Biomarkers Predict p53 Gene Therapy Efficacy in Recurrent Squamous Cell Carcinoma of the Head and Neck

Abstract

Purpose: Most recurrent squamous cell carcinomas of the head and neck have a dysfunctional p53 tumor suppressor pathway contributing to treatment resistance. We hypothesized that tumor p53 biomarkers may predict the efficacy of normal p53 delivered by gene therapy in these patients. Experimental Design: Tumor p53 biomarkers were evaluated in 116 patients, including 29 treated with methotrexate in a phase III randomized controlled trial. Profiles favorable for p53 gene therapy efficacy were hypothesized to have either normal p53 gene sequences or low-level p53 protein expression, whereas unfavorable p53 inhibitor profiles were predicted to have high-level expression of mutated p53 that can inhibit normal p53 protein function. Results: A statistically significant increase in tumor responses was observed for patients with favorable p53 efficacy profiles compared with those with unfavorable p53 inhibitor profiles [phase I/II trials: favorable (34 of 46, 74%) versus unfavorable (1 of 5, 20%), P = 0.0290; phase III trial: favorable (17 of 24, 71%) versus unfavorable (2 of 11, 18%), P = 0.0088]. In the phase III trial, there was statistically significant increased time to progression (TTP) and survival following p53 gene therapy in patients with favorable p53 profiles compared with unfavorable p53 inhibitor profiles (median TTP, 2.7 months versus 1.4 months, P = 0.0121; median survival, 7.2 months versus 2.7 months, P < 0.0001). In contrast, the biomarker profiles predictive of p53 gene therapy efficacy did not predict methotrexate response, TTP, or survival outcomes. Conclusions: These results indicate that tumor p53 biomarker profiles may predict p53 gene therapy efficacy in recurrent squamous cell carcinoma of the head and neck. (Clin Cancer Res 2009;15(24):7719-25)

Prognostic Significance of Truncating TP53 Mutations in Head and Neck Squamous Cell Carcinoma

“…Recent trials have shown success in patients with recurrent HNSCCs (38). Interestingly, tumors showing a TP53 mutation and lack of p53 expression by immunohistochemical staining had a higher chance of response when compared with tumors showing a mutation with expression of p53 (39). In the report of that study, no details on the type of TP53 mutation were described, but it is likely that the tumors without p53 expression are the ones that have a truncated TP53 mutation.…”

Oncolytic Adenovirus Coding for Granulocyte Macrophage Colony-Stimulating Factor Induces Antitumoral Immunity in Cancer Patients

“…Virus administration was performed by ultrasound-guided intratumoral or intracavitary (ovarian cancer, mesothelioma) injection, and one fifth of the dose was given i.v. The starting dose of 8 × 10 9 viral particles (VP) was chosen based on safety results published by others (1,(5)(6)(7)(8)(9)21). Subsequently, the dose was escalated to 1 × 10 , and 4 × 10 11 (Table 2).…”

“…Adenoviruses are among the most advanced cancer gene therapy platforms and their safety and efficacy has been validated in several randomized studies (6)(7)(8)(9). With regard to oncolytic adenoviruses, a few dozen trials have been performed and although there is anecdotal evidence of activity in most trials, overall single-agent efficacy has been nonimpressive.…”

Therapeutic Targeting of p53-Mediated Apoptosis Pathway in Head and Neck Squamous Cell Carcinomas: Current Progress and Challenges

“…Loss of heterozygosity 17p and mutations of the p53 have been detected in approximately half of all primary and most of recurrent cases of HNSCC (Nemunaitis et al, 2009;Gasco & Crook, 2003;Osman et al, 2002;Taylor et al, 1999). Studies of HNSCC and cell lines suggested that after mutation of one TP53 allele, the remaining wild-type allele is deleted and accordingly the mutant phenotype expressed (Nylander et al, 2000 as cited in Yin et al, 1999).…”