How targeting tumor blood vessels may help overcome treatment resistance in glioblastoma

3D brain against purple background
Targeting the Wnt/beta-catenin pathway in endothelial cells may be an effective way of overcoming treatment resistance in glioblastoma, University of Pennsylvania scientists have found. (alex-mit/iStock/Getty Images Plus)

Tumors often fuel their growth by forming new blood vessels to provide oxygen and nutrients. Widely used drugs directed against VEGF or VEGFR inhibit this process. Unfortunately, though, those drugs have failed to rein in the aggressive brain cancer glioblastoma.

Now scientists at the University of Pennsylvania have demonstrated that targeting a mechanism in a subset of stromal cells known as endothelial cells—which line the inside of blood vessels—might help overcome drug resistance in glioblastoma. They believe the finding could point to a new therapeutic strategy to make these malignant cancer cells vulnerable to chemotherapy.

The team found that a mechanism within the well-known Wnt/beta-catenin signaling pathway causes endothelial cells to act more like stem cells, leading to an abnormal growth of blood vessels that makes brain cancer cells resistant to treatment. Blocking Wnt/beta-catenin sensitized glioblastoma (GBM) to chemotherapy in mice, according to a new study published in Science Translational Medicine.

GBM is difficult to treat partly because the tumors themselves often harbor different mutations, which makes treatments focused on one molecular target ineffective. So the UPenn team, led by Yi Fan, M.D., Ph.D., looked beyond particular genetic abnormalities in different groups of cancer cells and instead focused on overcoming resistance.

Fan's team searched GBM endothelial cells for the regulatory mechanisms that control chemoresistance, and found increased activation of multiple stem cell-associated transcriptional factors. The upregulation of these factors allowed the cells to propagate and also correlated with cell resistance to the widely used chemotherapy drug temozolomide (TMZ).

RELATED: Immuno-oncology combo targeting rogue enzyme in glioblastoma extends survival in mice

Further analysis revealed that the resistance is enabled by the Wnt/beta-catenin pathway, which regulates stem cell renewal. Its abnormal activation has perviously been linked to multiple cancer types. 

In mice that had their endothelial cell-specific beta-catenin knocked out, treatment with TMZ cut tumor volume by 90%, whereas treating normal mice only slowed tumor growth. In a mouse model of GBM, the researchers combined Wnt inhibitor XAV939 with TMZ and significantly extended survival when compared to animals that got either drug alone.

There’s huge demand for better treatment options for GBM, as the disease’s five-year survival rate remains low at around 5% to 10%. Researchers at the MD Anderson Cancer Center recently found that blocking the immune-suppressing enzyme CD73 could add benefits to inhibiting the immune checkpoints PD-1 and CTLA-4 in GBM. And a team at Cedars-Sinai developed a polymer scaffold to deliver either one of these two types of checkpoint inhibitors cross the blood-brain barrier directly to brain tumor sites.

Ziopharm Oncology used its experimental drug veledimex to boost the immune response to IL-12 gene therapy. Investigators recently found signs of positive responses of the regimen among a small group of patients with recurrent glioblastoma.

Fan believes his team’s approach of using Wnt inhibitors to block endothelial cells boasts several advantages over directly attacking cancer cells. For one thing, treating these stromal cells would get at the root cause of tumor survival. Secondly, because it doesn’t aim for genetic markers, it should remain effective even after tumors mutate.

“Because stromal cells have a more stable genome, they will not mutate the way cancer cells do, meaning secondary resistance is unlikely,” Fan said in a statement. The team now hopes to test the method in a clinical trial.

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