Translating Molecular Biology Discoveries to Develop Targeted Cancer Interception in Barrett's Esophagus

Abstract

Esophageal adenocarcinoma (EAC) is a rapidly increasing lethal tumor. It commonly arises from a metaplastic segment known as Barrett's esophagus (BE), which delineates the at-risk population. Ample research has elucidated the pathogenesis of BE and its progression from metaplasia to invasive carcinoma; and multiple molecular pathways have been implicated in this process, presenting several points of cancer interception. Here, we explore the mechanisms of action of various agents, including proton pump inhibitors, non-steroidal anti-inflammatory drugs, metformin, and statins, and explain their roles in cancer interception. Data from the recent AspECT trial are discussed to determine how viable a multipronged approach to cancer chemoprevention would be. Further, novel concepts, such as the repurposing of chemotherapeutic drugs like dasatinib and the prevention of post-ablation BE recurrence using itraconazole, are discussed.

Keywords: Barrett’s esophagus; chemoprevention; esophageal adenocarcinoma.

Figure 1

Proposed molecular pathways involved in Barrett’s esophagus initiation. Specific drugs (in red) with their postulated targets are highlighted. PPI—proton pump inhibitor; HIF2—Hypoxia inducible factor 2; IL1β—Interleukin 1 Beta; Hh—Hedgehog; PTCH1—Patched 1; Wnt—Wingless/Integrated; SOX9—SRY-box transcription factor 9; FOXA2—Forkhead Box A2; CDX1—Caudal Type Homeobox 1; CDX2—Caudal Type Homeobox 2; SOX2—Sex-determining region Y-box 2.

Figure 2

Proposed molecular pathways involved in progression of Barrett’s esophagus to dysplasia to esophageal adenocarcinoma. Specific drugs (in red) with their postulated targets are highlighted. Activation of NFkB mirrored by concomitant increase in COX2, IL8, and IL1β along the spectrum of BE, dysplasia, and EAC. LGD—Low Grade Dysplasia; HGD—High Grade Dysplasia; EAC—Esophageal Adenocarcinoma; ATM—Ataxia telangiectasia mutated; BRCA1—Breast Cancer gene 1; VEGF—Vascular Endothelial Growth Factor; VEGFR—Vascular Endothelial Growth Factor Receptor; EGF—Epidermal Growth Factor; src, Src family protein-tyrosine kinase; PI3K—Phosphoinositide 3-kinase; AKT—Protein Kinase B; NF-κB—Nuclear Factor kappa-light-chain-enhancer of activated B cells; COX-2—Cyclooxygenase-2; IL8—Interleukin-8; IL1B—Interleukin 1 Beta; Her2—Human epidermal growth factor receptor 2; AMPK—Adenosine Monophosphate activated protein kinase; mTOR—Mammalian target of rapamycin; S6K1—Ribosomal Protein S6 Kinase 1; S6R—Ribosomal Protein S6; ObR—Leptin Receptor; Jak2—Janus Kinase 2; STAT3—Signal Transducer and Activator of Transcription 3; AND—Adiponectin; AdipoR1—Adiponectin Receptor 1; PTP1B—Protein Tyrosine Phosphatase 1B; WGD—Whole Genome Doubling; SCA—Somatic Chromosomal Alterations.