A gene therapy joins the armory against aggressive glioblastoma

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Scientists and clinicians have long been searching for an effective treatment for highly aggressive cases of glioblastoma. Now researchers at the Cincinnati Children’s Hospital Medical Center have reported on an experimental therapy that stops the cancer in a human cell and a mouse model.

The multi-institutional research team, led by Qing Richard Lu (Cincinnati), published its results in the journal Cancer Cell earlier this week. 

The group used a gene therapy to stop the activation of a gene known as Olig2; the misfiring of Olig2 has been well characterized in the progression and severity of glioblastomas. Previous groups have attempted to target Olig2, which is a transcription factor, with small molecules, showing some variable success

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The current group show that while removing the Olig2 gene may halt the cancer, if you take out the Olig2-producing cells you can block tumor formation altogether.

"We find that elimination of dividing Olig2-expressing cells blocks initiation and progression of glioma in animal models and further show that Olig2 is the molecular arbiter of genetic adaptability that makes high-grade gliomas aggressive and treatment resistant," said Lu. 

By finding a way to inhibit Olig2 in tumor forming cells, he added, we were able to change the tumor cells' makeup and sensitize them to targeted molecular treatment. This suggests a proof of principle for stratified therapy in distinct subtypes of malignant gliomas."

The team utilized an engineered herpes simplex virus to deliver a suicide gene into replicating Olig2-positive cancer cells during tumor formation. They then delivered ganciclovir, a mainstay herpes drug in the clinic, showing that growth was halted in the Olig2-deleted tumors. 

The researchers observed that after Olig2 was taken out of the cells, which initially looked like oligodendrocyte (Olig2-positive) precursor-like cells, the cells appeared more like astrocyte-like brain cells. 

Astrocyte brain cancer cells are known to produce epidermal growth factor receptor (EGFR) at high levels. As such, the researchers then administered a drug called gefitinib, which is an EGFR-targeted chemotherapeutic and could ultimately stop the growth of new tumor cells and of the glioblastoma cancer. 

In a cancer that is typified by drug resistance, Lu believes this may provide another approach to target a different pathway and to complement radiation, surgery, and other chemotherapies. 

- here’s the release
- here’s the Cancer Cell article

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