An international team of researchers co-led by the Singh Lab at McMaster has developed a treatment that shows promise in blocking and destroying tumours in the most aggressive form of brain cancer.

The research, published this month in Nature Medicine, reveals a newly discovered pathway that cancer cells use to infiltrate the brain in glioblastoma, offering new hope and potential treatments.

Currently, the tumours often return after surgery, radiation therapy and chemotherapy, and glioblastoma patient survival is limited to a few months.

With this new treatment, returning cancer cells were destroyed at least 50 per cent of the time in two of the three diseases tested in preclinical animal models.

Mapping the pathway  

Researchers used large-scale gene editing technology, comparing gene dependencies when glioblastoma was initially diagnosed and when it returned after standard treatment. They discovered a new pathway used for axonal guidance — a signalling axis that helps establish normal brain architecture – that can become overrun with cancer cells.

“In glioblastoma, we believe that the tumour hijacks this signalling pathway and uses it to invade and infiltrate the brain,” says co-senior author Sheila Singh, professor with the department of Surgery and director of the Centre for Discovery in Cancer Research.

The research was also co-led by Jason Moffat, head of the Genetics and Genome Biology program at The Hospital for Sick Children (SickKids) in Toronto.

“If we can block this pathway, the hope is that we can block the invasive spread of glioblastoma and kill tumor cells that cannot be removed surgically,” says Singh.

Promising new therapeutic

To stop the invasion of cancer cells, researchers targeted the hijacked signalling pathway using different strategies, including a drug developed in John Lazo’s group at the University of Virginia, and also developed a new therapy with help from Kevin Henry and Martin Rossotti at the National Research Council Canada using CAR T cells to target the pathway in the brain.

They homed in on a protein called Roundabout Guidance Receptor 1 (ROBO1) that helps guide certain cells, similar to a GPS.

“We created a type of cell therapy where cells are taken from a patient, edited and then put back in with a new function,” says lead author Chirayu Chokshi, a former PhD student who worked alongside Singh at McMaster.

“In this case, the CAR T cells were genetically edited to have the knowledge and ability to go and find ROBO1 on tumor cells in animal models.”

The treatment can also apply to other invasive brain cancers, Singh and Chokshi say.

Researchers examined models for three types of cancer — adult glioblastoma, adult lung-to-brain metastasis, and pediatric medulloblastoma.

In all three, treatment led to a doubling of survival time. In two of the three models, it led to tumour eradication in at least 50 per cent of the mice.

“In this study, we present a new CAR T therapy that is showing very promising preclinical results in multiple malignant brain cancer models, including recurrent glioblastoma,” Singh says.

“We believe our new CAR T therapy is poised for further development and clinical trials.”

The study was performed with samples derived from patients treated by neurosurgeons from Hamilton Health Sciences. Proteomics discovery was done in collaboration with Thomas Kilinger at Princess Margaret Cancer Centre and the University of Toronto. The research was made possible through collaborations the National Research Council Canada, University of Virginia, University of Pittsburgh and the Princess Margaret Cancer Centre.

The study received funding from Brain Cancer Canada, the Brain Tumour Foundation of Canada, the Canadian Institutes of Health Research, the Foundation for the National Institutes of Health, the US National Institutes of Health Mitacs and the Terry Fox Research Institute.