Tumor-targeted pan-RAS inhibition as a novel biologic therapy for diffuse midline glioma
Abstract
Background: Pediatric high-grade gliomas (pHGG) are the leading cause of childhood cancer-related deaths. Those arising in the midline harboring a lysine to methionine substitution at position 27 in histone 3 (H3K27M), termed diffuse midline glioma (or DIPG when occurring in the pons), are particularly deadly and in need of additional therapeutic options. Our group and others have found upregulation of the RAS/MAPK pathway across HGGs, including DIPG; however, RAS is notoriously difficult to target therapeutically, with no approved drugs that can target nonmutant RAS proteins.
Methods: We leveraged a pan-RAS-cleaving biologic (RRSP-DTB) to define RAS dependency in DIPG and employed proteomic profiling of patient-derived tumors to identify enriched cell-surface receptors for tumor-selective targeting. RRSP was re-engineered to engage the lead candidate receptor, tumor endothelial marker 8 (TEM8/ANTXR1), generating a targeted RAS-degrading biologic evaluated in vitro and in orthotopic DIPG xenograft models.
Results: Pan-RAS cleavage revealed DIPG to be critically dependent on RAS/MAPK signaling compared to other RAS/MAPK HGGs. Targeting RRSP to TEM8 enabled efficient intracellular delivery, resulting in complete RAS ablation and apoptotic cell death in patient-derived DIPG cells at low picomolar concentrations. In vivo, intracerebroventricular delivery reduced leptomeningeal disease burden (P = .04), while convection-enhanced delivery extended survival in orthotopic DIPG models (median survival 68 vs. 57 days; P = .016).
Conclusions: We demonstrate RAS-dependency in DIPG targetable by RRSP-DTT-TEM8, a novel, first-in-class pan-RAS biotherapeutic, supporting its potential as a therapeutic strategy for this otherwise untreatable disease.
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BibTeX
@article{sbergio2026tumortargeted,
title = {{Tumor-targeted pan-RAS inhibition as a novel biologic therapy for diffuse midline glioma}},
author = {Stefanie-Grace Sbergio and Huazhu Liang and Lucy Chen and Laura Canty and Sheyenne Carette and Sanja Pajovic and Nesrin Sabha and Arun Kumaran Anguraj Vadivel and Greg L Beilhartz and Roman A Melnyk and Cynthia Hawkins},
journal = {Neuro-Oncology},
year = {2026},
month = jun,
doi = {10.1093/neuonc/noag148},
url = {https://doi.org/10.1093/neuonc/noag148},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - Tumor-targeted pan-RAS inhibition as a novel biologic therapy for diffuse midline glioma
AU - Stefanie-Grace Sbergio
AU - Huazhu Liang
AU - Lucy Chen
AU - Laura Canty
AU - Sheyenne Carette
AU - Sanja Pajovic
AU - Nesrin Sabha
AU - Arun Kumaran Anguraj Vadivel
AU - Greg L Beilhartz
AU - Roman A Melnyk
AU - Cynthia Hawkins
PY - 2026
DA - 2026/06/29
JO - Neuro-Oncology
DO - 10.1093/neuonc/noag148
UR - https://doi.org/10.1093/neuonc/noag148
AB - Background: Pediatric high-grade gliomas (pHGG) are the leading cause of childhood cancer-related deaths. Those arising in the midline harboring a lysine to methionine substitution at position 27 in histone 3 (H3K27M), termed diffuse midline glioma (or DIPG when occurring in the pons), are particularly deadly and in need of additional therapeutic options. Our group and others have found upregulation of the RAS/MAPK pathway across HGGs, including DIPG; however, RAS is notoriously difficult to target therapeutically, with no approved drugs that can target nonmutant RAS proteins. Methods: We leveraged a pan-RAS-cleaving biologic (RRSP-DTB) to define RAS dependency in DIPG and employed proteomic profiling of patient-derived tumors to identify enriched cell-surface receptors for tumor-selective targeting. RRSP was re-engineered to engage the lead candidate receptor, tumor endothelial marker 8 (TEM8/ANTXR1), generating a targeted RAS-degrading biologic evaluated in vitro and in orthotopic DIPG xenograft models. Results: Pan-RAS cleavage revealed DIPG to be critically dependent on RAS/MAPK signaling compared to other RAS/MAPK HGGs. Targeting RRSP to TEM8 enabled efficient intracellular delivery, resulting in complete RAS ablation and apoptotic cell death in patient-derived DIPG cells at low picomolar concentrations. In vivo, intracerebroventricular delivery reduced leptomeningeal disease burden (P = .04), while convection-enhanced delivery extended survival in orthotopic DIPG models (median survival 68 vs. 57 days; P = .016). Conclusions: We demonstrate RAS-dependency in DIPG targetable by RRSP-DTT-TEM8, a novel, first-in-class pan-RAS biotherapeutic, supporting its potential as a therapeutic strategy for this otherwise untreatable disease.
SN - 1522-8517
SN - 1523-5866
ER -