Regulated ATF5 loss-of-function in adult mice blocks formation and causes regression/eradication of gliomas

Area of Science:

• Neuro-oncology
• Cancer biology
• Molecular genetics

Background:

• Glioblastomas are highly aggressive and currently incurable brain tumors.
• The transcription factor ATF5 (activating transcription factor 5) is essential for glioblastoma cell survival.
• The in vivo efficacy of targeting ATF5 in gliomas remains uninvestigated.

Purpose of the Study:

• To investigate whether inhibiting ATF5 function can prevent or induce regression/eradication of malignant gliomas in vivo.
• To establish and utilize a novel mouse model for spatiotemporal control of ATF5 inhibition in gliomas.

Main Methods:

• Developed bi-transgenic mice with doxycycline-inducible dominant-negative ATF5 (d/n-ATF5) expression under the glial fibrillary acidic protein (GFAP) promoter.
• Induced endogenous gliomas using retroviral delivery of platelet-derived growth factor (PDGF)-B and p53-short hairpin RNA (shRNA).
• Administered doxycycline to regulate d/n-ATF5 expression before or after glioma induction.

Main Results:

• Induction of d/n-ATF5 prior to glioma induction significantly reduced tumor formation rates.
• Post-tumorigenesis induction of d/n-ATF5 led to the regression or eradication of detectable gliomas in all assessed mice (n=24).
• Interference with ATF5 function did not cause apparent damage to normal brain cells.

Conclusions:

• Targeting ATF5 is a viable therapeutic strategy for glioblastoma.
• Inhibition of ATF5 can both prevent glioma development and induce regression of established tumors.
• This approach offers a potential treatment for malignant gliomas with a favorable safety profile for normal brain tissue.