By Dr. Nathan Schachter
For years, scientists have struggled to understand why cancers that return – or ‘relapse’ – are so difficult to treat. How can therapies which were initially effective at controlling the disease fail to combat tumors that re-emerge? Why do relapses often behave more aggressively than pre-treatment tumors?
These questions have plagued the field of pediatric oncology for decades and have been frustratingly difficult to answer. Despite ongoing improvements in cancer care, our inability to understand the biology of cancer recurrence has continuously undermined our efforts to treat it. Consequently, relapses have become a leading cause of cancer-related deaths and are particularly problematic for those afflicted with Medulloblastoma, one of the deadliest childhood malignancies.
In Canada, Medulloblastoma is the most frequently diagnosed pediatric brain cancer. While doctors can achieve 70-85% 5-year survival rates1, tumors that recur after therapy are almost universally fatal and pose a tremendous clinical challenge. Even with modern treatment methods, relapsed Medulloblastoma remains a formidable clinical adversary. In principle, biological differences in pre- and post-treatment tumors would explain their ability to resist treatment but what causes these differences has remained elusive.
Fortunately, researchers led by Dr. Michael Taylor, a surgeon-scientist at Sickkids Hospital, have made some game-changing advances in our understanding of this enduring problem. Their study, recently published in Nature, elegantly describes the dramatic differences between pre- and post-treatment Medulloblastoma2.
Using cutting-edge DNA sequencing technology, Dr. Taylor’s group gathered compelling evidence that some tumors harbor a rare population of cells that possess an innate capacity to resist therapy and drive re-growth after treatment. Although these cells only represent a tiny fraction of the original tumor (often less than 5%), they allow the cancer to regenerate with therapy-resistant properties.
Dr. Sorana Morrissy, lead author of the study, likens this situation to the emergence of antibiotic-resistant bacteria. After the onset of an infection, antibiotic treatment readily kills the population of ‘sensitive’ bacteria but fails to extinguish rare cells harbouring resistance. Given the opportunity, these cells can re-establish an infection that is now unresponsive to treatment. This too, appears to be the case with therapy-resistant cells in recurrent brain tumors.
So what makes these rare cells resistant to therapy?
To answer this question, Dr. Morrissy and her colleagues compared the mutations carried by different groups of Medulloblastoma tumor cells. Remarkably, cells driving recurrence carried mutations that were vastly different from those in the rest of the tumor. Importantly, many of the ‘unique’ mutations found in cells fueling relapses appear to promote aggressive behavior and confer the ability to evade therapy. This explains why, despite being ancestrally-related, pre-treatment and recurring tumors often behave differently.
In light of these surprising genetic insights, Dr. Taylor’s group suggests we re-think our approach to brain cancer treatment. Given the enormous biological differences between pre- and post-treatment Medulloblastoma, targeted therapies initially used to treat a tumor may ultimately fail when the cancer returns because relapses have different vulnerabilities than pre-treatment cancers. Thus, when choosing appropriate therapies, it might be wise to treat recurrences as entirely ‘new’ tumors.
Armed with this information, scientists can begin improving cancer treatment strategies and revising therapeutic regimens to overcome clinical roadblocks.
This article was written by Nathan Schachter. Nathan is currently finishing his PhD at the University of Toronto where he studies breast cancer. To learn more about Nathan and his work be sure to visit our members page.
 Ramaswamy et al., (2013) Recurrence patterns across medulloblastoma subgroups: an integrated clinical and molecular analysis. Lancet Oncol doi: 10.1016/S1470-2045(13)70449-2
 Morrissy et al., (2016) Divergent clonal selection dominates medulloblastoma at recurrence. Nature doi: 10.1038/nature16478