2025 · Wang et al. Journal of Nanobiotechnology · BioMed Central · added 2026-04-20
Background
Patients with colorectal cancer (CRC) harboring BRAF mutation have a poor prognosis. The median survival time for patients with advanced BRAFV600E-mutant CRC is only appr Show more
Background
Patients with colorectal cancer (CRC) harboring BRAF mutation have a poor prognosis. The median survival time for patients with advanced BRAFV600E-mutant CRC is only approximately one year. Owing to the insensitivity to standard chemotherapy, there are still no effective and highly specific treatment strategies available in clinical practice for CRC patients with BRAF mutation. Therefore, targeting the BRAFV600E mutation site, researching and exploring novel targeted therapies are essential to improve the survival rate of patients with this CRC subtype.
Aim
This study aims to develop a precise therapeutic system for BRAFV600E CRC, based on the carrier properties of extracellular vesicles (EVs) and gene therapy targeting BRAFV600E.
Method
We first obtained engineered cells capable of stably producing EVs loaded with BRAFV600E nucleic acid drugs (siBRAFV600E). Next, BRAFV600E-mutant and wild-type CRC cell lines, as well as corresponding subcutaneous and metastasis models, were used to evaluate the therapeutic efficacy of EVs-siBRAFV600E and explored the mechanism. Notably, patient-derived xenograft (PDX) models, which share the same molecular characteristics, pathological features, and heterogeneity as patients do, were utilized to further explore the therapeutic efficacy and mechanisms.
Result
EVs-siBRAFV600E specifically inhibited BRAFV600E CRC but didn't affect BRAF wild-type CRC in vitro and vivo. EVs-siBRAFV600E exerts its therapeutic effect by regulating the MEK1/2-ERK1/2 pathway, and it has demonstrated excellent therapeutic efficacy in PDX models.
Conclusion
The therapeutic EVs we constructed are effective and specific for the BRAFV600E-mutant CRC. This study provides a novel strategy for the treatment of CRC patients with BRAFV600E mutation. Show less
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 re Show more
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.
Citation: Greene, L.A.; Zhou, Q.;
Siegelin, M.D.; Angelastro, J.M.
Targeting Transcription Factors ATF5, Show less