The Koschmann lab is studying the molecular mechanisms by which mutations in pediatric High-Grade Glioma and Diffuse Intrinsic Pontine Glioma (DIPG) can be therapeutically targeted. The Koschmann Lab’s work in precision medicine pushes the boundaries of targeted therapies and precision diagnostics for children diagnosed with these brain tumors. Through highly collaborative basic, translational, and clinical research, the Koschmann Lab strives towards improving outcomes and providing hope for children fighting these devastating diseases.
Genetic Drivers of Pediatric DMG and DIPG
The Koschmann lab is studying the molecular mechanisms by which mutations promote tumor formation and genetic instability in pediatric high-grade glioma (HGG), and diffuse intrinsic pontine glioma (DIPG) and diffuse midline glioma (DMG). Their work is currently focused on how mutations in pediatric and young adult DIPG/DMG/HGG might affect response to novel precision medicine therapies.
Targeting PDGFRA-driven HGG
High-grade gliomas (HGGs) confer a median survival of 12-18 months due to their aggressive phenotype and lack of therapeutic options. We have demonstrated that molecular characterization of high-grade gliomas can result in effective targeted therapies. PDGFRA is frequently focally amplified in younger patients (age 5-12) (3). PDGFRA mutations are more common in young adults (age 12-30) , resulting in ligand-independent receptor activation and oncogenic activity . Previous trials with promising PDGFRα inhibitors for HGG have failed, most likely because they did not consider tumor genetics or drug resistance. Therapies for PDGFRA-driven HGG remain non-targeted with few long-term survivors.
Given the failure of single-agent trials in targeting PDGFRα-HGG, combinatorial therapy will be essential in treatment strategies. We previously demonstrated that combining the PDGFRα inhibitor dasatinib with the mTOR inhibitor everolimus improved survival in mice and feasibility in six HGG patients (Miklja et al, JCI, 2020).
Avapritinib is FDA-approved for gastrointestinal stromal tumors with PDGFRα and KIT mutations. We co-lead a recently completed phase 1 clinical trial to determine avapritinib dosing in pediatric brain tumors. Avapritinib is a type I kinase inhibitor designed to maintain its exceptional potency against wild-type PDGFRα for exon 18-mutations by binding to the mutated activation loop in the active state. In collaboration with FIlbin (DFCI) and Gojo (Vienna) labs, we found that avapritinib has high specificity for wildtype PDGFRα. Avapritinib extends survival and reduces tumor p-PDGFRα in tumor tissue in our aggressive PDGFRα-driven HGG mouse model. We gathered the first series of patients with HGG treated with avapritinib which shows radiographic response in 3 of 8 cases (Mayr et al, Cancer Cell, 2025)
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.
Subsequnetly, we discovered that ATRX binds the regulatory elements of cell-cycle phase transition genes in GBM cells, and there is a marked reduction in Checkpoint Kinase 1 (CHEK1) expression with ATRX loss, leading to the early release of G2/M entry after irradiation (Qin et al, Cell Reports 2022). ATRX-deficient cells exhibit enhanced activation of master cell-cycle regulator ATM with irradiation. Addition of the ATM inhibitor AZD0156 doubles median survival in mice intracranially implanted with ATRX-deficient GBM cells, which is not seen in ATRX-wild-type controls. This study demonstrates that ATRX-deficient high-grade gliomas (HGGs) display Chk1-mediated dysregulation of cell-cycle phase transitions, which opens a window for therapies targeting this phenotype.
Improved Molecular Understanding of DIPG Drivers and subsets of H3K27M-DMG
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.
Our lab identified enrichment of alterations in MAPK pathway genes in patients with LTS compared to those with typical survival (Roberts et al, Acta Neuropathologica 2024). Furthermore, H3K27M-DMGs with MAPK alterations demonstrate a unique DNA methylation signature, even in some cases without a MAPK in initial sample, thus raising the possibility of a unique evolutionary trajectory that selects for subsequent MAPK alteration. Our data demonstrates distinct clinical outcomes, DNA methylation patterns, MAPK mutations, and absence of TP53 mutations that supports a distinct LTS-associated subtype of H3K27M-DMG, which we propose as “diffuse midline glioma, H3K27M-mutant and MAPK pathway-altered”. As a few MAPK-wildtype cases clustered with the “MAPK-altered” group, methylation analysis should be considered with other clinical and molecular diagnostic elements. Our study also confirms that a subset of H3K27M-DMGs show circumscribed histology, and this contradiction with the diagnostic category “diffuse” midline glioma may need to be re-addressed in the future.
Ongoing work is exploring the impact and targetability of concurrent EGFR and MAPK alterations on H3K27M-DMGs.
