不良研究所

Dr. Jabado聽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.聽 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 鈥渙ncohistones鈥� 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.