Newswise — ATLANTA – After discovering how some hematologic cancer cells manage to elude death from a targeted therapy, Dana-Farber Cancer Institute scientists have double-crossed the cancer cells with a drug that renders them vulnerable to the targeted agent.
At the 59th American Society of Hematology (ASH) Annual Meeting and Exposition in Atlanta, the researchers presented laboratory findings that the drug azacitidine (5-azacytidine) can reverse tumor cells’ resistance to the targeted agent SL-401. The research, performed in human acute myeloid leukemia (AML) and blastic plasmacytoid dendritic cell neoplasm (BPDCN) cells, has prompted investigators to launch a Phase 1 trial combining SL-401 and azacitidine in patients with AML or myelodysplastic syndrome (MDS).
SL-401 is a “conjugate” therapy that consists of a cell protein called interleukin 3 (IL-3) and a shortened diphtheria toxin (a protein secreted by the bacterium that causes diphtheria). It works by adhering to the IL-3 protein receptor on tumor cells and infecting them with the diphtheria toxin, which kills them.
“We know that SL-401 can be effective against tumor cells with the CD123 protein – the IL-3 receptor – but, beyond that, it wasn’t clear why a certain cell might or might not respond to it,” said the study’s senior author, Andrew Lane, MD, PhD, director of the Blastic Plasmacytoid Dendritic Cell Neoplasm Center at Dana-Farber. “We didn’t understand why patients, or cells, after exposure to the drug, sometimes become resistant to it.”
In a series of laboratory experiments, Lane’s team discovered that tumor cells’ susceptibility to SL-401 lies in the diphthamide synthesis pathway – the series of steps by which cells make diphthamide, an amino acid. The pathway has the inadvertent effect of creating a target for diphtheria toxin. Cells that lose the ability to make diphthamide are no longer prey to the toxin.
Lane’s team found that the pathway shuts down when a process known as DNA methylation silences a gene called DPH1. When the researchers treated such cells with azacitidine, a drug that reverses the methylation process, DPH1 became active again, making the cells sensitive to SL-401 again.
“It’s an interesting mechanism of drug resistance that we don’t often see in cancer,” Lane said.
The Phase 1 clinical trial combining SL-401 and azacitidine in patients with AML or MDS opened over the summer at Dana-Farber, MD Anderson Cancer Center, and City of Hope.
“It’s something we’ve been able to take from the lab to the patient in less than two years,” Lane said. “That doesn’t happen very often.”
The lead author of the study is Jason Stephansky of Dana-Farber. Co-authors are Katsuhiro Togami, MD, PhD, and Joan Montero, PhD, of Dana-Farber; Mahmoud Ghandi, PhD, and Cory Johannessen, PhD, of the Eli and Edythe L. Broad Institute of MIT and Harvard; Nick vonEgypt, Ross Lindsay, PhD, and Christopher Brooks, PhD, of Stemline Therapeutics, New York, N.Y.; and Jon C. Aster, MD, PhD, of Brigham and Women’s Hospital.
About Dana-Farber Cancer Institute From achieving the first remissions in childhood cancer with chemotherapy in 1948, to developing the very latest new therapies, Dana-Farber Cancer Institute is one of the world’s leading centers of cancer research and treatment. It is the only center ranked in the top 4 of U.S. News and World Report’s Best Hospitals for both adult and pediatric cancer care. Dana-Farber sits at the center of a wide range of collaborative efforts to reduce the burden of cancer through scientific inquiry, clinical care, education, community engagement, and advocacy. Dana-Farber/Brigham and Women’s Cancer Center provides the latest in cancer care for adults; Dana-Farber/Boston Children's Cancer and Blood Disorders Center for children. The Dana-Farber/Harvard Cancer Center unites the cancer research efforts of five Harvard academic medical centers and two graduate schools, while Dana-Farber Community Cancer Care provides high quality cancer treatment in communities outside Boston’s Longwood Medical Area. Dana-Farber is dedicated to a unique 50/50 balance between cancer research and care, and much of the Institute’s work is dedicated to translating the results of its discovery into new treatments for patients in Boston, and around the world.
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