The underlying cause of the chemo-resistance has baffled doctors until now.
Novel research led by The Hospital for Sick Children (SickKids) is the first to demonstrate a valid reason for why standard chemotherapies don’t work on ependymomas, and has also identified an existing FDA-approved drug that may help these young patients. The study is published in the February 19 online edition of Nature.
To date, all human cancers that have been studied had mutations or errors in the DNA: either something is missing, duplicated or in the wrong spot on the DNA strand. In search of an underlying genetic cause of this chemo resistance, the research team did whole-genome and whole-exome sequencing on 47 ependymoma samples, and what they found was surprising. “There were zero significant mutations. Our findings indicate that ependymoma is the first malignancy for which genome sequencing failed to identify any significant or recurring mutated genes,” says Dr. Michael Taylor, principal investigator of the study and Neurosurgeon and Senior Scientist at SickKids.
The problem, the researchers found, was not that there were errors in the tumour’s DNA code, but that the DNA was improperly packaged, so the cancer cells were behaving like stem cells with the continuous ability to divide. “One could compare DNA to a book, with most cancers having spelling mistakes, missing pages or having chapters in the wrong order. Ependymomas have none of these mistakes but instead the book is written in the wrong font,” explains Taylor. “Most chemotherapies function by promoting damage to DNA, which subsequently induces cancer cells with mutated genomes to self-destruct. Since ependymomas don’t have significant mutations, it explains why chemotherapy has not worked.”
Once the research team knew what the problem was, they could start working on the solution. There were existing drugs that can modify the way DNA is packaged, but the team first needed to grow ependymoma cell lines to test the drugs; something that had not been done before. Using pieces of real patient tumours, Dr. Peter Dirks’ lab figured out how to grow ependymoma cell lines so the team could test whether the drugs would have an effect on the ependymoma cells in the dish. And they did. Dirks is Neurosurgeon and Senior Scientist at SickKids.
“This was the foundational step in making this research something real and potentially meaningful for our patients,” says Taylor, who is also Professor in the Departments of Surgery and Laboratory Medicine and Pathobiology at the University of Toronto, and Garron Family Chair in Childhood Cancer Research at SickKids. The team didn’t stop there: once they discovered that the drugs were effective in the grown cell lines, they took it a step further by testing the drugs on an ependymoma tumour removed from a current patient.
“We were able to go from the OR table back to the lab to test this medicine on a specific patient’s tumour,” says Taylor. Just as in the cell lines, the medicine worked on the tumour and is currently being used to treat this child. “This step towards individualized cancer care is very exciting, and we hope that this can be adapted to other brain tumours as well.”
The researchers explain that these drugs that target the improperly-packaged DNA represent the first strategy for therapy of this currently untreatable disease, and should be considered for testing in clinical trials for children with ependymoma.
Funding Acknowledgments: Dr. Michael D. Taylor holds a Canadian Institutes of Health Research (CIHR) Clinician-Scientist Phase II Award, was a Sontag Foundation Distinguished Scholar, and is supported by The Garron Family Chair in Childhood Cancer Research. He is supported by grants from the Cure Search Foundation, The Younger Foundation, the National Institutes of Health (R01CA148699 and R01CA159859), The Pediatric Brain Tumor Foundation, The Canadian Cancer Society, The Terry Fox Research Institute, and Brainchild. Stephen C. Mack is supported by a Vanier Scholarship from CIHR. This study was conducted with the support of SickKids Foundation, the Ontario Institute for Cancer Research through funding provided by the Government of Ontario. This work was also supported by a Program Project Grant from the Terry Fox Research Institute and a Grand Challenge Award from Cure Search for Children’s Cancer. Additionally, this work was supported by the PedBrain Tumor Project contributing to the International Cancer Genome Consortium, funded by German Cancer Aid (109252) and by the German Federal Ministry of Education and Research (BMBF, grants 01KU1201A, MedSys 0315416C and NGFNplus 01GS0883). This study was supported by grants from the Sander Foundation and DKTK (Molecular Diagnostics of Pediatric Malignancies).
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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