TMOD-29. A MOUSE MODEL OF FGFR3-TACC3 UNCOVERS MECHANISMS OF GLIOMAGENESIS AND MAINTENANCE

Glioblastoma harboring Fibroblast Growth Factor Receptor 3 (FGFR3)-Transforming Acidic Coiled-Coil containing 3 (TACC-3) (FGFR3-TACC3) fusion is a distinct molecular subclass of tumors that can be targeted by FGFR kinase inhibitors. We generated a knock-in mouse in which the expression of FGFR3-TACC3 is doxycycline inducible and reversible. The tetO-FGFR3-TACC3-IRES-GFP cassette was placed into the Rosa26 locus and the FGFR3-TACC3 knock-in strain was intercrossed with GFAP-rtTA*M2 mice to trigger expression of the tetracycline transactivator (and the fusion gene) from the GFAP promoter. To recapitulate the genetic lesions that are more frequently associated with FGFR3-TACC3 in human glioblastoma, we also intercrossed the tetO-FGFR3-TACC3-IRES-GFP;GFAP-rtTA*M2 mice with TP53+/-or Ink4A+/-mouse strains. Both strains developed aggressive and infiltrating gliomas within 90 days after induction of FGFR3-TACC3 by doxycycline containing diet. Tumors occurred with a prevalence of ~50% and were found almost exclusively at two brain locations: the lateral septum and the neuro-epithelium adjacent to the fimbria of the hippocampus, thus recapitulating the restricted expression of endogenous FGFR3 in the ventral telencephalon and ganglionic eminence during development. The FGFR3-TACC3-positive glioma resembled human glioblastoma as they exhibited marked invasiveness and vascularization, elevated proliferative index and positivity for Nestin and GFAP. Rapid tumor progression caused appearance of neurological symptoms and death within few weeks. Doxycycline withdrawal from the diet of mice diagnosed with brain tumors by MRI resulted in rapid loss of FGFR3-TACC3 from glioma cells, marked inhibition of tumor growth with essentially complete glioma regression in some cases and recovery of general and neurological clinical symptoms. Our findings validate FGFR3-TACC3 as powerful oncogene that drives development of high-grade glioma from distinct areas of the brain. They also provide an accurate pre-clinical model in which glioma maintenance requires continuous expression of the fusion gene, thus supporting therapeutic targeting of the fusion protein in patients with FGFR3-TACC3-positive glioblastoma.