ΔNp73/ETS2 complex drives glioblastoma pathogenesis— targeting downstream mediators by rebastinib prolongs survival in preclinical models of glioblastoma

• Published in: Neuro-oncology (Charlottesville, Va.) Va.), 2020-03, Vol.22 (3), p.345-356
• Main Authors: Cam, Maren, Charan, Manish, Welker, Alessandra M, Dravid, Piyush, Studebaker, Adam W, Leonard, Jeffrey R, Pierson, Christopher R, Nakano, Ichiro, Beattie, Christine E, Hwang, Eugene I, Kambhampati, Madhuri, Nazarian, Javad, Finlay, Jonathan L, Cam, Hakan
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - administration & dosage; Basic and Translational Investigations; Brain Neoplasms - drug therapy; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Cell Line, Tumor - drug effects; Disease Models, Animal; Glioblastoma - drug therapy; Glioblastoma - metabolism; Glioblastoma - pathology; Humans; Mice, Transgenic; Neovascularization, Pathologic - metabolism; Proto-Oncogene Protein c-ets-2 - metabolism; Pyrazoles - administration & dosage; Pyridines - administration & dosage; Quinolines - administration & dosage; Survival Analysis; Tumor Protein p73 - metabolism; Zebrafish
• ISSN: 1522-8517; 1523-5866
• DOI: 10.1093/neuonc/noz190

Abstract Background Glioblastoma (GBM) remains one of the least successfully treated cancers. It is essential to understand the basic biology of this lethal disease and investigate novel pharmacological targets to treat GBM. The aims of this study were to determine the biological consequences of elevated expression of ΔNp73, an N-terminal truncated isoform of TP73, and to evaluate targeting of its downstream mediators, the angiopoietin 1 (ANGPT1)/tunica interna endothelial cell kinase 2 (Tie2) axis, by using a highly potent, orally available small-molecule inhibitor (rebastinib) in GBM. Methods ΔNp73 expression was assessed in glioma sphere cultures, xenograft glioblastoma tumors, and glioblastoma patients by western blot, quantitative reverse transcription PCR, and immunohistochemistry. Immunoprecipitation, chromatin immunoprecipitation (ChiP) and sequential ChIP were performed to determine the interaction between ΔNp73 and E26 transformation-specific (ETS) proto-oncogene 2 (ETS2) proteins. The oncogenic consequences of ΔNp73 expression in glioblastomas were examined by in vitro and in vivo experiments, including orthotopic zebrafish and mouse intracranial-injection models. Effects of rebastinib on growth of established tumors and survival were examined in an intracranial-injection mouse model. Results ΔNp73 upregulates both ANGPT1 and Tie2 transcriptionally through ETS conserved binding sites on the promoters by interacting with ETS2. Elevated expression of ΔNp73 promotes tumor progression by mediating angiogenesis and survival. Therapeutic targeting of downstream ΔNp73 signaling pathways by rebastinib inhibits growth of established tumors and extends survival in preclinical models of glioblastoma. Conclusion Aberrant expression of ΔNp73 in GBM promotes tumor progression through autocrine and paracrine signaling dependent on Tie2 activation by ANGPT1. Disruption of this signaling by rebastinib improves tumor response to treatment in glioblastoma.