# Polyamines and Electrophiles in Gastric Cancer

> **NIH NIH P01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2024 · $349,540

## Abstract

PPG PROJECT 2 SUMMARY
H. pylori is the strongest risk factor for gastric cancer, the fourth leading cause of cancer deaths, and >50% of
humans harbor this infection. With the other PPG Projects and Cores, new insights into gastric carcinogenesis
from Project 2 during the current award period included a deeper understanding of the role of polyamines in
epithelial dysfunction and immunoregulation, altered immune cell remodeling/metabolism, and implication of
electrophiles in gastric cancer. By elucidating mechanisms of carcinogenesis, we will now address our goal of
new interventions for cancer prevention and treatment. We have demonstrated the essential role of spermine
oxidase (SMOX) in H. pylori-induced carcinogenesis. We have new evidence that this occurs independently of
the conversion of spermine to spermidine, and is likely due to acrolein and H2O2, also products of SMOX activity.
Acrolein is a highly reactive aldehyde and electrophile, which exhibits a half-life far longer than transient reactive
oxygen species. Acrolein and H2O2 support lipid peroxidation, enhancing generation of other potent dicarbonyl
hese strong oxidants form irreversible adducts with proteins and DNA, leading to changes in cell
signaling, somatic genomic abnormalities, and epigenetic changes, but their role
We recently reported that dicarbonyl
electrophile adducts are increased in H. pylori-infected gastric tissues and .
electrophiles. T
in carcinogenesis is unproven.
Linking SMOX-derived electrophiles to gastric cancer is a new concept.
patient-derived gastric organoids 2-
hydroxybenzylamine (2-HOBA) is a scavenger of reactive electrophiles that prevents adduct formation with
macromolecules. We reported that an analog of 2-HOBA
reduced somatic genomic abnormalities and prevented
cancer development in rodents infected with H. pylori. We will now focus on
2-HOBA itself, because: 1) it is a
natural product that is not toxic or mutagenic; 2) Phase 1 clinical trials at VUMC have demonstrated its safety;
3) we have shown that 2-HOBA prevents H. pylori gastritis and carcinogenesis in INS-GAS mice, and restricts
growth of tumor xenografts; and 4) we have a partnership with MTI Biotech for use of 2-HOBA. Our hypothesis
is that reactive aldehydes derived from SMOX activity are major contributors to gastric carcinogenesis and tumor
growth and are a therapeutic target for both cancer prevention and treatment. Through the strong integration in
this PPG we will address our Aims, which are to determine: 1) if effects of SMOX in gastric carcinogenesis are
mediated by electrophiles in vivo; we will use cancer prone INS-GAS mice +/- Smox deletion and +/- 2-HOBA
treatment, and study cancer development and its mechanisms; 2) effects of SMOX-derived reactive aldehydes
in human gastric organoids, assessing carcinogenic signaling and effects on the transcriptome/proteome and on
H. pylori; 3) if electrophiles are a therapeutic target for gastric cancer development, by investigating human
tis...

## Key facts

- **NIH application ID:** 10767085
- **Project number:** 2P01CA116087-17
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Keith T. Wilson
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $349,540
- **Award type:** 2
- **Project period:** 2009-01-01 → 2029-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10767085

## Citation

> US National Institutes of Health, RePORTER application 10767085, Polyamines and Electrophiles in Gastric Cancer (2P01CA116087-17). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10767085. Licensed CC0.

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