Abstract 4593: Glioblastoma tumors that respond poorly to bevacizumab therapy show upregulation of an angiogenesis gene set

Abstract Glioblastoma (GBM) is the most common primary brain tumor in adults with a 15-month median survival, despite surgical-resection and radio-chemotherapy, and a recurrence rate of 90%. Despite improving survival in only a small percentage of patients, bevacizumab, a monoclonal antibody toward vascular endothelial growth factor-A, is frequently used to treat recurrent-GBM. To find predictors of poor-response to bevacizumab, we performed RNA-sequencing on multiple GBM patient-derived xenograft (PDX) tumors after orthotopic propagation in athymic nude mice. The study was repeated, and once PDX-tumors were established, mice were treated with bevacizumab and grouped based on survival. Bioinformatic-analysis of RNA-sequencing data demonstrated differential gene expression in tumors that were poor-responders to bevacizumab (no survival change) as compared to tumors that were good-responders (longer survival), along with upregulation of an angiogenesis gene set in poor-responders. Within this gene set, multiple genes known to be regulated by the early growth response 1 (EGR1) transcription factor were identified; CHRNA7 (cholinergic-receptor-nicotinic-α7-subunit) was selected for further study based on the reported role in promoting cancer cell migration and proliferation. Results were validated at the protein level using immunohistochemical staining. Additionally, Sry-box transcription factor-10 (SOX10) showed upregulation in poor-responders, potentially driven by impaired proteosome degradation. SOX10 is known to promote mural-cell coverage of neovasculature, cancer cell migration, and glioma development when cooperating with platelet-derived growth factor-B (PDGFB). In summary, GBM PDX-tumors with upregulated expression of an angiogenesis gene set and of two transcriptional regulators (EGR1 and SOX10) demonstrated a poor response to bevacizumab; upregulation of these genes could be used to predict bevacizumab response. Citation Format: Roshan Lodha, Gaelle Muller-Greven, Lydia Guo, Candece Gladson. Glioblastoma tumors that respond poorly to bevacizumab therapy show upregulation of an angiogenesis gene set. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4593.