Researchers from the Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine have received a $9.5 million National Cancer Institute Program Project (P01) grant to investigate esophageal adenocarcinoma (EAC), the most common form of esophageal cancer in the United States.
“People with chronic gastroesophageal reflux disease, known as GERD, can develop a precancerous condition called Barrett’s esophagus,” says Wael El-Rifai, MD, Ph.D., associate director of basic science at Sylvester, co-leader of the Tumor Biology Research Program and principal investigator of the grant. “The cells in the esophagus adapt to protect themselves from the acid, and that increases the risk of developing esophageal cancer.”
“This grant is a testament to the impressive research already underway at Sylvester that is paving the way to provide the best care for patients today, and I am confident that the team, led by Dr. El-Rifai, will make great progress,” said Stephen. D. Nimer, MD, director of Sylvester Comprehensive Cancer Center, Oscar de la Renta Endowed Chair in Cancer Research, and executive dean for research at Miller School. “With these resources, our researchers can learn more about this disease and create better tools to continuously improve patient care.”
While only about 2% to 3% of patients progress from Barrett’s esophagus to EAC in their lifetime, these cancers have a dismal five-year survival rate of 15%. Over the past 30 years, EAC prevalence has increased by 600%.
“While surgery can be curative, many patients with esophageal cancer show advanced disease that has already progressed beyond the hope of a complete surgical cure,” said Omaida C. Velazquez, MD, FACS, chair of the DeWitt Daughtry Family Department of Surgery at the Miller School and chief surgeon at UHealth – University of Miami Health System.
“Innovation is needed to advance early detection and complementary medication. Together, these three critical branches of care, preventive, medical and surgical, hold great promise to reduce or eliminate deaths from this cancer,” said Dr. Velazquez. “Dr. El-Rifai and his team are making groundbreaking contributions that will translate into state-of-the-art, personalized life-saving care.”
Cells adapt and become more susceptible to cancer
The team will focus on how esophageal cells remodel themselves in response to GERD, making them more vulnerable to cancer-causing mutations. These cellular changes activate oncogenic transcription factors – enzymes that turn on cancer-promoting genes.
“The cells in the esophagus are not like those in the stomach — they’re not built to withstand acid,” said Dr. El-Rifai. “However, esophageal cells adapt to this acidic environment by rewiring themselves and expressing different genes, making them more susceptible to cancer. Transcription factors are the nodes that control gene expression, and if we can control these nodes, we can control everything else in the cancer cell.”
The problem starts with increased oxidative stress. In response to GERD, interactions between the protein STAT3 and APE1 and isolevuglandins (IsoLGs) activate adducts (protein modifications) oncogenic transcription factors, increasing the risk of cancer progression.
These changes alter other proteins, including SOX9, STAT3, and SOX4, which play critical roles in cellular transformation and growth. Usually these proteins are tightly controlled; however, with the GERD-induced changes, they turn on and stay on, increasing the risk of cancer.
Exploring Prevention Strategies
In addition to investigating the biology that drives Barrett’s esophagus and EAC, the team will explore compounds that may counteract these oncogenic processes.
“STAT3 plays a central role in the regulation of inflammation,” said professor of surgery Alexander Zaika, MD, co-investigator of the grant. “By studying STAT3 regulation, we can better assess the contribution of inflammatory processes to esophageal cancer. Our studies have also shown that certain natural compounds can prevent the generation of isolevuglandins. Based on these findings, our group will investigate new strategies to treat esophageal cancer. to prevent.”
The team will also look for molecular biomarkers that could help identify which Barrett esophagus patients are most at risk for developing EAC. Currently, all Barrett esophagus patients undergo regular endoscopies to see if they are progressing. New biomarkers could help clinicians track only those patients most likely to make progress, reducing the need for endoscopies.
“In the lab, we are investigating experimental biomarkers that assess a patient’s risk of developing cancer, as well as how patients with cancer may respond to different therapies,” said co-investigator and Associate
Professor Oliver McDonald, MD, Ph.D., who leads both the gastrointestinal translational pathology research and the molecular pathology core. “All the promising biomarkers discovered in the lab can then be rigorously validated in patient tissue samples and refined into new tools that could change the way cancer is diagnosed and treated.”
This large and complex research program also includes Steven Chen, Ph.D., professor and director of core bioinformatics and biostatistics at the fellowship, and Jianwen Que, MD, Ph.D., associate professor of medicine at Columbia University.
“We are at the forefront of prevention. Our physician-scientists are highly skilled and equipped to do this important work and reduce the growth and prevalence of EAC,” said Henri R. Ford, MD, MHA, dean and chief academic officer of the Miller School of Medicine.
“When they talk about bench-to-bedside research, this is exactly what they describe,” says Craig Moskowitz, MD, interim assistant director, chief physician of the oncology service line, and professor in the Department of Medicine. “This is an incredible opportunity to pursue impactful, translational research that has great potential to change the way we deliver care.”
“This grant underscores why Sylvester is a global leader in both basic discovery research and patient care,” said Dorothy Graves, Ph.D., assistant vice president and associate director for administration at Sylvester. “We are proud of Dr. El-Rifai’s team and what they will achieve.”
The NCI grant gives the team the necessary resources to research esophageal cancer and hopefully learn how to stop it.
“We are beginning to understand how esophageal cells adapt to the acidic environment of GERD and how those changes can lead to Barrett’s esophagus and eventually cancer,” said Dr. El-Rifai. “Now we have to find better ways to intervene. More than 18,000 people in the US die from EAC each year – we need to do better.”