The Koschmann lab is studying the molecular mechanisms and correlate biomarkers underpinning therapeutic response in diffuse midline glioma (DMG) and pediatric high-grade glioma (pHGG).
1. ATRX Mutation and Epigenetic Control of Cell Cycle: Loss of function mutations in the chromatin remodeling protein ATRX are found in 30% of pHGG and DIPG, usually with concurrent mutation in the histone variant H3F3A (H3.3). We previously developed a mouse model of ATRX-deficient HGG and showed that loss of ATRX results in increased sensitivity to radiation treatment. We recently discovered that ATRX regulates the expression of cell cycle regulatory genes in glioma precursor cells. HGG cells with isogenic ATRX loss demonstrate inappropriate release of cell cycle checkpoints after irradiation and radio-sensitization with inhibitors of the master cell cycle regulator ATM. Our ongoing NIH-funded work on this project will determine how ATRX loss deregulates cell cycle checkpoints, and to clarify the impact of concurrent H3F3A mutation on cell cycle regulation and radiation sensitizing therapy.
2. Optimizing anti-dopaminergic receptor therapy for H3K27M-mutant HGG: Recently, our group has studied the use of ONC201, a pro-apoptotic dopamine receptor 2 (DRD2) antagonist, in H3K27M gliomas, based on early anecdotal activity in this clinical population. In our exciting preliminary data, we have observed that H3K27M-mutant tumors show pre-clinical and clinical efficacy with ONC201, indicating the first clinical response to any agent in this patient population. The response is most pronounced in thalamic H3K27M patients. We are also assessing the response of DIPG cells to combinatorial treatment with ONC201 and clinically-available agents chosen from an ongoing RNAi screen of ONC201-treated DIPG cells. Our ongoing work on this project will integrate novel pre-clinical models (in vitro, in vivo, organoid) with human data from pediatric patients with H3K27M-HGG treated with ONC201 to determine the following mechanism of EGFR-driven resistance ONC201, and how to optimize combinatorial treatment.
3. One of the most frequently altered genes in DMG/HGG is platelet-derived growth receptor alpha (PDGFRA), which is either mutated or amplified in 12% of adult glioblastoma (GBM) and 21% of pediatric high-grade glioma (pHGG). We have shown that different PDGFRA variants (i.e., mutation vs amplification), correlate closely with age, tumor region, and survival. However, the mechanism driving the regional and genetic attributes of PDGFRα-driven HGG remains unknown. In preliminary data, we found that the tyrosine kinase inhibitor (TKI) avapritinib demonstrates unprecedented CNS penetration and selectivity for PDGFRα, leading to in vivo efficacy and early human clinical responses. Unfortunately, previous trials with PDGFRα inhibitors for HGG have failed, as they did not consider tumor genetics or drug resistance. Therefore, there is a critical need to determine how regional/genetic factors impact PDGFRα-HGG tumor growth and treatment response/resistance patterns to avapritinib. Our central hypothesis is: (i) amplified wild-type PDGFRA in HGG generates a “dimerized PDGFR”-driven kinase signaling program with increased sensitivity to avapritinib; and (ii) ERK-mediated anti-apoptotic resistance to avapritinib can be targeted with co-treatment with direct ERK inhibition. This is based on our preliminary data showing: (i) greater PDGF ligand-dependent pPDGFRα activation and sensitivity to avapritinib in amplified PDGFRα HGG models, and (ii) unexpected MAPK/ERK activation in avapritinib-treated HGG cells.
