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Cancer is a group of diseases characterized by uncontrolled growth and spread of abnormal cells. The underlying cause of cancer relates to the cell cycle, during which DNA is replicated. Cancer cells accumulate DNA mutations that help them acquire cancerous features, such as evading cell death and indefinite growth [1]. If these DNA mutations are in coding regions, they are translated to mutated proteins. The epitopes that contain these mutations are called neoantigens. Neoantigens are highly tumor-specific and can be targeted with immunotherapies [2]. During cell division, tumor suppressor genes play a role in the case of DNA damage or replication errors. The p53 protein is a tumor suppressor gene product that prevents tumor formation by activating processes that block cell division when DNA damage has occurred [3]. Mutant p53 does not effectively bind DNA or activate the production of proteins necessary for the stop signal. This project explored a hypothesis that a set of distinct p53 protein mutations can be selected to serve as potential targets for cancer immunotherapy and vaccines by using immunoinformatics predictive analysis tools. By comparing these potential targets with experimental results, we can predict epitopes that may serve as neoantigen targets for immunotherapy. We identified candidate immunogenic epitopes using the NCI’s TP53 Database (NCI DB - tp53.isb-cgc.org), Cancer Epitope Database and Analysis Resource (CEDAR - cedar.iedb.org), and a powerful new bioinformatics tool (nextgen-tools.iedb.org/) [4] hosted by Immune Epitope Database (IEDB - iedb.org) and CEDAR. Comparing predicted epitopes to highly mutable regions of p53 in tumor variants from NCI DB revealed areas of overlap that may be priority candidate epitopes for immunotherapy. Experimental data from CEDAR tested the immunogenicity of normal and mutated protein versions to help avoid harmful cross-reactions. These results help predict cancer epitope amino acid sequences relevant to understanding the immune system's role in cancer progression, prevention, and treatment. These studies also set the stage for important subsequent undergraduate research projects to further characterize predicted cancer neoantigens.
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This content will become publicly available on April 16, 2027
A Personalized Therapeutic Approach for Liver Cancers Expressing the African-Centric P47S Variant of TP53
Abstract The P47S missense germline variant of TP53 exists in approximately 2% of Americans of African descent and may account for the increased cancer risk and poorer response to therapy evident in African-descent populations. In this work, we sought to identify personalized therapeutic approaches for cancer containing the P47S variant, with a focus on the most common cancer evident in the P47S mouse, liver cancer. We identify the microtubule-targeting agents lexibulin, colchicine, and combretastatin A-4 as three compounds that bind to the colchicine-binding pocket of the α/β-tubulin dimer, and which show increased efficacy in a P47S liver cancer cell line compared with parental cells with wild-type p53. We find evidence for an unusual mechanism underlying this increased efficacy: Our data indicate that the P47S variant shows increased ability to bind to the peptidyl-prolyl isomerase PIN1; this leads to decreased PIN1–cyclin D1 complexes in P47S cells, along with increased cell-cycle arrest in response to lexibulin. Implications:These findings support the growing literature that particular mutant forms of TP53 may have specific therapeutic vulnerabilities that can be targetable; improved understanding of these unique vulnerabilities can lead to improved understanding of p53 function.
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- PAR ID:
- 10680173
- Publisher / Repository:
- American Association for Cancer Research (AACR)
- Date Published:
- Journal Name:
- Molecular Cancer Research
- ISSN:
- 1541-7786
- Page Range / eLocation ID:
- OF1 to OF12
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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