EXTH-46. TESTING PRECISION GENOMICS-GUIDED THERAPY IN A MODEL OF ANAPLASTIC PLEOMORPHIC XANTHOASTROCYTOMA: DUAL INHIBITION OF CDK4/6 AND MEK

• Published in: Neuro-oncology (Charlottesville, Va.) Va.), 2024-11, Vol.26 (Supplement_8), p.viii247-viii247
• Main Authors: Koenig, Jenna, Saadatzadeh, M Reza, Bailey, Barbara J, Pandya, Pankita H, Dobrota, Erika A, Coy, Kathryn, Kennedy, Felicia M, Sinn, Anthony L, Tailor, Jignesh K, Angus, Steven P, Damayanti, Nur P, Pollok, Karen E
• Format: Article
• Language: English
• ISSN: 1522-8517; 1523-5866
• DOI: 10.1093/neuonc/noae165.0977

Abstract Typical survival for pediatric high-grade gliomas remains less than 18 months despite recent improved understanding of the molecular drivers of these tumors. Hyperactivating MAPK and CDK4/6 pathway mutations are common and targetable alterations implicated in tumorigenesis and malignant transformation in pediatric glioma. We have established and characterized a novel patient-derived xenograft (PDX) model, RHT128, from a pediatric patient diagnosed with the high-grade glioma anaplastic pleomorphic xanthoastrocytoma (APXA). The molecular landscape of PDX RHT128 exhibits molecular fidelity to the patient’s tumor. Clinical precision genomics analysis of the tumor revealed a novel BRAF chromosomal rearrangement and CDKN2A/B deletion. Based on this molecular signature, the patient was treated with MEK inhibitor trametinib as a monotherapy and, following progression of disease, with CDK4/6 inhibitor ribociclib. However, the tumor continued to progress. In this study our objective is to simultaneously target the CDK4/6 and MAPK pathways in RHT128 and determine to what extent this combination therapy minimizes emergence of therapeutic resistance. Single-agent efficacy assessments in a subcutaneous RHT128 model, showing significant dose-dependent reduction in tumor volume after treatment with abemaciclib (p