WEHI Wednesday Seminar hosted by Dr James Whittle
Nada Jabado, MD, PhD
Professor, Department of Pediatrics, McGill University
Therapeutic approaches in histone mutant gliomas
Rameen Beroukhim, MD PhD
Associate Professor of Medicine, Harvard Medical School
Associate Member, Broad Institute
Divisions of Medical Oncology and Cancer Biology, Dana-Farber Cancer Institute
Effects of Positive and Negative Selection on Structural Variants in Cancer
Including Q&A session
Nada Jabado has embarked on elucidating genetic signatures of pediatric astrocytomas and examining how they compare to adults. These are deadly brain tumours that originate in brain and include glioblastomas (GBM, the highest grade of astrocytomas), which are one of the deadliest cancers in humans. Her group uncovered that pediatric high-grade astrocytomas (HGA) are molecularly and genetically distinct from adult tumors. They also identified a new molecular mechanism driving pediatric HGA, namely recurrent somatic driver mutations in the tail of histone 3 variants (H3.3 and H3.1). These mutations lead to amino acid substitutions at key residues and are tightly correlated with a distinct global DNA methylation pattern, neuroanatomical locations and age specificities. Their findings position them as leaders in the field of HGA, at the forefront of significant breakthroughs for this deadly brain tumor. Crucial impediments to progress are the lack of reliable in vitro and in vivo models for these “oncohistones” and understanding their effects in driving tumors and therapeutic resistance. they aim to identify events affected downstream of each mutation, and validate targets in their new models to better advise the use of experimental or pipeline drug(s) or drug combinations that could be rapidly translated into clinical trials. Ultimately, based on their findings, patients could be stratified based on their genetic/molecular signature, and assigned to a beneficial therapeutic strategy, bringing needed effective interventions in this devastating cancer. Additionally, they established a TCGA-like initiative by creating the International CHildhood Astrocytoma INtegrated Genomic and Epigenomic (ICHANGE) Consortium. This is a unique set of resources which enables the scientific world to investigate astrocytomas in children. It includes databases and access to technology as well as international collaborations from 15 participating countries, including ~1500 annotated glioma tissue samples representative of all grades and ages.
Rameen Beroukhim, MD, PhD, is an associate professor of medicine at the Dana-Farber Cancer Institute and Harvard Medical School, and an associate member of the Broad Institute of Harvard and MIT. In addition to directing a genomics-focused lab, he sees patients in an adult neuro-oncology clinic. Raised in Milwaukee, Wis., Rameen studied physics and philosophy at the University of California, Berkeley. He obtained an MPhil and PhD from the University of Cambridge for work done at the Medical Research Council Laboratory of Medical Biology on electron crystallographic studies of ion channels. He then completed his MD and internal medicine residency at the University of California, San Francisco, before completing a medical oncology fellowship at Dana-Farber Cancer Institute and Massachusetts General Hospital. He has traveled to over 50 countries; highlights include avoiding leeches in Borneo (the same could not be said for his daughter) and getting attacked by penguins in Patagonia.