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Researchers identify new treatment target in long-term survivors of glioblastoma

Glioblastoma is the most common and aggressive type of brain cancer.

Researchers from the University of Arizona have discovered a genetic difference between short and long-term survivors of glioblastoma, an aggressive and common type of brain cancer. The study, published in Neuro-Oncology, identified that patients who survived longer had relatively high concentrations of a protein called WIF-1, which could be a potential target in future treatments for glioblastoma.

“Glioblastoma essentially is incurable”, says study lead and radiation oncologist, Dr Baldassarre Stea. “In the past 15 years, only one drug – temozolomide – has been invented, whereas the rest of the cancer field is zooming forward.”

Less than 5% of people with glioblastoma survive more than 5 years after diagnosis. People survive on average 11 to 15 months, and are generally treated with surgery, followed by chemotherapy and radiation. However, there are some who outlive their initial prognosis by months, or even years.

“I was curious to know how genes are differentially expressed in patients who live longer”, said Dr Michael Hammer, who contributed to the study. “If we can identify a pathway in the tumour that we might be able to target, we can try to make the short-lived patients look more like the long-lived patients.” 

The University of Arizona team analysed over 800 genes in 23 glioblastoma samples, which had been removed from patients during surgery. They discovered that long-term survivors produced the protein WIF-1 in relatively large quantities. The WIF-1 protein is an important inhibitor of the Wnt pathway, which can fuel tumour growth if it becomes overactive.

“The Wnt pathway is deranged, and WIF-1 is the police”, said Dr Stea. “Cancer grows when there aren’t enough police to keep the deranged person in check”.

So, patients who expressed higher levels of the ‘police’ – WIF-1 – were found to survive longer than their counterparts.

Dr Stea believes that new approaches are essential to extend survival for glioblastoma patients.

Study lead, Dr Baldassarre Stea, believes that new approaches are essential to extend survival for glioblastoma patients. 

“I think we have reached the apex of what the surgeon can do, and have achieved the most we can with radiation”, he said. “The cure will not come from more radiation or more surgery – glioblastoma is a genetic problem that we have to solve genetically.”

A potential way to solve this genetic problem, is by harnessing WIF-1 to enhance the effects of radiation, a therapy which attempts to kill cancer cells by damaging their DNA.

Dr Shea delivers radiation to patients with glioblastoma and says, “I’m poking holes in the DNA of glioblastoma cells, and the Wnt pathway goes back and helps to repair the damage. It’s like I’m exploding a bridge so the enemy cannot cross, but overnight they rebuild the bridge.”

By taking cues from WIF-1, scientists might now be able to weaken glioblastoma’s ability to repair radiation-damaged DNA and make cancer cells more sensitive to radiation therapy. “The Wnt pathway activates DNA repair. If we can suppress Wnt, we can also suppress DNA repair,” says Dr Eric Weterings, who contributed to the study.

Researchers hope that this work will lead to the development of a drug that targets glioblastoma tumours with more precision and efficiency than current treatments. “We hope to create a drug to suppress the Wnt pathway so that everybody survives longer,” Dr Stea said. “It would be the pot of gold at the end of the rainbow.”

This is still early research, and it will take some years until these results are translated into new treatments for the clinic. “The next step is to validate [the study results] with hundreds of patients and then to perform further studies with inhibitors of the Wnt pathway”, said Dr Shea.

“It’s a step forward,” Dr Weterings added. “In the future, this work might give us a larger and yet more specific arsenal of options to treat this disease."

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