Developing Natural Products to Target IL-8 Signaling and Intercept Progression of Barrett’s Esophagus to Esophageal Adenocarcinoma

Esophageal adenocarcinoma (EAC) is a growing health problem characterized by rising incidence, substantial morbidity, and poor prognosis (5-year survival rates <20%) supporting the urgent need for improved strategies for prevention and interception. The only precursor lesion to EAC is Barrett’s esophagus (BE), a metaplastic protective adaptation to chronic reflux of injurious bile salts and acidic gastric contents, known as gastroesophageal reflux disease (GERD). Acid-reducing proton pump inhibitors (PPIs) are the mainstay of treatment for GERD, yet widespread use of PPIs has not translated into meaningful declines in EAC. Thus, our long-term goal is to identify non-toxic efficacious natural products to intercept BE progression to EAC by targeting the major drivers and sequelae of BE. Reflux components stimulate cytokine-chemokine mediated inflammation in the esophagus contributing to epithelial injury, immune cell migration, genetic instability and EAC progression. Multiple lines of evidence support that IL-8, a proinflammatory and immune suppressive chemokine, is an early and key driver of BE progression to EAC. We and others have documented a step-wise increase in IL-8 expression from normal through BE to EAC. We identified elevated levels IL-8 and its receptors in a BE cohort with high-grade dysplasia (HGD) or EAC compared to low-grade dysplasia (LGD). IL-8 signaling was identified in >60% of pathway maps upregulated in BE.HGD. Deconvolution analysis revealed an immune suppressive environment with BE progression, showing activation of neutrophils in BE.HGD versus BE.LGD. Our findings align with a comprehensive report pinpointing altered IL-8-neutrophil signaling as an early driver of BE to EAC progression and one intriguingly linked to a racially influenced immunological basis for esophageal cell transformation. Finally, circulating levels of IL-8 are elevated in BE and EAC and correlate with poor patient prognosis. Based on the published literature coupled with our unpublished data we hypothesize that inhibiting IL-8 signaling by natural products can be exploited as a promising strategy to intercept BE progression to EAC. In collaboration with NCATS, we propose to screen the NCI’s natural product (NP) library and identify top hits targeting IL-8 through three aims. Aim 1 studies focus on IL-8 HTS assay optimization, initial NP screening and dose determination in BE.HGD cells. Aim 2 will first, employ orthogonal and counter assays to eliminate false positives and interference NPs and screen for toxicity in the top 20 on-target hits in normal, BE and EAC cell lines and second, characterize and validate NPs in patient derived models utilizing pharmacologic and genetic approaches. Aim 3 evaluates the pharmacokinetics/dynamics of five lead NP hits via microsomal stability testing, plasma stability determinations and in vivo rodent studies to estimate half-life, drug clearance and oral bioavailability culminating in a cancer prevention bioassay. This research holds strong potential to identify new NPs and validate cellular targets critical for informing efficacious strategies for EAC prevention or interception.