# Clonal Reconstruction and Targeting of the Correa Sequence

> **NIH NIH R01** · UNIVERSITY OF HOUSTON · 2020 · $561,961

## Abstract

PROJECT SUMMARY/ABSTRACT
 It is now well established that epithelial cancers arise in a multi-decade process from precancerous lesions.
Esophageal adenocarcinoma, a cancer whose incidence has risen 5-fold since 1950, initiates with precancerous lesions
known as “Barrett's esophagus”, progresses to dysplasia, and finally emerges as malignant esophageal adenocarcinoma
along a path that parallels the Correa Sequence for gastric adenocarcinoma. As the average life expectancy of patients
diagnosed with esophageal adenocarcinoma is approximately one-year, considerable efforts are underway to define its
Correa sequence, and especially its pre-malignant stages, as potential targets for interdiction ahead of the onset of
malignant disease. Toward this end, we have applied novel stem cell cloning technologies originally developed in our
laboratories for normal human gastrointestinal tract stem cells to reconstructing the Correa sequence in patients with early
esophageal adenocarcinoma. Significantly, each of these patient-matched endoscopic biopsies of Barrett's, dysplasia, and
esophageal adenocarcinoma yields discrete populations of stem cells that respectively yield intestinal metaplasia,
dysplasia (but not tumors), and aggressive adenocarcinoma following transplantation to immunodeficient mice. From a
detailed molecular genetics analysis of nearly 100 independent clones from across the Barrett's, dysplasia, and
adenocarcinoma lesions of one patient, we have been able to reconstruct, at unprecedented resolution, both the direct
phylogenetic sequence that led to this tumor as well as identify “dead-ends” at both the Barrett's and dysplasia stages that
did not contribute to the final tumor. Moreover, each of the cloned stem cells of Barrett's, dysplasia, and adenocarcinoma
lesions represent permanent lines that have enabled powerful approaches to drug discovery that has culminated in leads
that selectively target the entire Correa sequence while sparing normal esophageal stem cells. In three specific aims, we
will 1.) clonally reconstruct the Correa sequence from 10 patients with early esophageal adenocarcinoma; 2.) establish
high-throughput screens involving co-cultures of normal esophageal and Correa sequence stem cells for lead discovery;
and 3.) develop in vivo xenograft models of patient-matched normal esophageal and Correa sequence stem cells for
validating lead combinations targeting these lesions. Based on extensive preliminary studies, we anticipate the analysis of
patient-matched stem cells of these progressive lesions will provide fundamental insights into the evolution of esophageal
adenocarcinoma and as well as epithelial cancers in general. From the standpoint of filling important gaps in patient care,
the drug discovery enabled by these sets of lesional stem cells offers promising and novel interventions to prevent to onset
of esophageal adenocarcinoma as well as ones to address disease that has already taken hold.

## Key facts

- **NIH application ID:** 9980818
- **Project number:** 5R01CA241600-02
- **Recipient organization:** UNIVERSITY OF HOUSTON
- **Principal Investigator:** FRANK D. MCKEON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $561,961
- **Award type:** 5
- **Project period:** 2019-07-19 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9980818

## Citation

> US National Institutes of Health, RePORTER application 9980818, Clonal Reconstruction and Targeting of the Correa Sequence (5R01CA241600-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9980818. Licensed CC0.

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