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Y. Pina, S. Houston, W. Scott, L. Nathanson, A. Schefler, T. Lampidis, M. Celdran, E. Hernandez, T. Murray; Retinoblastoma Molecular Genomics: Regional Differences in the Molecular Genomics Expression Following Treatment With 2-Deoxy-D-Glucose in LHBETATAG Retinal Tumors. Invest. Ophthalmol. Vis. Sci. 2010;51(13):1576.
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© ARVO (1962-2015); The Authors (2016-present)
We have previously shown that 2-deoxy-D-glucose (2-DG) effectively targets the chemoresistant, hypoxic cells in LHBETATAG retinal tumors. We have also reported significant regional differences in the tumor microenvironment (e.g., vascular development, hypoxic levels). The purpose of this study is to analyze the effect of 2-DG on gene expression in LHBETATAG retinal tumors.
This study was approved by the IACUC and follows ARVO guidelines. LHBETATAG transgenic mice (n=15) were treated bi-weekly with either 2 or 6 periocular injections of 2-DG (500 mg/kg) or saline control at 16 weeks of age. A gene expression array analysis was performed on five different tumor regions per eye (i.e., base, center, anterior margin, posterior margin, apex). Molecular analysis focused on number of injections and treated versus non-treated animals. RNA was amplified and sense-strand cDNA was created using NuGEN reagents. Samples were scanned using a GeneChip scanner 3000 7G. Tumor hypoxia and tumor burden were evaluated histopathologically.
2-DG treatment elicited decreases in tumor hypoxia and total tumor burden for both two and six injection schedules in the apical regions (p<0.05). While no gene expression differences were significant when adjusting for multiple comparisons at a false discovery rate of 5%, several nominal differences were noted in the genomic expression profile of the tumors (p<0.001). Comparison between the 2 injections and 6 injections treatments schedule showed more than 2 fold difference in expression of 86 genes (p<0.001). In the non-treated group, three genes were consistent in their changes with tumor progression and age, including Olfr124, Pisd, and Csnk2a2. Comparison between treated eyes versus non-treated eyes showed an overall increase in the molecular genomics expression difference for both the 2 injections (49 genes with fold change over 2 at p<0.05) and 6 injections (919 genes with fold change over 2 at p<0.05) groups when compared to control.
Periocular delivery of 2-DG eliminates intratumoral hypoxia and decreases tumor burden. This study, for the first time, documents the molecular genomic profile of RB and notes differential gene expression associated with both regional tumor variation and 2-DG. This molecular data is critical in understanding intratumoral variation and defining unique opportunities for targeted therapy in retinoblastoma.
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