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Regression/eradication of gliomas in mice by a systemically-deliverable ATF5 dominant-negative peptide
Charles C Cates1,2, Angelo D Arias1,3, Lynn S Nakayama Wong1
1Department of Molecular Biosciences, University of California, Davis School of Veterinary Medicine, Davis, CA, USA.
Abstract:
Malignant gliomas have poor prognosis and urgently require new therapies. Activating Transcription Factor 5 (ATF5) is highly expressed in gliomas, and interference with its expression/function precipitates targeted glioma cell apoptosis in vitro and in vivo. We designed a novel deliverable truncated-dominant-negative (d/n) form of ATF5 fused to a cell-penetrating domain (Pen-d/n-ATF5-RP) that can be intraperitoneally/subcutaneously administered to mice harboring malignant gliomas generated; (1) by PDGF-B/sh-p53 retroviral transformation of endogenous neural progenitor cells; and (2) by human U87-MG xenografts. In vitro Pen-d/n-ATF5-RP entered into glioma cells and triggered massive apoptosis. In vivo, subcutaneously-administered Pen-d/n-ATF5-RP passed the blood brain barrier, entered normal brain and tumor cells, and then caused rapid selective tumor cell death. MRI verified elimination of retrovirus-induced gliomas within 8-21 days. Histopathology revealed growth-suppression of intracerebral human U87-MG cells xenografts. For endogenous PDGF-B gliomas, there was no recurrence or mortality at 6-12 months versus 66% mortality in controls at 6 months. Necropsy and liver-kidney blood enzyme analysis revealed no adverse effects on brain or other tissues. Our findings thus identify Pen-d/n-ATF5-RP as a potential therapy for malignant gliomas.
Insights
A novel therapy targeting Activating Transcription Factor 5 (ATF5) effectively eliminated malignant gliomas in mice. This treatment, Pen-d/n-ATF5-RP, induced selective tumor cell death with no observed adverse effects.
Area of Science:
- Neuro-oncology
- Molecular Biology
- Drug Development
Background:
- Malignant gliomas exhibit poor prognosis, necessitating innovative therapeutic strategies.
- Activating Transcription Factor 5 (ATF5) is upregulated in gliomas and is a viable therapeutic target.
- Targeting ATF5 can induce apoptosis in glioma cells both in vitro and in vivo.
Purpose of the Study:
- To develop and evaluate a novel, deliverable dominant-negative ATF5 construct for malignant glioma treatment.
- To assess the efficacy and safety of Pen-d/n-ATF5-RP in preclinical glioma models.
Main Methods:
- Designed a cell-penetrating dominant-negative ATF5 construct (Pen-d/n-ATF5-RP).
- Administered Pen-d/n-ATF5-RP intraperitoneally/subcutaneously in mice with PDGF-B/sh-p53-induced gliomas and U87-MG xenografts.
- Evaluated therapeutic effects using MRI, histopathology, and survival analysis.
Main Results:
- Pen-d/n-ATF5-RP demonstrated effective penetration into glioma cells and induced significant apoptosis in vitro.
- In vivo, Pen-d/n-ATF5-RP crossed the blood-brain barrier, selectively targeting and eliminating tumor cells.
- Complete elimination of retrovirus-induced gliomas was observed within 8-21 days; significant survival benefit was noted in xenograft models.
- No adverse effects were detected in brain or other organs through necropsy and blood enzyme analysis.
Conclusions:
- Pen-d/n-ATF5-RP is a promising therapeutic agent for malignant gliomas.
- The compound exhibits selective tumor targeting and efficacy across different glioma models.
- The therapy demonstrates a favorable safety profile, warranting further clinical investigation.
