“Our clinicians work closely with our researchers in taking a bedside-to-bench-to-bedside approach to treating EAC patients at Sylvester Comprehensive Cancer Center,” said Alan S. Livingstone, M.D., professor and Chairman of the DeWitt Daughtry Family Department of Surgery and co-author on this study. “This research lays the foundation for clinical trials using these experimental therapeutics at Sylvester and has the potential to impact clinical care of EAC patients in the near term.”
Currently, EAC treatments typically involve chemotherapy followed by surgery and removal of the esophagus, said senior author and study leader Anthony J. Capobianco, Ph.D., professor and Director of the Molecular Oncology Research Program in the Division of Surgical Oncology. “While many patients have partial responses, only about 15 percent of patients respond completely to the chemotherapy, and this greatly improves their five-year survival rates,” he said. “Our team of surgeons and scientists takes a collaborative approach in seeking to determine why cancer cells are resistant to treatment in the vast majority of patients with EAC.”
The Miller School study focused on the role of the Notch signaling pathway, which can “turn on” gene regulation mechanisms that affect cellular development. Activating that pathway in cancer patients can delay the cell maturation process, leading to an overabundance of cancer stem-like cells that are relatively unaffected by chemotherapy and are thought to contribute to metastatic disease.
“Our study clearly shows that Notch activity provides the tumor with protection against chemotherapy,” said Capobianco, who is also co-leader of the Experimental Therapeutics Program at Sylvester. “Therefore, inhibiting or blocking the Notch signaling pathway should improve the effectiveness of EAC treatment and thereby ease the burden and improve outcomes for our patients.”
The study, “Notch Signaling Drives Stemness and Tumorigenicity of Esophageal Adenocarcinoma” was published online in the American Association for Cancer Research (AACR)‘s prestigious journal, Cancer Research. Joining Capobianco and Livingstone were lead author Zhiqiang Wang, M.D., Ph.D., assistant scientist in the Department of Surgery, Dido Franceschi, M.D., professor of surgery, and several other Miller School faculty.
Noting that Livingstone and Franceschi are experienced surgeons with longstanding expertise in treating patients, Capobianco said, “This study represents a step forward in their ability to treat patients by providing them with another potential weapon to combat cancer. Our clinical laboratory studies can identify the absence or presence of an activated Notch pathway in cancer cells taken from a biopsy, indicating which patients will respond better to chemotherapy,” he said. “It is another example of personalized medicine, where clinical treatments can be customized for different individuals.”
EAC ranks sixth in cancer mortality in the world and its incidence has risen dramatically in the U.S. over the last decades, according to various studies. However, various combinations of neoadjuvant chemotherapy (NAC) and surgery are effective in fewer than one-third of patients.
“Therefore, it would be a useful strategy to sensitize tumors to neoadjuvant chemotherapy and therefore improve both the local response and outcome of treatment,” said Capobianco. “The use of a targeted therapy in combination with a typical chemotherapeutic and surgical treatment strategy will ultimately provide a more durable cure to this disease.”
University of Miami