PHILADELPHIA - A research group at the Perelman School of Medicine of the University of Pennsylvania, led by John Lynch, MD, PhD, assistant professor of Medicine in the Division of Gastroenterology, has received a National Cancer Institute (NCI) grant to establish a Barrett's esophagus translational research network (BETRNet) with Columbia University (led by Dr. Timothy Wang) and the Mayo Clinic (led by Dr. Kenneth Wang). The award is for nearly $8 million across all sites.
Barrett's esophagus (BE) is an increasingly prevalent, pre-cancerous disorder that results primarily from reflux of acid and bile. It afflicts millions of Americans and is a precursor to esophageal adenocarcinoma (EAC), which has the fastest rate of increase of any cancer in the US.
Co- principal investigators are Lynch, Gary Falk, MD, professor of Medicine; Greg Ginsberg, MD, professor of Medicine and director of endoscopy; Antonia Sepulveda, MD, PhD, professor of Pathology and Laboratory Medicine, and Anil K. Rustgi, MD, T. Grier Miller professor of Medicine and chief of the Division of Gastroenterology. Drs. Rustgi, Timothy Wang and Kenneth Wang direct the BETRNet's coordination with two other funded institutions -- the University of Michigan as and Case Western Reserve University -- in conjunction with the NCI and Vanderbilt University (coordinating center).
"We are all very excited to be a part of this multicenter research network," says Lynch. "Our understanding of the pathogenesis of Barrett's esophagus and esophageal adenocarcinoma has lagged behind that of other cancers because we have not yet developed physiologically relevant laboratory models and an integrated research network, both of which are supported by this award."
The award provides for a multidisciplinary, translational research program to study the origins and pathogenesis of the disorder. The team, which has collaborated in the past, will focus on the role of chronic inflammation and bile acids in the upregulation of molecular pathways and stem/progenitor cells, and possible ways to target these cells for developing preventive and therapeutic treatments.
The Penn project members will bring to the network a large patient population and Barrett's inflammatory animal models. Three main projects comprise the network's goals:
- Identify the role of Notch signaling proteins in animal models of Barrett's esophagus to determine the effects of Notch inhibition or Notch activation on progression to cancer.
- Characterize the stem/progenitor cell of origin in Barrett's esophagus in mouse models. A pilot clinical trial using an antagonist of a G-protein coupled receptor expressed on stem/progenitor cells upregulated in the disease will be conducted to determine if regression of Barrett's esophagus occurs.
- Identify novel biomarkers and gene signatures in Barrett's esophagus, correlating data sets from animal and human models to clarify which cells play the most important role in disease progression. A cohort of patients undergoing radiofrequency ablation for Barrett's esophagus will be assembled to identify biomarkers of response to therapy and to study the development of BE.
"Our novel preclinical models serve as the foundation for testing hypotheses, which are then brought ultimately to the clinic in a true translational 'bench-to-bedside' approach through biomarker, chemoprevention and therapeutic studies," says Rustgi.
The other subtype of esophageal cancer is esophageal squamous cell carcinoma (ESCC), which is common worldwide. Penn investigators have a long-standing NCI-funded program project in this cancer, dating to 2003, funded to nearly $10 million every five years. This group's Principal Investigator is also Dr. Rustgi; other investigators include Penn researchers Dr. J. Alan Diehl, professor of Cancer Biology and director of cancer cell biology in the Abramson Family Cancer Research Institute; Dr. Hiroshi Nakagawa, research associate professor of Medicine; Dr. Phyllis Gimotty, professor of Biostatistics; Dr. Jonathan Katz, assistant professor of Medicine; Dr. Gary Wu, professor of medicine; and Dr. Sunil Singal, assistant professor of Surgery, as well as Dr. Meenhard Herlyn, professor at the Wistar Institute and Dr. Andres Klein-Szanto at Fox Chase Cancer Center, collaborating with groups at Massachusetts General Hospital and Dana Farber Cancer Institute.
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