The glycoprotein, Decorin is a novel anti-proliferative and anti-angiogenic treatment for glioblastoma multiforme


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Hannah Shereef1, Lisa Hill1,2, Kismet Hossain-Ibrahim3, Roy Bicknell4, Ann Logan1, Garth Cruickshank2
1School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK, 2Department of Neurosurgery, University Hospitals Birmingham, Birmingham, UK, 3Department of Neurosurgery, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, UK, 4School of Immunity and Infection and Cancer Studies, University of Birmingham, Birmingham, UK

Background

Glioblastoma multiforme (GBM) is the commonest and most malignant primary brain tumour in adults. Its prognosis remains poor with current treatment options. Existing targeted agents such as bevacizumab, a monoclonal antibody to VEGF-A, have had limited efficacy due to inherent and acquired resistance - probably as a result of redundancy in biological systems promoting GBM growth and angiogenesis. Decorin, a naturally occurring proteoglycan, antagonises several growth factors such as VEGF(1) and TGF-β(2) and receptor tyrosine kinases such as EGFR(3) and c-Met(4), which positively regulate GBM growth and angiogenesis. We hypothesised that Decorin inhibits growth and angiogenesis in GBM by blocking multiple signalling pathways. We have available to us GCP-grade human recombinant Decorin; we aimed to test our hypothesis by administering this in a pre-clinical model of GBM.

Method

An in vivo tumour xenograft model of U-87 MG (human glioma) cells was developed in immunocompromised mice. Tumours identical in size were administered Decorin or PBS (control) locally to the tumour site every 24 hours for 8 days. Tumour sizes were measured prior to each treatment dose. Immunohistochemistry was done on excised tumour tissue to quantify proliferating cells and blood vessel density.

Results

Decorin-treated GBM tumour xenografts had a substantially slower growth rate compared to PBS-treated tumours (mean tumour volume 389mm3 vs 816mm3 at end of treatment period) (p<0.001, n=5 per treatment group). Immunohistochemistry revealed a 2.8-fold reduction in proliferating cell density and 2-fold reduction in vascular density in Decorin-treated tumour sections compared to PBS-treated tumour sections.

Conclusion

Decorin inhibits GBM growth and angiogenesis. Decorin’s combinatorial mode of action, by inhibiting several signalling pathways involved in both processes, make it an exciting and novel candidate for targeted therapy in GBM, and one that is less susceptible to resistance. Further work will confirm its mechanism of action in GBM and take the drug into clinical trials.