Projects

medulloblastoma

Medulloblastoma is a cancer of the hindbrain that arises during brain development, months before birth. Despite being the most common malignant childhood cancer of the brain and spinal cord, there are no current targeted molecular therapies - treatment consists of surgical tumour removal, radiation and chemotherapy. The World Health Organization recognizes 4 molecular subgroups of medulloblastoma. While Group 1 and 2 affect the WNT and Sonic Hedgehog pathway, Group 3 and 4 (60% of all tumours) remain a mixture of poorly characterized tumours. We aim to understand the molecular defects that give rise to Group 3 and 4 tumours arise during typical brain development and develop novel actionable molecular targets for these cancers.

  1. CRISPRi/dCAS9 genetic screen of epigenetic mediators of stalled differentiation in Group 3 cell lines

  2. Dissecting epigenetic heterogeneity of Group 3 and 4 medulloblastoma tumours with single-cell DNA methylation profiling in primary tumours

  3. Delineating evolutionarily recent gene regulatory networks in the developing hindbrain and origins of Group 4 medulloblastoma with single-cell transcriptomic analysis of the developing hindbrain and tumours

  4. Identifying and characterizing functional non-coding DNA mutations in Group 3 and 4 medulloblastoma

  5. Characterizing the DNA methylome of putative cells-of-origin in human developing hindbrain to identify enhancers involved in typical hindbrain development and dysregulated in cancer.

  6. Using iPSC-derived neural stem cells and cerebellar organoids to model neurotypical hindbrain development and genomic aberrations in Group 3 and 4 medulloblastoma

GLIOBLASTOMA

Glioblastoma is a highly aggressive brain cancer affecting otherwise healthy individuals, that remains a major unmet clinical need. The median time of survival from time of diagnosis is 12-14 months, and 30-50% patients fail to show a remission following temozolomide treatment, the first line of therapy. We are working to identify genomic biomarkers of temozolomide resistance, and discover novel epigenetic therapies for this devastating diagnosis.

  1. Discovering DNA methylome-based biomarkers of temozolomide resistance in primary tumours.

  2. Pharmacological screens using novel epigenome-targeting molecule libraries in patient-derived primary and recurrent GBM cell lines.

algorithms for
drug discovery

We collaborate with OICR’s Drug Discovery team to develop algorithms to identify novel cancer-specific vulnerabilities in the WD Repeat protein family. A joint project between the OICR Adaptive Oncology and Drug Discovery teams, we integrate multi-modal genomic data from normal and tumour tissues and cells, and prior knowledge of tissue-specific molecular associations, to prioritze protein targets for cancers of specific tissues.