Abstract 4095: Stimulation of blood based biomarker release in primary tumor models of the head and neck
Authors: Mariana Brait, Ethan Soudry, Mamoru Uemura, Christina Michailidi, Joseph A. Califano, Yonggang Zhang, Theodore L. DeWeese, David Sidransky
Journal: Cancer Research (2012)

Abstract Approximately 50,000 head and neck cancers (HNC) occur in the United States per year and are responsible for 11,000 deaths. Identification of early detection tumor biomarkers in bodily fluids has been the goal of many studies in recent years, however none have gained wide clinical acceptance. New approaches are needed to improve detection of biomarkers with higher sensitivity and specificity for HNC. Epigenetic changes, such as DNA methylation, are hallmarks of cancer and are potential biomarker candidates. Promoter methylation of DCC, KIF1A and EDNRB were shown by our group to be cancer specific in HNC. Proof of principal of techniques enhancing detection sensitivity in an animal model may allow us, in the future, to translate our results to human clinical trials. We aim to study methods to enhance the sensitivity of blood based biomarker detection in a head and neck tumorgraft model. The model proposed is based on acquisition of human HNC tumor tissue and implantation into immunodeficient mice. We exposed these mice to various stimulations that consist of low dose treatments, which would not be expected to cause much cell death or damage, nor considerable adverse effects. They comprise Radiation (1Gy), Cisplatin (2.5μg/g), Taxol (25μg/g), Cetuximab (15μg/g), Erlotinib (10μg/g). Every group consisted of 7 mice implanted with the same tumor that was grown until the same size: one mouse for each treatment and two control mice. Blood from a mouse without tumor was first analyzed to confirm that our detection was restricted to human DNA sequences. Thus far we have analyzed 5 tumors (5 groups). Following the exposures, promoter methylation levels of DCC, KIF1A and EDNRB were evaluated by quantitative methylation specific PCR (QMSP) in the tumor as well as in the serum. Although, high levels of methylation were observed in the tumors, we were not able to detect hypermethylation in the bloodstream of non-stimulated animals. In one of our groups, the mouse stimulated with Taxol showed sufficient biomarker release into the bloodstream to provide signal amplification of all 3 genes analyzed, under very stringent conditions of qPCR analysis. The corresponding tumor showed high levels of promoter methylation of DCC, KIF1A and EDNRB, however these were undetectable in the non-stimulated group, or those mice stimulated with any condition other than Taxol. We did not observe any changes in any of the other four groups analyzed; no epigenetic alteration was detectable in any serum samples, although observed in the tumor tissue. These preliminary data suggest that low dose of Taxol was able to increase the concentration of biomarkers circulating in the blood. Clinical applications of biomarker release include monitoring patients that are at high risk for disease recurrence, and detecting the presence of cancer cells before clinical symptoms appear. We will now expand our study to explore other experimental variables that facilitate biomarker release. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4095. doi:1538-7445.AM2012-4095