Landon Bone
Landon Bone
Landon Bone
Helios Scholar
School: Arizona State University
Hometown: Glendale, Arizona
Mentor: Timothy Whitsett, Ph.D.
Email This Article Print This Page

Novel therapeutic strategies for esophageal adenocarcinoma

Prevalence of esophageal adenocarcinoma (EAC) has increased six-fold in the United States over the past four decades due to increases in associated risk factors, namely obesity and gastroesophageal reflux disease. The most common genomic drivers of EAC, TP53 mutation and NF-κB over-expression, have previously been therapeutically intractable, affirming the unmet clinical need to deploy novel therapeutic strategies targeting these genomic drivers in this tumor type. Fibroblast growth factor inducible 14 (FN14) expression is elevated in patient samples of EAC compared to normal esophageal tissue, and TNF-like weak inducer of apoptosis (TWEAK)-FN14 signaling promotes NF-κB mediated cell migration and therapeutic resistance in other tumor types. Seventy-two percent of EAC patients have mutations in TP53, making tumors more reliant on the G2/M checkpoint to repair DNA damage, increasing likelihood of efficacious G2/M abrogation via targeting WEE1, a modulator of this checkpoint. We hypothesize that the TWEAK-FN14 signaling axis and the G2/M checkpoint represent viable therapeutic avenues against the two main genomic drivers of EAC. Our previous work showed a significant induction of EAC cell migration in vitro when exposed to TWEAK, and thus we wanted to test TWEAK effects on cell survival. Utilizing a cell viability assay in EAC cell lines OE33 and FLO-1, we demonstrated a significant decrease in cell viability in vitro when exposed to TWEAK and cisplatin compared to cisplatin alone. It was concluded that TWEAK might be inducing apoptosis in these cell lines, making FN14 a less favorable target. As FN14 can signal independent of TWEAK, the role of FN14 suppression on EAC cell survival will be explored. Next, we investigated the efficacy of the WEE1 inhibitor AZD1775 on EAC cells. SK-GT-4 viability was significantly reduced by up to 30 percent when treated with AZD1775 and cisplatin when compared to cisplatin alone. Future research will explore combinational therapeutic strategies with WEE1 inhibitors to identify optimal combinations and dosing cadence. Immunoblot analysis will be employed to understand the mechanisms of G2/M checkpoint inhibitors in EAC. This research will provide insight into novel therapeutic targets for EAC leading to therapeutic testing and improved patient outcome.