# TGFβ and Smad Signaling Components in Esophageal Adenocarcinoma

> **NIH VA IK2** · LOUIS STOKES CLEVELAND VA MEDICAL CENTER · 2021 · —

## Abstract

Esophageal adenocarcinoma (EAC) is a highly fatal cancer with 5-year survival under 20%. Alarmingly,
the incidence of cancer of the esophagus has increased significantly over the past 30 years. EAC arises from a
known precursor lesion, termed Barrett's esophagus (BE), that can be easily recognized at endoscopy. However,
current clinical strategies of screening and surveillance are inadequate and EAC diagnosis often occurs at
advanced and unresectable stages of the disease. Veterans are increased risk for BE and EAC compared to the
general population due to increased risk factors (including age >50 and male gender). There is an urgent clinical
need to improve strategies for the detection, prognostication, and treatment of BE and EAC. This translational
research proposal aims to elucidate the molecular carcinogenesis of EAC, with the ultimate goal of reducing the
burden associated with this deadly cancer.
 We used integrative computational and genetic analyses to identify common mechanisms that underlie
EAC tumor progression. We identified that the TGFβ pathway is highly active in EAC compared to non-malignant
BE. The TGFβ/Smad pathway has tumor suppressive properties in epithelial cells, including inhibition of cell
proliferation and induction of apoptosis, and the functional TGFβ pathway elements are frequently lost through
mutation in gastrointestinal malignancies. However, in established cancers TGFβ signaling can promote invasion
and metastasis, suggesting opposing roles for TGFβ signaling that depend on disease stage. In contrast, our
preliminary findings show that the TGFβ pathway fails to inhibit the growth of pre-malignant dysplastic BE cells
in addition to EAC cells; on the contrary TGFβ induces growth of EAC cells even in the presence of functional
TGFβ pathway components. Further, the pro-tumorigenic TGFβ pathway effects are evident in EAC that are
either wild-type or mutant for Smad4, a canonical mediator of TGFβ signaling. Together, our preliminary studies
indemnify an alternative model for the oncogenic TGFβ with early hyperactivation of an unconventional, Smad4
independent, Smad2/3 dependent pathway.
 Our findings have important translational implications. In Aim 1, we will investigate the molecular
determinants of the oncogenic TGFβ signaling in EAC carcinogensis. In Aim 2, we will assess impact of
disrupting oncogenic TGFβ signaling in highly relevant pre-clinical models of EAC. Of particular importance,
LY2157299 (galunisertib), an orally bioavailable small molecule inhibitor of the TGFβ Receptor – Type 1, is
currently being tested in Phase II trials in other malignancies and represents a new therapeutic strategy that can
be rapidly evaluated for this lethal cancer.
 This study is highly innovative and will improve our ability to both prevent and treat cancer of the
esophagus. The scientific proposal and career development activities described here will serve an essential role
in my development as a clinical gastroenterologist at...

## Key facts

- **NIH application ID:** 10108946
- **Project number:** 5IK2CX001831-02
- **Recipient organization:** LOUIS STOKES CLEVELAND VA MEDICAL CENTER
- **Principal Investigator:** Andrew Edward Blum
- **Activity code:** IK2 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-02-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10108946

## Citation

> US National Institutes of Health, RePORTER application 10108946, TGFβ and Smad Signaling Components in Esophageal Adenocarcinoma (5IK2CX001831-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10108946. Licensed CC0.

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