Tackling childhood brain cancer at the root to improve survival and quality of life
Brain cancer remains a lethal and disabling disease, the leading cause of cancer-related deaths among children under age 20 and the third-leading cause in young adults aged 20-39. There are particularly aggressive forms of brain cancer, with barely 10 percent of children and young adults surviving three years after diagnosis, and other forms where those who do survive suffer severe lifelong disabilities due to the life-saving therapies they receive.
Through our previous large-scale genomics projects ICHANGE and MAGIC, our research group and collaborators Drs. Jacek Majewski of McGill University and Michael Taylor at SickKids have discovered that many pediatric brain tumours are driven by mutations in genes that play a significant role in brain development. To decrease the burden of survivorship and improve survival rates, this project is focused on fast tracking the use of treatments targeting specific genetic alterations early at diagnosis. We are also performing innovative investigations of the tumour genome and transcriptome, including at the single-cell level, to identify new alterations and specific vulnerabilities that can be targeted for therapy. Our team will ensure treatments are validated through relevant disease models and fast-track meaningful clinical trials to tackle refractory brain tumours; the goal is to work closely with health-care providers and regulators to ensure the rapid translation of validated treatments to the bedside.
Spatial and temporal homogeneity of driver mutations in 9 diffuse intrinsic pontine glioma (DIPG) patients. DIPG is a lethal type of high grade astrocytoma.
Nikbakht et al, Nature Communications 2016
Our team discovered mutations in H3K36M and NSD1 (an H3K36 methyltransferase) in a subset of head and neck squamous cell carcinomas that form a distinct DNA methylation cluster.
Papillon-Cavanagh et al Nature Genetics 2017
Decoding the origin and modeling oncohistones in pediatric cancers
We and others recently identified mutations in histone 3 variants in a significant fraction of children and young adults with high grade astrocytomas and maiming bone cancers. This is a very new, uncharted area in cancer that will benefit from improved understanding of disease biology and the design of accurate experimental models to recapitulate these epigenetic cancers as we aim to do in this project.
Our data suggest these “oncohistones”, as we labeled them, possibly arise during specific windows of normal organ development. Indeed, each mutation in a given H3 isoform has age, organ and anatomic location within an organ, specificities. There is added complexity in HGA as we showed requirement of distinct added genetic alterations that are also age, brain location and H3 variant specific. Oncohistones are a new major paradigm shift in the field of cancer, and limited knowledge exists on how they act in tumor formation. Our group with collaborators in Canada and the US aims to overcome this major knowledge gap and obstacle to effective therapy.
PRecision Oncology For Young peopLE (PROFYLE)
Cancer is the leading cause of disease-related death in children, adolescents, and young adults (CAYA) beyond the newborn period. While the overall survival rate in Canada approaches 88% for all CAYA patients (0-29 years old), the prognosis for those with refractory, relapsed or metastatic (‘hard-to-treat’) disease is grim, and progress has stagnated for many disease groups over the last three decades.
To address this gap and to make new therapeutic inroads for CAYA patients with hard-to-treat childhood cancers, a group of Canadian leaders in oncology and genomics including Dr. Jabado initiated the PRecision Oncology For Young peopLE (PROFYLE) program. PROFYLE builds on Canada's world leading expertise in genomics to establish a national precision medicine platform for treating CAYA patients (Figure 1). Overall, the program aims to transform the care of CAYA patients by using next-generation molecular tools and cancer model systems to identify disease- and patient-specific biomarkers that are tractable targets for therapy. Dr. Jabado leads the biomarker node of the program.
First ICHANGE retreat, May 19, 2017