"A Distinguished Scientist Award from The Sontag Foundation will allow us to follow up on our preliminary data suggesting that genes responsible for proper methylation of histone lysine moieties are mutated in medulloblastoma. Further characterization of these events may allow us to identify novel targets to develop more effective and less toxic treatment of pediatric brain tumors."
- Dr. Michael D. Taylor
- Neurosurgeon, The Hospital for Sick Children
- Senior Scientist, Developmental & Stem Cell Biology, The Arthur and Sonia Labatt Brain Tumour Research Centre
- Professor, Departments of Surgery and Laboratory Medicine and Pathobiology, University of Toronto
About DSA-Funded Research
Medulloblastoma, the most common pediatric brain tumor is very aggressive with 30% of children succumbing to the disease, and many survivors being left with a diminished quality of life secondary to both the disease and its treatment.
Medulloblastoma resembles cells of the normal embryonic cerebellum, from which it arises. There is massive growth of the normal cerebellum during development, and the failure of cerebellar cells to differentiate and stop dividing, is thought to cause medulloblastoma. The underlying basis of this maturation defect is unknown.
My preliminary data describes mutations in medulloblastoma affecting 10 novel genes that take part in a single biological pathway: control of the histone code. Proper control of the histone code has not previously been implicated in medulloblastoma, but plays a critical role in cellular differentiation in other organ systems. Excitingly, of over 25 known histone modifications, these 10 genes converge on a single modification: control of methylation of a single amino-acid, histone 3 lysine 9 (H3K9). H3K9 methylation blocks formation of RNA (transcription) and thereby proteins which are critical for stem cell differentiation. I hypothesize that failure of H3K9 methylation results in loss of normal cerebellar maturation, persistence of immature cell types, and ultimately medulloblastoma.
I outline experiments to determine how often, and by what mechanism H3K9 methylation is inactivated in medulloblastoma. Disruption of H3K9 methylation in mouse models will confirm its contribution to medulloblastoma initiation. As mechanisms disrupting H3K9 methylation are targeted in 20-50% of medulloblastomas, this pathway represents a key target for future rationale therapy.
"Michael is a rare individual who has the capacity for excellence in basic science research, yet all the while being closely associated with the clinical problems of brain tumors. Simply put, he is the single most talented M.D., Ph.D. clinician-scientist whom it has been my great pleasure to know over the past 20 years."
James T. Rutka, M.D., Ph.D.
University of Toronto
"I consider Michael to be among the top five junior investigators in brain tumor research in the world. A Distinguished Scientist Award from The Sontag Foundation would allow him to expand his preliminary findings and open up new frontiers in the study of medulloblastoma."
Richard Gilbertson, M.D., Ph.D.
St. Jude Children's Research Hospital