Overcoming treatment resistance in glioblastoma through targeted Wnt inhibition

Written by Louis Gautier (Future Science Group)

A team from the Perelman School of Medicine at the University of Pennsylvania (PA, USA) has overcome chemotherapy resistance in glioblastoma cultures through the targeted inhibition of the Wnt pathway in neighboring stromal cells. The study builds on research showing how glioblastoma triggers stromal cells to act more like stem cells to support tumor growth.

Most estimates indicate that around 11,000 new cases of glioblastoma develop in the USA each year. It is a particularly aggressive form of brain cancer that has a 5-year survival rate of just 5–10% and has had very few developments in treatment over the past decade.

Current standard treatment for glioblastoma involves maximum possible surgical resection followed by maintenance chemotherapy; however, the likelihood of developing resistance to chemotherapy is very high.

One mechanism that causes glioblastoma to become so difficult and resistant to treatment is its effect on the normal brain microenvironment, particularly on glioblastoma-associated stromal cells. The tumor causes these cells to behave more like stem cells, supporting growth and encouraging heterogeneity, which makes treatment resistance more likely.

The novel treatment approach of this research team focused on overcoming resistance, rather than developing new treatments. They found that the effect of stromal cells (specifically, endothelial cells) on glioblastoma is driven by the Wnt pathway: the greater the degree of activation of Wnt, the more the tumor is able to resist treatment like chemotherapy.

The team used mouse xenograft models and cell cultures from human patients to show that glioblastoma was more vulnerable to chemotherapy once the signal was blocked. An experimental approach was used to inhibit Wnt, so a targeted therapy is yet to be developed.

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“Because stromal cells have a more stable genome, they will not mutate the way cancer cells do, meaning secondary resistance is unlikely,” claimed study author Yi Fan (University of Pennsylvania).

Targeting stromal cells, rather than the highly mutating and heterogeneous glioblastoma cells, carries several benefits for prolonged vulnerability to treatment. Fan and colleagues suggest that the Wnt pathway is a crucial component of why glioblastoma is so aggressive – effective inhibition targets this root cause, potentially making any therapy more efficient.

Furthermore, they suggest that not only will Wnt inhibition help to overcome the initial treatment resistance developed by glioblastoma but will also cause treatments to remain effective, even as the tumor continues to change.

After proving the concept of this treatment, the team hope to test the approach in clinical trials.

Sources: www.eurekalert.org/emb_releases/2020-02/uops-tsc022020.php; Clavreul A, Guette C, Faguer R et al. Glioblastoma associated stromal cells (GASCs) from histologically normal surgical margins have a myofibroblast phenotype and angiogenic properties. J. Pathol. 233(1), 74–88 (2014); https://emedicine.medscape.com/article/283252-treatment