Genetic Drivers of Pediatric High-Grade Glioma and DIPG

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The Koschmann lab is studying the molecular mechanisms by which mutations promote tumor formation and genetic instability in pediatric high-grade glioma (HGG), including anaplastic astrocytoma (AA), glioblastoma (GBM) and diffuse intrinsic pontine glioma (DIPG). Their work is currently focused on how mutations in pediatric and young adult HGG might affect response to novel DNA-damaging and immune-based therapies.

ATRX Mutation and DNA Damage Repair

ATRX is a histone chaperone protein that is mutated in a large number of adolescent GBMs. In collaboration with the lab of Drs. Pedro Lowenstein and Maria Castro, the Koschmann lab is using a genetically engineered mouse model of ATRX-deficient high-grade glioma.  Data from the project has demonstrated the role of ATRX in GBM tumor progression, treatment response and loss of tumor genetic stability (Koschmann et al, Science Translational Medicine, 2016). Ongoing work in the Koschmann lab is aimed at continued study of the impact of ATRX mutation on the quality and quantity of mutations in adolescent and young adult GBM.  As well, the mouse model and multiple genetically-engineered human tumor cell models have provided a platform for future development of targeted therapy for patients with ATRX-deficient GBM.

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Improved Molecular Understanding of DIPG Drivers

Improved molecular understanding is needed for rational treatment of diffuse intrinsic pontine gliomas (DIPG).  The Koschmann lab is studying mechanisms of tumor progression, tumor evolution and epigenetic regulation in DIPG, using paired and multi-focal sequencing of human DIPG samples, and novel mouse models of DIPG.

 In our previous work, we performed multi-focal paired tumor and germline exome DNA and RNA sequencing to uncover the role of phosphatase and tensin homolog (PTEN) loss as an early event in the case of a 6-year-old boy with a DIPG (Koschmann et al, npj Precision Oncology, 2016).  This data strengthened the association with PTEN loss in DIPG and provided further argument for the inclusion of PTEN in future targeted sequencing panels for pediatric diffuse intrinsic pontine gliomas and for the development and optimization of mTOR/PI3K inhibitors with optimal central nervous system penetration.

Ongoing work in the Koschmann lab is focused on uncovering and targeting tumor drivers in non-coding regions of the DIPG tumor genome and further exploration of tumor evolution and therapeutic resistance.  As well, the Koschmann lab is currently exploring whether novel agents impact DNA damage repair can be employed to target histone alterations in DIPG.

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