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Preclinical Studies and Early Drug Development: Predicting Tumor Response to Cytotoxic Therapy

Gene expression profile in patients' samples with recurrent and persistent squamous cell cancer of head and neck

City of Hope National Medical Center, Duarte, CA

Abstract

B23

Gene expression correlation with clinical outcome was studied in samples from patients enrolled in the PH-II clinical trial. Patients had stage IV, locally recurrent, locally persistent squamous cell cancer (SCC). The intra-tumoral mRNA expression level before treatment with hydroxyurea and gemcitabine was determined using microarray analysis (Affymetrix 2.0) and real-time PCR array for DNA damage (SuperArray Inc.). The microarray analysis compared the average gene expression of 3 patients with stable (S) disease to 5 patients with progressive (P) disease. The analysis resulted in a list of 116 genes with significantly different expression levels (p<0.01, difference in expression level >2-fold) between patients with stable and progressing disease. Genes involved in cancer cell proliferation, cellular movement, and DNA damage are on the list. The top 3 genes with the highest significance, are not well-studied (COL10A1, ADCY2, ITGBL1) and their roles in squamous cell carcinoma is not known. More studies are needed to determine the role these genes play in predicting SCC outcome. The real-time PCR array showed increased expression of the following genes in patients with stable disease (N=4) compared to progressing cases (N=6): GADD45A, GADD45G, FANCG, DDIT3, and MAPK12. The GADD45A and GADD45G expression correlates with the microarray data. Another group of genes were down-regulated in patients with stable disease: EXO1, FEN1, HUS1, IGHMBP2, MAP2K6, MSH2, RAD1, SESN1, PDCD8, PMS2, and XRCC2. These genes might be indicators of the potential outcome of the treatment. Our trial had a limited number of samples. Future studies with a larger number of cases can prove the expression of which gene acts as a potential biomarker to be used as target for therapy.