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TAR1, a human anti-p53 single-chain antibody, restores tumor suppressor function to mutant p53 variants
Sara Orgad1, Hemi Dimant, Eyal Dor-On
1Department of Molecular Microbiology and Biotechnology, Tel-Aviv University, Ramat Aviv, Tel-Aviv, Israel. orgad@post.tau.ac.il
Abstract:
The tumor suppressor gene p53 is mutated in more than half of human tumors. One important characteristic of p53 mutants is their accumulation in the nucleus of cancer cells. Thus, reactivation of mutant p53 proteins may trigger massive apoptosis in tumor cells. Pharmacologic methods are currently under development to induce mutant p53 proteins to resume their wild-type function. We have identified a human single-chain Fv fragment, designated as transcriptional transactivation and apoptosis restoring (TAR1), which specifically and with high affinity binds to mutant p53 and restores its wild-type active conformation. Binding of TAR1 to mutant p53 induced transcriptional transactivation of p53 target genes and down-regulation of mutant p53 transcriptional target genes. TAR1 treatment induced apoptosis in a variety of cell lines endogenously expressing p53 carrying different point mutations DNA contact or structural p53 mutants. Moreover, in an animal model of mice carrying human xenografts, TAR1 induced tumor regression with no apparent deleterious side effects. Thus, it may be considered as a potential candidate for anticancer treatment, targeting tumors with mutant p53.
Insights
Researchers identified a novel therapy, transcriptional transactivation and apoptosis restoring (TAR1), that restores wild-type function to mutant p53 proteins, inducing cancer cell death and tumor regression.
Area of Science:
- Oncology
- Molecular Biology
- Biotechnology
Background:
- The tumor suppressor gene p53 is frequently mutated in human cancers.
- Mutant p53 proteins accumulate in cancer cells, contributing to tumor progression.
- Reactivating mutant p53 to its wild-type function holds therapeutic potential for inducing cancer cell apoptosis.
Purpose of the Study:
- To identify and characterize a novel agent capable of restoring wild-type function to mutant p53.
- To evaluate the therapeutic efficacy of this agent in preclinical cancer models.
Main Methods:
- Identification of a human single-chain Fv fragment, TAR1, that specifically binds mutant p53.
- Assessment of TAR1's ability to restore p53 wild-type conformation and transcriptional activity.
- Evaluation of TAR1-induced apoptosis in various cancer cell lines.
- Testing TAR1 efficacy in a xenograft mouse model.
Main Results:
- TAR1 binds mutant p53 with high affinity, restoring its wild-type active conformation.
- TAR1 treatment reactivated p53 target gene transcription and suppressed mutant p53 target genes.
- TAR1 induced apoptosis in diverse cancer cell lines with different p53 mutations.
- TAR1 treatment led to significant tumor regression in a xenograft mouse model without apparent side effects.
Conclusions:
- TAR1 is a promising therapeutic candidate for targeting cancers with mutant p53.
- Restoring p53 function via TAR1 effectively induces cancer cell death and tumor regression.
- TAR1 represents a potential novel anticancer strategy for mutant p53-driven tumors.
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