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.
About The Hospital for Sick Children
The Hospital for Sick Children (SickKids) is recognized as one of the world’s foremost paediatric health-care institutions and is Canada’s leading centre dedicated to advancing children’s health through the integration of patient care, research and education. Founded in 1875 and affiliated with the University of Toronto, SickKids is one of Canada’s most research-intensive hospitals and has generated discoveries that have helped children globally. Its mission is to provide the best in complex and specialized family-centred care; pioneer scientific and clinical advancements; share expertise; foster an academic environment that nurtures health-care professionals; and champion an accessible, comprehensive and sustainable child health system. SickKids is proud of its vision for Healthier Children. A Better World. For more information, please visit www.sickkids.ca.
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