Understanding a complex brain cancer: SickKids-led study links genetics of cells with diverse growth and drug-resistant behaviours within the same tumour

TORONTO – Stricken with the most aggressive cancerous brain tumour and offered radiation therapy and chemotherapy, 1,500 Canadian adults every year begin treatment knowing that with an average survival of 15 months, glioblastoma will soon take over their brain, with fatal consequences.

Despite advances in research, glioblastoma, the most common primary malignant brain tumour in adults, remains one of the most difficult cancers to treat. One of the barriers to successful treatment is the extreme heterogeneity, or diversity from cell to cell, within the same tumour.  This diversity resides in glioblastoma cell clones, identical daughter cells derived from a single parent cell that can have different genetic changes from other clones.

A Canadian research team led by The Hospital for Sick Children (SickKids) has developed an integrated functional and genomic analysis technique to study the different behaviours of individual human cells within a patient-specific glioblastoma. They were able to identify a link between the functional properties of single clones and their genetic changes. The study is published in the Jan. 5 online edition of Proceedings of the National Academy of Sciences (PNAS).

The scientists developed a strategy to isolate single cell-derived clones from different adult glioblastoma tumours. They linked each clone’s varied genetic changes with different functional properties, including capacity for growth, maturation and drug responsiveness. In a proof-of-principle study, they screened existing cancer drugs and demonstrated that a single tumour can contain many unique clones that respond differently to the same therapy.

“Genomic sequencing has already given us an exquisite map of the heterogeneity of glioblastoma, but we now know it’s important to link this information with functional properties to understand which genetic changes are causing specific cancer behaviours,” says Dr. Peter Dirks, principal investigator of the study, Staff Neurosurgeon and Senior Scientist at SickKids. “As proof of principle, this study is an important step toward identifying the most aggressive and therapy-resistant clones, and targeting new patient-specific treatments accordingly. We will need the right therapy for the right cancer clone,” he adds.

“This study gives us a better understanding of the complexity of the heterogeneity of glioblastoma, and this integrated approach to functional and genomic analysis at a clonal level may be critical to improving understanding of drug resistance and cell proliferation in other types of cancers,” he says. “Although the complexity of this cancer is daunting, we believe that approaches such as this will help us come to grips with this complexity to develop therapies that more effectively target the treatment-resistant cancer clones.”

Dirks is also Principal Investigator at The Arthur and Sonia Labatt Brain Tumour Research Centre at SickKids and Professor of Neurosurgery and Molecular Genetics at the University of Toronto.

This work was performed in close collaboration with Dr. Gary Bader, principal investigator at the Donnelly Centre for Cellular and Biomedical Research at the University of Toronto. The study is also a collaboration with investigators at the University of Toronto, the University Health Network, St. Michael’s Hospital and Queen’s University.

The research is supported by the Ontario Institute for Cancer Research, Genome Canada, Canadian Institutes of Health Research, the National Institutes of Health, and SickKids Foundation.