anti-angiogenic drug, showed limited success in treating glioblastoma (GBM). Targeting both VEGF and YKL-40 may offer a better strategy for brain tumors, but model choice is critical.
Area of Science:
- Neuro-oncology
- Cancer Biology
- Tumor Microenvironment Research
Background:
- Glioblastoma (GBM) is a complex brain tumor characterized by its heterogeneity and vascularity, leading to treatment resistance.
- Despite extensive research into anti-angiogenic agents, immunotherapy, and targeted therapies, glioblastoma patients have a poor prognosis with a median survival of approximately 15 months.
- Bevacizumab, an anti-VEGF antibody, initially showed promise but failed to demonstrate an overall survival benefit in subsequent clinical trials for recurrent GBM.
Purpose of the Study:
- To discuss the mechanisms of bevacizumab resistance in glioblastoma.
- To explore dual targeting strategies focusing on vascular endothelial growth factor (VEGF) and YKL-40 for improved glioblastoma treatment.
- To emphasize the importance of appropriate model selection in preclinical studies for translational significance in GBM therapy.
Main Methods:
- Review of existing literature on bevacizumab resistance in glioblastoma.
- Discussion of dual targeting strategies involving VEGF and YKL-40.
- Analysis of the impact of preclinical model choice on study outcomes and translational relevance.
Main Results:
- Bevacizumab resistance is a significant challenge in glioblastoma treatment.
- Dual targeting of pro-angiogenic factors VEGF and YKL-40 presents a potential therapeutic avenue.
- The choice of preclinical models significantly influences the interpretation and applicability of research findings in glioblastoma.
Conclusions:
- Effective glioblastoma treatment may require multitarget strategies addressing the tumor microenvironment.
- Further investigation into dual targeting of VEGF and YKL-40 is warranted.
- Careful consideration of preclinical models is crucial for advancing glioblastoma therapeutics.
