The study, led by investigators at Cedars-Sinai in collaboration with the National University of Singapore, was published in the journal Gastroenterology. It focused on esophageal squamous cell cancer, which involves the inner lining of the esophagus—the tube that connects the mouth to the stomach.
More than 18,000 cases of esophageal squamous cell cancer, which most often affects men, are expected to be diagnosed in the U.S. in 2020 and about 16,000 people are expected to die from the disease, according to the American Cancer Society. Rates are higher in Asia and Africa. The disease commonly resists current treatments, which include surgery and drugs.
"With aggressive esophageal squamous cell cancer, the five-year survival rate is less than 20 percent," said Yuan Jiang, PhD, a postdoctoral scientist at Cedars-Sinai and co-corresponding author of the study. "There is a pressing need to find effective, genetic-guided therapies for these patients."
In gene-guided approaches, specific segments of genetic code are edited or "spliced" to turn off cancer-promoting activity or to turn on cancer-fighting activity. The study team focused on the epigenome, the complex interaction of chemicals that regulate gene activity.
Using human esophageal squamous cell cancer cells obtained from previous studies, investigators analyzed the activity of substances and regions within cells that promoted tumor growth, to learn how switching on and off individual genes affects cell reproduction and death. They edited out tiny pieces of regulatory DNA sequences called enhancers—which can activate transcription over long distances—using the CRISPR gene-splicing and editing tool.
By deleting factors known as TP63, SOX2, and KLF5, the investigators altered certain genetic pathways, which in turn decreased the ability of cancer cells to thrive and reproduce. Specially bred immunodeficient mice were then injected under the skin with the cancer cells, and some of the mice were treated with the newly identified epigenetic inhibitors.
The study found that mice treated with a combination of epigenetic inhibitors at lower doses had smaller, slower growing tumors than did the untreated mice and mice given either agent alone.
In a secondary finding, the team identified a potential link between impaired metabolic breakdown of alcohol and susceptibility of East Asian individuals to esophageal squamous cell cancer. "This association is intriguing and warrants further study," said De-Chen Lin, PhD, assistant professor of Medicine at Cedars-Sinai. "If proven by further investigations, this finding could be of clinical significance in the future."
Lin was also co-corresponding author of the study, along with Melissa J. Fullwood, PhD, from the National University of Singapore, where the research involving mice was performed.
Funding: Research reported in this publication was funded by the Singapore Ministry of Health’s National Medical Research Council (NMRC) under its Singapore Translational Research (STaR) Investigator Award to H. Phillip Koeffler; the NMRC Centre Grant Programme award to the National University Cancer Institute of Singapore and the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiatives; the National Research Foundation Singapore through an NRF Fellowship awarded to Melissa. J. Fullwood; the RNA Biology Center at the Cancer Science Institute of Singapore, as part of funding under the Singapore Ministry of Education Academic Research Fund Tier 3 awarded to Daniel Tenen; Cedars-Sinai through the Translational Oncology Program Developmental Fund; the DeGregorio Family Foundation, The Savone Family and the Esophageal Cancer Awareness Association.