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). Their work is currently focused on how mutations in pediatric and young adult HGG might affect response to novel precision medicine therapies.
PDGFRA-driven HGG and combinatorial PDGFRA/mTOR targeting
Pediatric and adult high-grade gliomas (HGGs) frequently harbor PDGFRA alterations. We hypothesized that cotreatment with everolimus may improve the efficacy of dasatinib in PDGFRα-driven glioma through combinatorial synergism and increased tumor accumulation of dasatinib. We found that dasatinib effectively inhibited the proliferation of mouse and human primary HGG cells with a variety of PDGFRA alterations (Miklja et al, JCI, 2020). Dasatinib exhibited synergy with everolimus in the treatment of HGG cells at low nanomolar concentrations of both agents, with a reduction in mTOR signaling that persisted after dasatinib treatment alone. Prolonged exposure to everolimus significantly improved the CNS retention of dasatinib and extended the survival of PPK tumor–bearing mice (mutant TP53, mutant PDGFRA, H3K27M). Six pediatric patients with glioma tolerated this combination without significant adverse events, and 4 patients with recurrent disease (n = 4) had a median overall survival of 8.5 months. Our results show that the efficacy of dasatinib treatment of PDGFRα-driven HGG was enhanced with everolimus and suggest a promising route for improving targeted therapy for this patient population.
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.
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.
