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The combination drugs may be effective against the second type of leukemia

April 26, 2019 11:24

Each year, about 11,000 Americans die from acute myeloid leukemia (AML), a blood cancer that affects mainly older people. While most patients initially respond to chemotherapy, more than half of those in charge, eventually recur, because cancer cells develop resistance to treatment. In a new paper published today in Cell Research, a group of scientists led by Pier Paolo Pandolfo, MD, director of the Cancer Center and Institute of Cancer Research at the Medical Center Diakonessy Beth Israel, identifies vulnerabilities in a subset of AML, which can serve as a support for overcoming resistance to therapy.

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"There is an urgent need for the development of rational combinations for the treatment of diseases and to overcome the resistance that occurs in response to treatment," - said Pandolfo. "By providing a critical understanding of the mechanisms underlying the disease, we have identified a therapeutic strategy for the treatment of this type of AML."

About 20 percent of AML cases are associated with mutations in key metabolic enzyme known as IDH. Using previously published a genetically engineered mouse model, as well as a line of human cells for UML models with this mutation, Pandolfo and colleagues have identified the key processes that these cancer cells use for development - drug resistance in response to therapy.

Following the path of progressive resistance, the researchers, including first author Mugoni Vera, PhD, research associate laboratory Pandolfo, identified critical vulnerabilities that researchers can use for potential therapeutic benefit in all stages of development of the disease. Furthermore, the team demonstrated that the combination of drugs already used to treat other types of leukemia, worked well against this form of AML.

"The molecular processes that are often necessary to provide resistance to therapy, make tumors vulnerable in other areas", - said Mugoni. "In the case of AML with mutant IDH enzymes and differentiation pathways were altered, exposing vulnerabilities that are enhanced with the development of leukemia, and for which we have already approved agents that can be used."

Another form of leukemia, known as acute promyelocytic leukemia (APL), was once a fatal diagnosis. Currently the disease is considered to be curable due to researchers, including Pandolfo, who demonstrated that arsenic trioxide (ATO) is effective against APL in combination with another drug, called all-trans retinoic acid (ATRA). In the current study Pandolfo and his colleagues tested the combination of both the mouse model of AML with mutant IDH, as well as in human AML cells. They determined that while drugs target different vulnerabilities in various forms of leukemia, the combination was "powerful and exquisitely effective" against this subset of AML.

"With the previous discovery of my laboratory that all-trans retinoic acid and arsenic trioxide cure in the treatment of acute promyelocytic leukemia, certifying the translation of the same therapy for possible therapeutic approaches for other forms of AML is extremely useful", - he said .

Pandolfo added that his team is currently working to develop a clinical trial to evaluate the combination of ATRA and ATO for the treatment of AML with a mutation in IDH enzymes in many centers throughout the United States and beyond.



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