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 Arthur Zelent, Ph.D., and colleagues at the ICR have been working to unlock the potential of retinoids to treat other patients with AML. In a paper published in Nature Medicine today, 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 Kevin Petrie, Ph.D., 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."
Samuel Waxman, M.D., the Founder and the Scientific Director of the Samuel Waxman Cancer Research Foundation added, "The Samuel Waxman Cancer Research Foundation has supported the work of Arthur Zelent for more than a decade. This major finding is the direct result of years of collaborative research to better understand the mechanism of action using a combination therapy of drugs that are already available on the market today, which may lead to faster cures for patients."
The study was a collaboration between scientists at the ICR, Cardiff University and Queen's University, Belfast, in the UK; John 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 Leukaemia & Lymphoma Research along with the Samuel Waxman Cancer Research Foundation.
The Institute of Cancer Research (ICR) is one of the world's most influential cancer research institutes.
Scientists and clinicians at the ICR are working every day to make a real impact on cancer patients' lives. Through its unique partnership with The Royal Marsden Hospital and 'bench-to-bedside' approach, the ICR is able to create and deliver results in a way that other institutions cannot. Together the two organisations are rated in the top four cancer centres globally.
The ICR has an outstanding record of achievement dating back more than 100 years. It provided the first convincing evidence that DNA damage is the basic cause of cancer, laying the foundation for the now universally accepted idea that cancer is a genetic disease. Today it leads the world at isolating cancer-related genes and discovering new targeted drugs for personalised cancer treatment.
As a college of the University of London, the ICR provides postgraduate higher education of international distinction. It has charitable status and relies on support from partner organisations, charities and the general public.
The ICR's mission is to make the discoveries that defeat cancer. For more information visit http://www.icr.ac.uk
Leukaemia & Lymphoma Research
Leukaemia & Lymphoma Research is the only UK charity solely dedicated to research into blood cancers, including leukaemia, lymphoma and myeloma. Around 30,000 people of all ages, from children and teenagers to adults are diagnosed with a blood cancer in the UK every year.
We receive no government funding and rely entirely on voluntary support. In the next five years we need to raise £120 million to continue our lifesaving research. Further information, including patient information booklets, is available from http://www.beatingbloodcancers.org.uk or on 020 7405 0101.
The Samuel Waxman Cancer Research Foundation
The Samuel Waxman Cancer Research Foundation is an international organization dedicated to curing and preventing cancer. The Foundation is a pioneer in cancer research, focusing on uncovering the causes of cancer and reprogramming cancer cells.
We dedicate ourselves to delivering tailored, minimally toxic treatments to patients. Our mission is to eradicate cancer by bridging the gap between lab science and the patient.
Through our collaborative group of world-class scientists, the Institute Without Walls, investigators share information and tools to speed the pace of cancer research. Since our inception in 1976, the Foundation has awarded more than $75 million to support the work of nearly 200 researchers across the globe. Visit http://www.waxmancancer.org