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Treatment of terminal peritoneal carcinomatosis by a transducible p53-activating peptide
Eric L Snyder1, Bryan R Meade, Cheryl C Saenz
1Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
Abstract:
Advanced-stage peritoneal carcinomatosis is resistant to current chemotherapy treatment and, in the case of metastatic ovarian cancer, results in a devastating 15%-20% survival rate. Therapeutics that restore genes inactivated during oncogenesis are predicted to be more potent and specific than current therapies. Experiments with viral vectors have demonstrated the theoretical utility of expressing the p53 tumor suppressor gene in cancer cells. However, clinically useful alternative approaches for introducing p53 activity into cancer cells are clearly needed. It has been hypothesized that direct reactivation of endogenous p53 protein in cancer cells will be therapeutically beneficial, but few tests of this hypothesis have been carried out in vivo. We report that a transducible D-isomer RI-TATp53C' peptide activates the p53 protein in cancer cells, but not normal cells. RI-TATp53C' peptide treatment of preclinical terminal peritoneal carcinomatosis and peritoneal lymphoma models results in significant increases in lifespan (greater than 6-fold) and the generation of disease-free animals. These proof-of-concept observations show that specific activation of endogenous p53 activity by a macromolecular agent is therapeutically effective in preclinical models of terminal human malignancy. Our results suggest that TAT-mediated transduction may be a useful strategy for the therapeutic delivery of large tumor suppressor molecules to malignant cells in vivo.
Insights
A novel peptide reactivates the p53 tumor suppressor protein specifically in cancer cells. This approach significantly increased lifespan and led to disease-free survival in preclinical models of advanced cancers.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Advanced-stage peritoneal carcinomatosis, common in ovarian cancer, has poor survival rates (15-20%) due to chemotherapy resistance.
- Restoring inactivated tumor suppressor genes like p53 is a promising therapeutic strategy.
- Current methods for delivering p53 activity, such as viral vectors, have limitations.
Purpose of the Study:
- To investigate the therapeutic potential of reactivating endogenous p53 protein in cancer cells.
- To evaluate a novel transducible peptide, RI-TATp53C', for its ability to activate p53 in vivo.
- To assess the efficacy of this approach in preclinical models of advanced peritoneal malignancy.
Main Methods:
- Development of a transducible D-isomer RI-TATp53C' peptide designed to activate p53.
- Treatment of preclinical models of terminal peritoneal carcinomatosis and peritoneal lymphoma with the RI-TATp53C' peptide.
- Assessment of p53 activation specifically in cancer cells versus normal cells.
- Evaluation of survival rates and disease-free outcomes in treated animal models.
Main Results:
- The RI-TATp53C' peptide successfully activated endogenous p53 protein in cancer cells but not in normal cells.
- Treatment led to a significant increase in lifespan (over 6-fold) in preclinical models.
- A notable proportion of animals achieved disease-free status following peptide treatment.
Conclusions:
- Specific activation of endogenous p53 by the RI-TATp53C' peptide is a therapeutically effective strategy for advanced cancers.
- TAT-mediated transduction offers a viable approach for delivering large tumor suppressor molecules to malignant cells.
- This proof-of-concept study supports further development of peptide-based p53 reactivation therapies.
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