A bio-adjuvant combination approach for the chemoprevention of oral cancer: Preclinical trials
Bothwell, Katelyn Ann DiBernardo
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Purpose: Epidermal growth factor receptor (EGFR) activation is an early event in head and neck carcinogenesis. As a result, targeting EGFR has become an attractive strategy for chemoprevention. We examined the impact of using calcitriol, the active metabolite of vitamin D, as a bio-adjuvant in combination with the EGFR inhibitor, erlotinib, in the prevention of oral cancer. Methods: Experimental studies were conducted in the 4-nitroquinoline-1-oxide (4NQO) oral carcinogenesis model to study the chemopreventive efficacy of calcitriol and erlotinib treatment, as single agents and in combination. Imaging results were correlated with histology and immunoblotting analyses to assess the impact of the combination regimen on oral carcinogenesis. Incidence of tumor development and evidence of disease progression were utilized as measures of response. Body weight measurements were acquired throughout the study as an assessment of systemic toxicity and echocardiography was performed to assess the effect of combination treatment on cardiac function. Results: All control animals showed visible lesions on MRI examination at 26 weeks. Combination treatment was well tolerated and was not associated with any toxicity. MRI revealed a reduction in tumor incidence and tumor volume following treatment with erlotinib alone and in combination. Histopathologic evaluation revealed a reduction in the degree of dysplasia with combination treatment. Immunoblot analysis of whole tongue extracts revealed decreased expression of phospho-EGFR and phospho-Akt with the combination treatment. Conclusion: These results demonstrate the potential of combining calcitriol with erlotinib in the chemoprevention of head and neck cancer. Further investigation into the optimal schedule and dosing of this combination strategy is necessary. In addition, future studies examining the use of less calcemic vitamin D 3 analogues and dietary vitamin D against this disease is warranted.