Targeting the RhoGEF βPIX/COOL-1 in glioblastoma: proof of concept studies.
journal contributionposted on 11.12.2020, 17:00 by 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 Shiels, Francesca Lodi, Diether Lambrechts, Jann N Sarkaria, Raymond M Schiffelers, Marc Symons, Annette 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.
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
Associated research data fileshttp://www.mdpi.com/2072-6694/12/12/3531/s1
CommentsThe original article is available at https://www.mdpi.com/
Published CitationConnor 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 Date26 November 2020
- Physiology and Medical Physics
- Public Health and Epidemiology
- Beaumont Hospital
- Published Version (Version of Record)