Targeting the p53 pathway for reversal of oral premalignancy

University Of Texas Md Anderson Can Ctr, Houston TX

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): Premalignancies of the oral cavity and oropharynx have a high risk of progression to invasive squamous carcinomas. Our biochemoprevention studies suggest that these sites are tremendously resistant to our most active agents, including cis-retinoic acid, interferonalpha and alpha-tocopherol; while clinical and pathologic response rates approach 80% in the larynx, there is a response rate of only 15% in the oral cavity. We hypothesize that over-expression of the wild-type p53 tumor suppressor gene in premalignant cells will induce apoptosis, allowing for repopulation with epithelial cells of normal genotype and phenotype. Clinical studies show that adenovirus-mediated p53 gene transfer induces apoptosis in squamous cell carcinoma; apoptosis is observed without dose-limiting toxicity and independent of endogenous p53 genotype; importantly, non-malignant fibroblasts and epithelial cells remain unaffected. To address the hypothesis that over-expression of wild-type p53 will reverse the malignant process, we propose to conduct a clinical trial with an adenovirus vector encoding Ad5CMVp53 (RPR/INGN 201) administered via intramucosal injection and multiple oral rinses to patients with oral premalignant carcinoma. The study will be conducted as a Phase I/II study, with determination of maximum tolerated dose and effect of p53 gene transfer in reversing the clinical and histologic appearance of oral and oropharyngeal premalignancies to be evaluated in Specific Aim 1. In Specific Aim 2, we will determine the effect of p53 gene transfer on expression of molecular biomarkers of p53 activity in preneoplastic lesions of the oral cavity and oropharynx. We will determine the relationship between expression of the Coxsackie adenovirus receptor (CAR) expression and p53 induction in response to adenovirus p53 gene transfer. Other biomarkers to be studied include MDM2, MDMX, ARF, bcl-2, bax, and apoptotic index. In Specific Aim 3, we will determine the role of the p53 inhibitors MDM2 and MDMX in the development of SCCHN and in response to adenovirus p53 gene transfer; for these studies, we will correlate MDM2 and MDMX levels with p53 levels in tissue biopsies from patients with oral premalignancies enrolled in the clinical trial and in archival tissue samples from patients with SCCHN. Finally, we will conduct laboratory studies to begin to evaluate the therapeutic potential of alterations in MDM2 and/or MDMX in SCCHN. The data collected in this project will expand our understanding of the role of p53 and the p53 inhibitors MDM2 and MDMX in progression of oral cavity and oropharynx premalignancies and development of squamous cell carcinoma of the head and neck.