Mar. 12, 2012 An antidepressant combined with a drug derived from vitamin A could be used to treat a common adult form of leukemia, according to laboratory research led by a team at The Institute of Cancer Research (ICR).
A retinoid called all-trans retinoic acid (ATRA), which is a vitamin A-derivative, is already used successfully to treat a rare sub-type of acute myeloid leukemia (AML) *, however this drug has not been effective for the more common types of AMLs.
Team leader Dr Arthur Zelent and colleagues at the ICR, with principal funding from leukemia & Lymphoma Research, have been working to unlock the potential of retinoids to treat other patients with AML. In a paper recenlty published in Nature Medicine, they show that the key could be an antidepressant called tranylcypromine (TCP).
"Retinoids have already transformed one rare type of fatal leukemia into a curable disease. We've now found a way to harness these powerful drugs to treat far more common types of leukemia," senior author Dr Zelent, from the ICR, said. "Until now, it's been a mystery why the other forms of AML don't respond to this drug. Our study revealed that there was a molecular block that could be reversed with a second drug that is already commonly used as an antidepressant. We think this is a very promising strategy, and if these findings can be replicated in patients the potential benefits are enormous."
ATRA works by encouraging the leukemia cells to mature and die naturally. The team thinks the failure of AML to respond to this drug may be due to genes that ATRA normally targets becoming switched off. In their search for a drug that could be used to reboot the activity of ATRA, the team looked to an emerging area of research called epigenetics. Epigenetic drugs do not target genes directly but instead target whether genes are switched on or off. They discovered that inhibiting an enzyme called LSD1, using TCP, could switch these genes on again and make the cancer cells susceptible to ATRA.
Along with collaborators at the University of Münster in Germany, the team have already started a Phase II clinical trial of the drug combination in acute myeloid leukemia patients.
Co-author Dr Kevin Petrie from the ICR says: "Both the retinoid ATRA and the antidepressant TCP are already available in the UK and off-patent, so these drugs should not be expensive for the health service. AML remains very difficult to treat and sadly is often fatal, with rates of the disease projected to increase significantly as the population ages, so it is particularly pleasing to have identified this new treatment approach. Importantly, we believe these drugs are targeting only the cancer cells and leaving normal healthy cells largely untouched, so we are hopeful that they would have fewer side-effects for patients than standard drugs. We look forward to seeing the results of the clinical trials."
Each year, more than 2,200 people in the UK are diagnosed with acute myeloid leukemia, a type of cancer characterised by the uncontrolled growth of immature white blood cells in the bone marrow.
Professor Chris Bunce, Research Director at leukemia & Lymphoma Research, said: "These results are extremely significant. Current drugs for AML are very aggressive and many older patients have a poor outlook as they cannot tolerate treatment. ATRA has been a major success story in recent years in treating a particular subtype of AML. In finding a way to expand its use, we would have the potential to save thousands of lives a year."
The study was a collaboration between scientists at the ICR, Cardiff University and Queen's University, Belfast, in the UK; Johns Hopkins University, Baltimore, Progen Pharmaceuticals and Medical University of South Carolina in the US; the University Health Network and the University of Toronto in Canada; and the University of Münster in Germany. It was funded in the UK by leukemia & Lymphoma Research along with the Samuel Waxman Cancer Research Foundation.
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- Tino Schenk, Weihsu Claire Chen, Stefanie Göllner, Louise Howell, Liqing Jin, Katja Hebestreit, Hans-Ulrich Klein, Andreea C Popescu, Alan Burnett, Ken Mills, Robert A Casero, Laurence Marton, Patrick Woster, Mark D Minden, Martin Dugas, Jean C Y Wang, John E Dick, Carsten Müller-Tidow, Kevin Petrie, Arthur Zelent. Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia. Nature Medicine, 2012; DOI: 10.1038/nm.2661
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