Preclinical Efficacy of Brain Penetrant, Single Agent Avapritinib inPDGFRA EcDNA-amplified Glioblastoma
Recommended Citation
Berezovsky A, Datta I, Gurdziel K, Transou A, Irtenkauf S, Hasselbach L, She R, Rosenfeld S, Snyder J, Poisson L, deCarvalho A. Preclinical Efficacy of Brain Penetrant, Single Agent Avapritinib inPDGFRA EcDNA-amplified Glioblastoma. Neuro Oncol 2025; 27(Supplement 5):v372-v373.
Document Type
Conference Proceeding
Publication Date
11-11-2025
Publication Title
Neuro Oncol
Keywords
Oncology, Neurosciences & Neurology
Abstract
The high prevalence of platelet derived growth factor receptor alpha (PDGFRA) alterations and its mitogenic function in oligodendrocyte precursor cells (OPC) make PDGFRA a promising therapeutic target in adult glioblastoma (GBM). Towards validating PDGFRA as an essential driver of GBM tumor maintenance, we have isolated subpopulations from a patient-derived model (HF3253), harboring two alterations in PDGFRA: internal deletion leading to constitutive activation and extrachromosomal (ecDNA) amplification driving high copy number and heterogeneity. HF3253 symptom-free survival correlated with the initial frequency of PDGFRA ecDNA(+) population implanted; prolonged symptom-free survival was due to selection for initially low-frequency PDGFRA ecDNA(+) clones. Employing bulk and single-cell RNA sequencing, PDGFRA modulated a biphasic injury response/developmental transcriptional signature corresponding to hijacked functions of OPCs and CNS fibroblasts. Exploiting intra-tumoral heterogeneity, we have isolated single cell clones from bulk cells that exhibit diploid PDGFRA copy number, very low levels of PDGFRA mRNA and undetectable PDGFRA protein. Symptom-free survival was substantially increased in 4 ecDNA(-) clones compared to parental ecDNA(+) (Log rank p< 0.0001; n ≥ 4/group). Rescue of wild-type PDGFRA by lentivirus in two ecDNA(-) populations decreased median survival by 50% in orthotopic xenograft relative to controls (log rank p = 0.3118, 0.0028; n=5/group). Avapritinib, a PDGFRA/KIT-selective kinase inhibitor, has shown promising efficacy in PDGFRA-mutated pediatric high-grade glioma. 5-week avapritinib (40 mg/kg) treatment abrogated HF3253 tumor growth by bioluminescent imaging. While treatment significantly improved survival compared to control in orthotopic male and female xenografts (log rank p=0.0047; n ≥ 9/group), independent of sex (pairwise log rank p=0.232), PDGFRA+ tumors rapidly developed within two weeks of drug removal. Similar to 5-week treatment, continuous avapritinib therapy improved xenograft survival (log rank p > 0.0001; n ≥ 8/group), increasing median survival by an additional 4 days in males. Our work validates PDGFRA ecDNA as a predictive biomarker for PDGFRA-targeted therapies and justifies the clinical implementation of avapritinib in the treatment of PDGFRA-altered brain tumors.
Volume
27
Issue
Supplement 5
First Page
v372
Last Page
v373
