Drugs Treatment and Gene Expression Analysis to Target Glioblastoma Cancer Stem Cells: Towards a Personalized Medicine for Brain Cancer (GBM)

Our study aimed to develop targeted strategies against Notch1, EGFR and PDGFR, which have a pivotal role in stemness and invasiveness of both GBM CSC( CSC-­-c) and those derived from the peritumoral tissue (p-­-CSC). We first performed an analysis of the expression profile of these receptors on the two classes of CSC and then we conducted pharmacological experiments and by using small inhibitory synthetic molecules to study the biological effects. We evaluated the combinatorial effects of anti-EGFR/Notch1 or anti-EGFR/PDGFR on survival and invasiveness of CSC. We also evaluated the effects of silencing of PDGFRalpha expression on stemness angiogenesis, invasiveness and differentiation of GBM CSC. Our results show for the first time that the axis PDGFR alpha/ PDGFAA is a possible regulator of the interaction between STAT3 and the oncosuppressor RB1 in GBM CSC. We have shown that exposure of GBM CSC to PDGFAA induced the up-regulation of phosphorylation of STAT3 Tyr 705 in conjunction with a decrease of the Retinoblastoma protein into its active hypophosphorylated form. Evidence reported in the literature have shown that phosphorylation of STAT3 is persistent in the GBM and is associated with a poor prognosis and also the pathway of RB1 is among the most altered signaling pathways in the GBM. For this reason we think that the newly discovery of PDGFR / STAT3 / RB1 regulatory axis, could represent a potential therapeutic target for the treatment of GBM.