Abstract 3271: Gene expression changes underlying glioblastoma resistance to anti-angiogenic therapy
Authors: Chen William C. , Jahangiri Arman , Yagnik Garima , Sidorov Maxim , Rick Jonathan , Kuang Ruby , DeLay Michael , Aghi Manish K. 
Published: July 2016

Introduction: Despite positive pre-clinical and clinical trials, treatment of glioblastoma with bevacizumab has been limited by acquired resistance and transient response. To study gene expression changes underlying tumor resistance and progression during bevacizumab therapy, we performed microarray gene expression analysis on a novel multigenerational xenograft model of acquired bevacizumab resistance.

Methods: Using a two-component normal mixture model, we identified a set of genes exhibiting significant inter-generational variance. Protein-protein interaction scores among these genes were extracted from the String 10 database and used as undirected edge weights in a network representation of the significant gene set. Gene set over-representation (GSO) analysis via ConsensusPathDB of gene clusters identified biologically meaningful clusters and subnetworks mediating distinct functions and molecular pathways.

Results: Gene set enrichment analysis revealed significant overexpression across generations of previously identified gene signatures of the mesenchymal subtype, as well as a tumor mesenchymal metabolic signature. Key mesenchymal markers, including putative tumor-stemness marker CD44, NT5E, SNAI2, and ZEB2, were found to be upregulated across generations. These results suggest tumor progression under bevacizumab challenge to be accompanied by a shift in gene expression towards the mesenchymal subtype, a subtype of GBM associated with enhanced invasiveness, resistance, and worse outcome.

Our analysis also revealed expression changes in pathways related to angiogenesis. Pro-angiogenic genes FGF2, MMP1, HIF1A, UGCG, LPAR1, and ITGB3 were found to be upregulated. Furthermore, GSO analysis identified angiogenesis as a significantly enriched ontology within the inflammatory response and ECM remodeling subnetworks identified by spectral clustering. Angiogenesis related genes identified via GSO included highly upregulated inflammatory mediators such as COX2, IL6, IL1A, upregulated pro-angiogenic factors TGFA, WNT5A, FGF2, and a downregulated anti-angiogenic gene, SPARC.

Conclusions: These results suggest a mesenchymal and pro-angiogenic response to bevacizumab treatment supported by multiple converging pathways involving inflammation, hypoxia, and ECM remodeling. Strategies preventing the evolution of these responses should be developed and tested in the context of our novel xenograft model in order to improve the durability of response to these therapies and allow them to fulfill their therapeutic promise.

Citation Format: William C. Chen, Arman Jahangiri, Garima Yagnik, Maxim Sidorov, Jonathan Rick, Ruby Kuang, Michael DeLay, Manish K. Aghi. Gene expression changes underlying glioblastoma resistance to anti-angiogenic therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3271.