BPix paper 2020 cancers-12-03531.pdf (2.24 MB)
Download file

Targeting the RhoGEF βPIX/COOL-1 in glioblastoma: proof of concept studies.

Download (2.24 MB)
journal contribution
posted on 11.12.2020, 17:00 by Kate ConnorKate Connor, David W Murray, Monika A Jarzabek, Nhan L Tran, Kieron WhiteKieron White, Patrick DickerPatrick Dicker, Kieron J Sweeney, Philip J O’Halloran, Brian MacCarthy, Liam ShielsLiam Shiels, Francesca Lodi, Diether Lambrechts, Jann N Sarkaria, Raymond M Schiffelers, Marc Symons, Annette ByrneAnnette Byrne
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.

Funding

Science Foundation Ireland Technology Innovation Award (15/TIDA/2963).

“GLIOTRAIN” (http://www.gliotrain.eu) award, a Horizon 2020 Research and Innovation program funded under the Marie Skłodowska-Curie ETN initiative (Grant Agreement #766069).

Beaumont Hospital Cancer Research and Development Trust

History

Associated research data files

http://www.mdpi.com/2072-6694/12/12/3531/s1

Comments

The original article is available at https://www.mdpi.com/

Published Citation

Connor K, Murray DW, Jarzabek MA, Tran NL, White K, Dicker P, Sweeney KS, O’Halloran PJ, MacCarthy B, Shiels LP, Lodi F, Lambrechts D, Sarkaria JN, Shiffelers R, Symons M, Byrne AT. Targeting the RhoGEF βPIX/COOL-1 in glioblastoma: proof of concept studies. Cancers. 2020;12(12):E3531.

Publication Date

26 November 2020

PubMed ID

33256106

Department/Unit

  • Physiology and Medical Physics
  • Public Health and Epidemiology
  • Beaumont Hospital

Research Area

  • Cancer

Publisher

MDPI

Version

  • Published Version (Version of Record)