Regulation of protein aggregation and tumorigenesis by gastroesophageal reflux

Background and Innovation: The incidence of esophageal adenocarcinoma (EAC) has increased 600% in the last three decades, making this tumor one of the fastest-rising solid tumors in the U.S. EAC has a signifi- cant clinical, humanistic and economic burden as it is frequently a lethal disease, and because the surgery that is the mainstay of current therapy has notable morbidity. EAC tumorigenesis is tightly linked to chronic gas- troesophageal reflux disease (GERD), a digestive disorder in which acidic stomach contents enter the esopha- gus, causing tissue injury and development of Barrett’s esophagus (BE, also known as Barrett’s metaplasia). BE is an entity that is considered to be a precursor to EAC. Along with others, we have shown that chronic re- flux causes strong oxidative stress and is associated with DNA damage in BE cells, which is believed to drive the disruption of normal cellular signaling and progression to EAC. However, it remains unknown how cells damaged by reflux survive, escape the surveillance of the tumor suppression system and become cancer transformed. In this project, we have developed an innovative hypothesis explaining how oxidative stress caused by reflux induces carcinogenic alterations in the esophagus through dicarbonyl-mediated protein ag- gregation. In aim 1, we will define novel, previously uncharacterized mechanisms regulating protein misfolding and aggregation in esophageal cells that is caused by reflux-induced oxidative stress. Novel approaches for the prevention of aberrant aggregation of the p53 tumor suppressor will be also explored. In aim 2, we will in- vestigate the regulation of oxidative stress and protein homeostasis in the esophageal niche using animal models of EAC and human clinical specimens. In aim 3, we will test various options to inhibit protein aggrega- tion in a pro-tumorigenic environment created by chronic gastroesophageal reflux in vivo and investigate how it affects esophageal carcinogenesis. Combined, this proposal is based on an innovative hypothesis, relevance to human disease etiology, and innovative mechanistic, functional, and translational studies that include the first proof-of-concept testing of new drugs that target protein aggregation and esophageal tumorigenesis. Significance and Impact to Veterans Healthcare: GERD and BE are common among veterans. Approxi- mately 20% of veterans are affected by GERD. Among veterans with GERD, more than 10% are also diag- nosed with BE. The existing medical treatment for GERD almost exclusively uses drugs intended to suppress the production of acid, such as proton pump inhibitors (PPIs). Clearly, PPIs provide symptomatic relief, but PPI treatment does not correct the underlying reflux diathesis in Barrett’s esophagus, and gastroesophageal reflux of weakly acidic material occurs frequently in GERD and BE patients who take PPIs. Furthermore, the high frequency of esophageal adenocarcinoma despite the widespread use of PPIs suggests the critical need for a better mechanistic understanding of the basis for carcinogenic alterations induced by GERD and BE. Path to translation/implementation: The proposed mechanistic and functional studies will investigate, for the first time, the link between reflux, protein aggregation and EAC tumorigenesis. This research will be inte- grated with translational studies that will explore targeting abnormal protein aggregation to prevent tumorigenic alterations and esophageal tumors. Upon completion, our results can spur the initiation of clinical trials for a new class of anticancer drugs. Project Number: 1I01BX006794-01A1 | Fiscal Year: 2026 | NIH Institute/Center: Veterans Affairs (VA) | Principal Investigator: ALEXANDER ZAIKA | Institution: MIAMI VA HEALTH CARE SYSTEM, MIAMI, FL | Activity Code: I01 | Study Section: Special Emphasis Panel[ZRD1 GAST-L (01)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11185178