View The Document

Accession Number:



Targeting Oncogene Amplification in Glioblastoma


Author Organization(s):

Report Date:



Using a panel of patient-derived models, we are identifying the factors affecting response of glioblastoma to novel and specific small molecule inhibitors of cyclin-dependent kinase 4 and 6 (CDK4/6) and mouse-double minute homologue 2 (MDM2), which are oncogenic negative regulators of tumor suppressors retinoblastoma protein (Rb) and tumor protein 53 (p53), respectively. The activation of CDK4 and MDM2 by gene amplification, frequently in extrachromosomal DNA (ecDNA), is considered in our study. CDK4/6 and MDM2 inhibitors, selected based on our previous studies showing specificity and potency, were tested as single agents and in combination with radiation therapy in patient derived cancer stem cells and orthotopic mouse xenografts. Our data show that MDM2 antagonist pre-treatment has the potential to sensitize resistant wildtype p53 glioblastoma tumors to radiation therapy, and to CDK4/6 inhibitors. Taking advantage of the heterogeneous ecDNA amplification of PDGFRA in glioblastoma, we report that single cell clones which are PDGFRA ecDNA negative present a significantly reduced tumor growth rate in mouse brains, relative to the ecDNA positive populations from the same tumor. Further, we identify pathways that are differentially active in the ecDNA positive and negative models, with significant implications for the treatment PDGFRA activated glioblastomas.



File Size:





Distribution Statement:

Approved For Public Release

View The Document