Abstract
LB-151
Multidimensional liquid chromatography - tandem mass spectrometry has been used for the analysis of biological samples labeled with isobaric mass tags (iTRAQ) to identify and quantify differentially expressed proteins in human head-and-neck/oral squamous-cell carcinomas (HNOSCCs) and Oral premalignant lesions (OPLs) for cancer biomarker discovery (Ralhan et al. Mol. Cell. Proteomics 2008, in minor revision). We identified a panel of three potential cancer biomarkers (PCMs), two of which, PCM 69 and PCM 70, scored the highest in sensitivity and specificity among all differentially expressed proteins. Here, we report the prognostic significance of these PCMs for HNOSCCs. Fifty-one HNOSCC tissue blocks were retrieved from the research tissue bank for immunohistopathological analysis. The 51 HNOSCC patients were investigated and evaluated in the head-and-neck follow-up clinic. Patients with T1 and T2 tumors were treated with radical radiotherapy or surgery alone, while the majority of patients with T3 and T4 staging were treated with a combination of radical surgery followed by postoperative radical radiotherapy and monitored for a maximum period of 42 months. Kaplan-Meier survival analysis revealed reduced disease-free survival (DFS) for HNOSCC patients overexpressing PCM 69, median DFS 19 months as compared to 38 months in HNOSCC patients who did not show overexpression (p= 0.06).[[Unsupported Character - ]] Patients with PCM 70 over-expression had a shorter median DFS 23 months than patients who did not (median DFS = 35 months; p = 0.08). Most remarkably, HNOSCC patients showing overexpressions of both PCMs had a significantly decreased median DFS of 13 months relative to patients showing no overexpression of these two proteins (median = 38 months, p = 0.02), underscoring the utility of these proteins as adverse prognosticators for HNOSCCs. As far as we know, this presentation is the first report of utilizing candidate biomarkers identified by MS-based proteomics for cancer prognosis, and the first demonstration that a combination of two such biomarkers may provide better survival predictions. The enhanced performance of combination of the two PCMs in prognosticating clinical outcome of HNOSCCs can be understood on the basis of their biological functions. Our in vitro studies demonstrate formation of heterodimers between the two PCMs, and binding to NFκB, β-catenin, and Bcl-2, thereby implicating the PCMs’ in many cellular processes associated with tumorigenesis. We speculate that targeting the heterodimer, using a small molecule modulator/peptide inhibitor that intervenes with its binding to client proteins, may serve as a plausible therapeutic strategy for head-and-neck cancer. Identity of the PCMs will be revealed in the presentation.
99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA