Madison Clausen

Combinatorial Targeting of Avapritinib-Driven MAP Kinase Activation in High-Grade Glioma

Carl Koschmann, Kallen Schwark, Kelsey Wink, Antonella De Cola et autres

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Feasibility of Using Real-Time Sequencing to Validate Somatic Variants and Copy Number Events for Novel Genetically Engineered Models

Fareen Momen, Madison Clausen, Tiffany Adam, Jack Wadden et autres

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ZFTA–RELA ependymomas make itaconate to epigenetically drive fusion expression

Siva Kumar Natarajan, Joanna Lum, James Haggerty Skeans, Minal Nenwani et autres

ZFTA–RELA+ ependymomas are malignant brain tumours defined by fusions formed between the putative chromatin remodeller ZFTA and the NF-κB mediator RELA1. Here we show that ZFTA–RELA+ cells produce itaconate, a key macrophage-associated immunomodulatory metabolite2. Itaconate is generated by cis-aconitate decarboxylase 1 (ACOD1; …

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ANGI-18. DISRUPTING INTEGRIN SIGNALING IMPAIRS MIGRATION, MYC-DRIVEN PURINE BIOSYNTHESIS, AND STEMNESS IN H3K27M DIFFUSE MIDLINE GLIOMAS

Rodrigo T. Cartaxo, Daniel de la Nava, Edwin Nieblas‐Bedolla, Michael Niculcea et autres

Abstract Diffuse midline glioma (DMG) is an aggressive pediatric brain tumor driven by the H3K27M histone mutation and represents the leading cause of cancer-related death in children. These tumors are highly infiltrative and can occasionally migrate to distant CNS regions. To uncover …

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EXTH-15. Combinatorial targeting of avapritinib-driven MAPK activation in pediatric high-grade glioma

Kallen Schwark, Madeline Miclea, Tirth K. Patel, Seongbae Kong et autres

Abstract PDGFRA is a frequently altered gene in pHGG, driving aggressive behavior and worse prognoses. Avapritinib, a CNS-penetrant inhibitor of mutated PDGFRα and KIT kinases, has shown promise in vitro, in vivo, and in pHGG patients. Single-agent trials in pHGG often fail …

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CSIG-28. ATRX LOSS LEADS TO H3K4ME3-DRIVEN EPIGENETIC DYSREGULATION OF OLIGODENDROCYTE DIFFERENTIATION AND CELL CYCLE CONTROL IN H3K27M-MUTANT DIFFUSE MIDLINE GLIOMA (DMG)

Dana Messinger, Jina Patel, Robert E. Doherty, Daniel de la Nava et autres

Abstract Diffuse midline gliomas (DMGs) are lethal pediatric cancers. Histone H3.3 (H3-3A) is the most commonly mutated gene in DMG; up to 80% exhibit a gain-of-function mutation at lysine 27 (K27M). K27M mutations often co-occur with loss of ATRX, a chromatin remodeler. …

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HGG-03. ATRX loss drives epigenetic dysregulation of p16 in pediatric high-grade glioma

Dana Messinger, Jina Patel, Robert E. Doherty, Kennedy Kuchinski et autres

Abstract Pediatric high-grade gliomas (pHGGs) are the most lethal pediatric cancers, with survival rarely exceeding 2 years. Histone H3.3 (H3-3A) is the most commonly mutated gene in pHGG; nearly 50% exhibit gain-of-function mutations at either lysine 27 (K27M) or glycine 34 (G34R/V). …

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DMG-47. Therapeutic Targeting of Beta Integrins disrupts H3K27M-DMG-specific Metabolic and Differentiation Programs

Rodrigo T. Cartaxo, Edwin Nieblas-Bedolla, Michael Niculcea, Sunjong Ji et autres

Abstract Diffuse midline gliomas (DMG) are characterized by the histone mutation H3K27M and infiltrative tumors that occasionally migrate to distant CNS regions. We established a novel two-step pooled whole-genome CRISPR-­Migration screen of metastatic H3K27M-DMG (n = 3) and glioblastoma (GBM, n = …

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HGG-06. Combinatorial targeting of avapritinib-driven MAPK activation in pediatric high-grade glioma

Kallen Schwark, Madeline Miclea, Tirth Patel, Seongbae Kong et autres

Abstract PDGFRA is a frequently altered gene in pHGG, driving aggressive behavior and worse prognoses. Avapritinib, a potent CNS-penetrant PDGFRA inhibitor, has shown promise in vitro, in vivo, and in pHGG patients. Given the failure of single-agent trials in targeting PDGFRA-altered HGG, …

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Updates in Diagnostic Techniques and Experimental Therapies for Diffuse Intrinsic Pontine Glioma

Luke McVeigh, Tirth K. Patel, Madeline Miclea, Kallen Schwark et autres

Diffuse intrinsic pontine glioma (DIPG) is a rare but extremely malignant central nervous system tumor primarily affecting children that is almost universally fatal with a devastating prognosis of 8-to-12-month median survival time following diagnosis. Traditionally, DIPG has been diagnosed via MR imaging …

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Training UAS Pilots for Divided Attention Demands With Cognitive Tasks and NIST Courses

Collin Scarince, Miguel Ángel Moreno, Madison Clausen, Tim Payne

Uncrewed aircraft system (UAS) operators often monitor multiple channels of information, such as radio communications and tracking visual targets. We investigated how exposing pilots to divided attention tasks during flights impacted performance and their improvement with practice. Pilots completed a UAS course …

TMOD-29. BETA INTEGRINS REGULATE MITOCHONDRIALLY-MEDIATED CELL MIGRATION IN H3K27M-DIFFUSE MIDLINE GLIOMA

Rodrigo T. Cartaxo, Edwin Nieblas‐Bedolla, Michael Niculcea, Siva Kumar Natarajan et autres

Abstract Infiltration into the brain tissue is one of the main features of diffuse midline gliomas (DMG), also characterized by the histone mutation H3K27M and overall survival of 12-15 months from diagnosis. To study which genes are critical for H3K27M-DMG tumor cell …

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