Research Mentor Name
Ana C. deCarvalho
Research Mentor Email Address
adecarv1@hfhs.org
Institution / Department
Henry Ford Health Neurosurgery Department
Document Type
Research Abstract
Research Type
other
Other Type of Research
Translational Research
Graduate Level Research
no
Abstract
Background: Avapritinib, a selective inhibitor of mutated class III receptor tyrosine kinases (RTKs), shows promise in PDGFRA-altered pediatric glioma. We studied its efficacy in a glioblastoma (GBM) model (HF3253) containing two PDGFRA alterations: constitutive activation via an indel mutation and extrachromosomal DNA (ecDNA) amplification. We hypothesized that Avapritinib would preferentially improve survival in PDGFRA-amplified tumors.
Methods: Orthotopic xenografts derived from HF3253 PDGFRA ecDNA(+) (n=19) and ecDNA(-) (n=10) cells were treated with 40 mg/kg Avapritinib (5 days/week). To validate the role of PDGFRA expression, wild-type PDGFRA was overexpressed in ecDNA(-) cells, generating high PDGFRA levels with minimal ligand-independent activation in vivo. Bulk RNA sequencing was performed on ecDNA(-) and ecDNA(-) xenografts (n=6/group). Using FDR=0.05 and log2FC≥1.5, we identified 1,048 differentially expressed genes.
Results: Avapritinib significantly improved symptom-free survival in PDGFRA ecDNA(+) tumors (p< 0.0001) but had no improvement in ecDNA(-) tumors (p=0.93). Terminal tumor analyses showed no significant differences in PDGFRA expression or phosphorylation (Y754) after treatment. Overexpression of PDGFRA in ecDNA(-) tumors partially rescued their typically slower growth. RNA-seq revealed upregulation of tyrosine kinase adaptors (SHC1, HCK, SYK) and VEGFC/KDR and EFNA4/EPHA3 ligand-RTK pairs in PDGFRA-expressing tumors, suggesting non-canonical RTK crosstalk capable of transactivating PDGFRA and contributing to accelerated growth.
Conclusion: PDGFRA overexpression via ecDNA amplification or ectopic expression drives aggressive GBM growth and represents a promising therapeutic target for Avapritinib. Additionally, PDGFRA activity in GBM may be amplified through non-canonical interactions with other RTKs.
Disciplines
Medicine and Health Sciences
Recommended Citation
Rosenfeld, Sydni; Berezovsky, Artem; Datta, Indrani; Transou, Andrea; Irtenkauf, Susan; Hasselbach, Laura; and deCarvalho, Ana C., "Promising Efficacy of Avapritinib in PDGFRA ecDNA–Amplified Glioblastoma" (2026). Medical Student Research Symposium. 496.
https://digitalcommons.wayne.edu/som_srs/496
Comments
Thank you to my research mentor, Artem Berezovsky, for his knowledge and support. This work was funded by Demchik Fund for Avatar Models, Department of Defense grant CA180174 to A.C.D