Oral Presentation Symposium on Proteases and the Tumouri Microenvironment 2017

Fibroblast activation protein in glioblastoma microenvironment- possible pathophysiological role and new approaches of its therapeutic targeting (#31)

Petr Busek 1 , Tomas Knedlik 2 3 , Petra Dvorakova 2 3 , Eva Balaziova 1 , Petr Vymola 1 , Ivana Matrasova 1 , Lucie Sromova 1 , Marek Hilser 1 , Pavel Sacha 2 3 , Jiri Schimer 2 , Vladimir Subr 4 , Karel Ulbrich 4 , Jan Konvalinka 2 , Aleksi Sedo 1
  1. Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, Prague, Czech Republic
  2. Institute of Organic Chemistry and Biochemistry, AS CR, v.v.i., Prague, Czech Republic
  3. Faculty of Science, Charles University, Prague, Czech Republic
  4. Institute of Macromolecular Chemistry, AS CR, v.v.i., Prague, Czech Republic

Glioblastomas (GBMs) are the most common primary brain tumors with dismal prognosis and limited therapeutic options. We have recently shown that a membrane bound serine protease fibroblast activation protein (FAP) is expressed by glioma and stromal cells in GBM. We aim to elucidate the role of FAP and FAP+ stromal cells in GBM microenvironment, and to design novel approaches for FAP targeting.

Human glioma cell lines, primary cultures, FAP transfectants, an orthotopic xenotransplantation model, FAP+ stromal cells isolated by MACS and their conditioned media were used to evaluate the role of FAP and FAP+ stromal cells in GBM. HPMA copolymer carriers conjugated with a highly specific FAP inhibitor as a targeting ligand (anti-FAP iBodies) were prepared and characterized using biochemical and cell based assays.

We show that soluble factors released from GBM derived FAP+ stromal cells promote the migration of glioma and endothelial cells. In glioma cells, transgenic FAP expression does not increase their malignant potential; similarly a low molecular weight FAP inhibitor does not influence the growth, migration and invasion of FAP+ glioma cell lines. Additionally we prepared and characterized the properties and the possible applications of anti-FAP iBodies. These compounds specifically interacted with FAP and FAP expressing cells, and showed potential for targeted delivery.

In summary, FAP is upregulated in GBM and FAP+ stromal cells may contribute to GBM invasive growth and angiogenesis. The direct role of FAP in promoting glioma cell aggressiveness remains unclear. Thus, approaches exploiting its selective expression in GBM microenvironment rather than directly inhibiting its function might represent a novel strategy for glioma treatment. Our anti-FAP iBodies can be used for such specific targeting of FAP expressing cells and are candidate molecules for developing new tools for targeted delivery into the GBM microenvironment.

Acknowledgement: Ministry of Health of CR grant 15-31379A and Progres Q28/1LFUK.

  1. Busek, P., E. Balaziova, I. Matrasova, et al. (2016). "Fibroblast activation protein alpha is expressed by transformed and stromal cells and is associated with mesenchymal features in glioblastoma." Tumour Biol 37(10): 13961-13971.
  2. Sacha, P., T. Knedlik, J. Schimer, et al. (2016). "iBodies: Modular Synthetic Antibody Mimetics Based on Hydrophilic Polymers Decorated with Functional Moieties." Angew Chem Int Ed Engl 55(7): 2356-2360.