Abstract 5077: Proteomic profiling reveals chemopreventive targets in esophageal adenocarcinoma
Authors: Katherine M. Weh, Connor L. Howard, Amy B. Howell, Jennifer L. Clarke, Laura A. Kresty
Journal: Cancer Research (2019)

Abstract Esophageal adenocarcinoma (EAC) is characterized by rising incidence rates and high mortality due to late stage diagnosis and a lack of efficacious options for prevention and treatment. While reasons for the rapid increase in EAC are being unraveled, persistent, symptomatic reflux of gastric and duodenal contents, known as gastroesophageal reflux disease is considered the strongest risk factor. Our laboratory utilizes a rat surgical model of reflux-induced EAC to evaluate mechanisms by which cranberry proanthocyanidins (C-PAC) delivered in the drinking water inhibit reflux-induced EAC. Findings show that C-PAC (690ug/rat/day) inhibits EAC formation by 83% at 40 weeks of study and mechanisms of inhibition are under investigation. We utilized nano LC-MS/MS proteomic profiling to identify proteins that were dysregulated due to reflux-induced EAC and reversed with C-PAC treatment. Proteomic profiling revealed that C-PAC treatment restored 63 proteins dysregulated in the context of reflux. EIF3F, PSMD2 and ACTR2 were the top proteins up-regulated by reflux; whereas, top markers restored by C-PAC included GSTT2, OGN and PCMT1. Metacore integrated software showed top pathways up-regulated by reflux and down-regulated C-PAC included Translation_regulation of translation initiation (EIF-linked), Immune response and Regulation of telomere length. Conversely, C-PAC treatment upregulated the glutathione metabolism pathway which is consistent with GSTT2 restoration. Disease enrichment analysis revealed multiple gastrointestinal tract diseases linked to reflux, which C-PAC down regulated supporting that proteomic profiling may inform other potential disease targets for C-PAC. Finally, beyond the 63 reflux-driven proteins C-PAC reversed, we considered proteins, pathways and processes which could not be reversed by C-PAC (n=269). As an example, Process networks upregulated by reflux (not reversed by C-PAC) included Translation initiation (RPL-linked), Elongation, mRNA processing, G2-M and S-phase of the cell cycle. Thus, proteomics profiling may inform the development of complementary preventive combinations for improved cancer inhibitory efficacy, especially for a cancer like EAC, with high mutational burden. Western blot analysis of several markers in the rat esophagus including GSTT2 and COX2 support the data obtained through proteomic profiling. Future directions include interrogating specific pathways that are highly modulated by reflux-induced EAC and restored by C-PAC including DNA damage, repair and extracellular matrix and adhesion. Last, proteomic profiling has also allowed for identification of post-translational modifications which may provide insight into regulation of key dysregulated proteins. Citation Format: Katherine M. Weh, Connor L. Howard, Amy B. Howell, Jennifer L. Clarke, Laura A. Kresty. Proteomic profiling reveals chemopreventive targets in esophageal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5077.