A PDGFRα-driven mouse model of Glioblastoma reveals a Stathmin1-mediated mechanism of sensitivity to Vinblastine. A PDGFRα-driven mouse model of Glioblastoma reveals a Stathmin1-mediated mechanism of sensitivity to Vinblastine

Glioblastoma multiforme (GBM) is an aggressive primary brain cancer that includes focal amplification of PDGFRα and for which there are no effective therapies. Herein, we report the development of a genetically engineered mouse model of GBM based on autocrine, chronic stimulation of PDGFRα and the analysis of GBM signaling pathways using proteomics. We discovered the tubulin-binding protein Stathmin1 (STMN1) as a PDGFRα phospho-regulated target and that this mis-regulation conferred selective sensitivity to vinblastine (VB) cytotoxicity. Treatment of PDGFRα GBMs with VB in mice drastically prolonged survival and was dependent on STMN1. Our work provides a rationale for evaluating genotype-specific anti-microtubule drugs as cancer treatment in select GBM patient populations. Overall design: Total RNA was isolated from flash frozen tumors freshly excised from mice using Qiagen RNeasy RNA Isolation Kit. Gene expression analysis was conducted using the GeneChip® Mouse 2.0 ST Array (Affymetrix) at the Yale Center for Genome Analysis. Three biological replicates were profiles for each condition