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Targeting Transcription Factors ATF5, CEBPB and CEBPD with Cell-Penetrating Peptides to Treat Brain and Other Cancers
Lloyd A Greene1, Qing Zhou1, Markus D Siegelin1
1Department of Pathology and Cell Biology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA.
Abstract:
Developing novel therapeutics often follows three steps: target identification, design of strategies to suppress target activity and drug development to implement the strategies. In this review, we recount the evidence identifying the basic leucine zipper transcription factors ATF5, CEBPB, and CEBPD as targets for brain and other malignancies. We describe strategies that exploit the structures of the three factors to create inhibitory dominant-negative (DN) mutant forms that selectively suppress growth and survival of cancer cells. We then discuss and compare four peptides (CP-DN-ATF5, Dpep, Bpep and ST101) in which DN sequences are joined with cell-penetrating domains to create drugs that pass through tissue barriers and into cells. The peptide drugs show both efficacy and safety in suppressing growth and in the survival of brain and other cancers in vivo, and ST101 is currently in clinical trials for solid tumors, including GBM. We further consider known mechanisms by which the peptides act and how these have been exploited in rationally designed combination therapies. We additionally discuss lacunae in our knowledge about the peptides that merit further research. Finally, we suggest both short- and long-term directions for creating new generations of drugs targeting ATF5, CEBPB, CEBPD, and other transcription factors for treating brain and other malignancies.
Insights
Novel peptide drugs targeting transcription factors ATF5, CEBPB, and CEBPD show promise for treating brain cancers. These drugs, including ST101 in clinical trials, effectively suppress tumor growth and survival with demonstrated safety.
Area of Science:
- Oncology
- Molecular Biology
- Drug Development
Background:
- Basic leucine zipper transcription factors ATF5, CEBPB, and CEBPD are implicated as targets in various malignancies.
- Developing effective therapeutics requires target identification, strategy design, and drug development.
Purpose of the Study:
- To review evidence identifying ATF5, CEBPB, and CEBPD as targets for brain and other cancers.
- To describe dominant-negative (DN) mutant strategies and peptide drugs for cancer therapy.
- To discuss the efficacy, safety, and mechanisms of action of these peptide drugs.
Main Methods:
- Review of existing literature on transcription factor targets and therapeutic strategies.
- Description of dominant-negative mutant design and cell-penetrating peptide drug development.
- Analysis of preclinical and clinical data for peptide drugs (CP-DN-ATF5, Dpep, Bpep, ST101).
Main Results:
- Four peptide drugs were developed by combining DN sequences with cell-penetrating domains.
- These peptide drugs demonstrated efficacy and safety in suppressing growth and survival of brain and other cancers in vivo.
- ST101 is currently undergoing clinical trials for solid tumors, including glioblastoma (GBM).
Conclusions:
- Targeting ATF5, CEBPB, and CEBPD with DN peptides represents a viable therapeutic strategy for malignancies.
- Peptide drugs show potential for treating brain and other cancers, with ST101 progressing to clinical trials.
- Further research into peptide mechanisms and combination therapies can lead to next-generation cancer drugs.
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