Targeting the rhogef βpix/cool-1 in glioblastoma: Proof of concept studies

Kate Connor, David W. Murray, Monika A. Jarzabek, Nhan L. Tran, Kieron White, Patrick Dicker, Kieron J. Sweeney, Philip J. O’halloran, Brian Maccarthy, Liam P. Shiels, Francesca Lodi, Diether Lambrechts, Jann N. Sarkaria, Raymond M. Schiffelers, Marc Symons, Annette T. Byrne

Research output: Contribution to journalArticlepeer-review

Abstract

Glioblastoma (GBM), a highly invasive and vascular malignancy is shown to rapidly develop resistance and evolve to a more invasive phenotype following bevacizumab (Bev) therapy. Rho Guanine Nucleotide Exchange Factor proteins (RhoGEFs) are mediators of key components in Bev resistance pathways, GBM and Bev-induced invasion. To identify GEFs with enhanced mRNA expression in the leading edge of GBM tumours, a cohort of GEFs was assessed using a clinical dataset. The GEF βPix/COOL-1 was identified, and the functional effect of gene depletion assessed using 3D-boyden chamber, proliferation, and colony formation assays in GBM cells. Anti-angiogenic effects were assessed in endothelial cells using tube formation and wound healing assays. In vivo effects of βPix/COOL-1-siRNA delivered via RGD-Nanoparticle in combination with Bev was studied in an invasive model of GBM. We found that siRNA-mediated knockdown of βPix/COOL-1 in vitro decreased cell invasion, proliferation and increased apoptosis in GBM cell lines. Moreover βPix/COOL-1 mediated endothelial cell migration in vitro. Mice treated with βPix/COOL-1 siRNA-loaded RGD-Nanoparticle and Bev demonstrated a trend towards improved median survival compared with Bev monotherapy. Our hypothesis generating study suggests that the RhoGEF βPix/COOL-1 may represent a target of vulnerability in GBM, in particular to improve Bev efficacy.

Original languageEnglish (US)
Article number3531
Pages (from-to)1-19
Number of pages19
JournalCancers
Volume12
Issue number12
DOIs
StatePublished - Dec 2020

Keywords

  • ARHGEF7
  • Anti-invasive therapy
  • Beta-Pix/COOL-1
  • Bevacizumab resistance
  • Glioblastoma
  • RhoGEF

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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