Leflunomide, a drug commonly used to treat rheumatoid arthritis, may also inhibit the growth of malignant melanoma, a deadly form of skin cancer, according to new research led by the University of East Anglia (UAE) in the UK and Children’s Hospital Boston in the US.
You can read how UAE researchers Dr Grant Wheeler and Dr Matt Tomlinson and colleagues made the discovery in a paper published online in Nature this week.
The breakthrough discovery is exciting scientists and clinicians because it takes much less time to trial a drug that is already licensed for another disease than it does for one never previously tested, leading to speculation that this treatment might be available in the next five years.
Wheeler, of UEA’s School of Biological Sciences, told the press that deaths from melanoma are increasing, and we desperately need new and better treatments.
“We are very optimistic that this research will lead to novel treatments for melanoma tumors which, working alongside other therapies, will help to stop them progressing,” he added.
For the study, Wheeler, Tomlinson and colleagues screened thousands of compounds looking for likely candidates by testing their ability to affect the development of pigment cells in tadpoles.
They used tadpole pigment cells because they are similar to human melanocytes that produce melanin, the pigment that is mainly responsible for skin colour. Melanoma occurs when melanocytes grow in an uncontrolled manner.
The researchers found a number of likely candidates, and after testing them on lab mice, found that leflunomide significantly restricted tumour growth.
They also tested the effect of combining leflunomide with PLX4720, a promising new drug that is currently being tested as a treatment for melanoma, and found it almost halted tumor growth completely.
The next stage will be to carry out clinical trials of leflunomide as a treatment for melanoma, and because it is already licensed for the treatment of arthritis, should the trials prove successful, it could be available in about five years, which is half the usual timescale for a new drug.
In another paper in the same issue of Nature, some of the researchers from this study describe how they and other colleagues used zebrafish to identify a new gene called SETDB1 that is responsible for promoting melanoma.
Surprisingly, melanocytes, the pigment-producing cells in humans and tadpoles, are also responsible for producing the dark stripes on zebrafish.
To find the gene, the researchers at Children’s Hospital Boston developed a transgenic zebrafish that had two other features that lead to melanoma: the correct mutation of a gene called BRAF, and the absence of the tumor suppressor gene p53.
They started out with a hunch that it took more than mutations in BRAF and the absence of p53 to trigger malignant tumors, and used the new zebrafish model to painstakingly sift through all the other genes, one by one.
The Xenopus tadpole used at UEA to find leflunomide as a possible treatment for melanoma, and this zebrafish model from Children’s Hospital Boston, are examples of the power of using developmental models to screen large numbers of compounds.
The researchers hope such approaches will help discover even more compounds and genes as candidates for other diseases.
As lead author Dr Richard White of Children’s Hospital Boston and Harvard Medical School explained, knowing more about cancer is not just a matter of finding mutations in genes, but also about knowing the types of cells that tumors spring from.
“By studying cancer development in zebrafish and frogs, we gain a unique insight into the very earliest changes that occur in those cells,” said White.
Melanoma is the most aggressive form of skin cancer and, unlike most other cancers, it is on the rise. It accounts for 5% of skin cancers.
More than 10,000 people are diagnosed with melanoma in the UK every year; in the US this figure was 68,000 in 2009, when 8,700 Americans also died from the disease.
If diagnosed early, melanoma tumors can be safely removed with surgery, but if diagnosed in the advanced stage, the chances of survival are thin.
About 2,000 people die every year in the UK because their melanoma returns after being removed surgically.
If you spot any changes to the shape or color of existing moles or find a new lump anywhere on your skin, get a doctor to check them, because these are possible signs of melanoma.
“DHODH modulates transcriptional elongation in the neural crest and melanoma.”
Richard Mark White, Jennifer Cech, Sutheera Ratanasirintrawoot, Charles Y. Lin, Peter B. Rahl, Christopher J. Burke, Erin Langdon, Matthew L. Tomlinson, Jack Mosher, Charles Kaufman, et al.
DOI:10.1038/nature09882
Additional source: University of East Anglia (23 Mar 2011)., UMass Medical School (24 Mar 2011).
Written by: Catharine Paddock, PhD