Abstract
Abstract
Despite the fact there are currently a dozen treatment options for esophageal adenocarcinoma (EAC), durable patient responses to anticancer therapies are hard to achieve in EAC patients. The rate of incidence of EAC is increasing faster than any cancer in our country, and the survival rates have remained very low for decades, even in the current era of molecular medicine. Therefore, our group designed an ambitious, large scale mass spectrometric experiment to cast a molecular dragnet across our patient samples to detect overexpression and downregulation patterns that contribute to the aggressiveness of EAC. We used FFPE tissue samples from esophagectomy surgery before any chemotherapy or radiation had been administered, analyzing unadulterated EAC tissue, Barrett's esophagus (BE) tissue, and normal esophageal squamous epithelium from 50 patients. Our platform consisted of pathologist-guided microdissection, a Liquid Tissue® process turning FFPE tissue into a digested lysate, discovery mass spectrometry (TripleTOF 6600) and extensive biostatistics. We discovered a perfect storm of pathogenic processes which explains from several perspectives the aggressiveness of this disease as well as EAC's proclivity to resist chemotherapeutic agents. We found 20 relevant proteomic events in which tumor suppressors are turned off, growth factors are overexpressed, chemoresistance markers are upregulated, chemosensitivity markers are downregulated as well as revealing eight new potential drug targets in which therapeutic antagonism could slow tumorigenesis in EAC. Of these 20 proteins we robustly investigated four markers (DAD1, ISG15, S100P and UBE2N) which all have mutual intersections with prognostic, diagnostic and therapeutic aspects of esophageal pathogenesis. Overexpression of DAD1 (9 out of 10), ISG15 (10/10), S100P (10/10) and UBE2N (10/10) was discovered in BE tissue. In the adjacent EAC tissue, we found significant overexpression of DAD1 (20 out of 20), ISG15 (20/20), S100P (20/20) and UBE2N (19/20) proteins. These expression levels spiked when transitioning from normal squamous epithelium to highly dysplastic BE tissue demonstrating that BE starts to act like cancer by using more glucose for energy (Warburg effect), increasing proliferative measures, and suppressing apoptosis. Also, overexpressed DAD1 protein levels contributes to cisplatin resistance which is striking since 95% of the 123 patients treated at CUMC for EAC received cisplatin in the first-line setting. S100P expression has been found to increase resistance to 5-FU in colorectal cancer. 5-FU was prescribed to 72% of the patients in our cohort (n=123), so if there is innate resistance to the two most prescribed drugs for EAC patients then alternative patient management strategies are needed. Here we've discovered four new prognostic and therapeutic biomarkers with potential clinical utility for EAC.
Citation Format: Joe Abdo, Chris Wichman, Nick E. Dietz, John Fleegel, Pawel Ciborowski, Sumeet K. Mittal, Devendra K. Agrawal. Discovery of novel markers in Barrett's-related esophageal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2691.