Targeting Oncogene Amplification in Glioblastoma
Abstract
High grade gliomas are still untreatable, in part due to co-deregulation of multiple oncogenic pathways, genetic variation within and between tumors. Using patient derived models we addressed these challenges by integrating genomic, molecular, and phenotypic data with response to pharmacological inhibitors targeting reactivation of retinoblastoma and p53pathways. We tested the efficacy of the combination of these inhibitors with radiation treatment in vitro and in vivo. Anticipating the development of resistance, we investigated the transcriptional reprograming and cellular phenotypes in longitudinal response to treatment. Sensitivity and adaptation to the treatments was tumor specific, even in a primary-recurrent pair. We also validated therapeutic targets for which effective inhibitors were not available by using RNA-interference mediated knockdown of DNA damage regulator DNAPK, which was effective in combination with radiation, temozolomide and CDK inhibitors; or by comparing PDGFRA ecDNA positive and negative subclones from the same tumor.
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 01, 2022
- Accession Number
- AD1215364
Entities
People
- Ana C. Decarvalho
- Artem Berezovsky
- Indrani Data
- James Snyder
- Laila Poisson
- Oluwademilade Nuga
- Susan Irtenkauf
- Yuling Meng
Organizations
- Henry Ford Health