Multiple Myeloma: An Epigenetic Cancer?

February 19, 2013

Years ago I collaborated with a hematologist, Dr. Philip Periman, in Amarillo Texas, whose research interest was multiple myeloma. He saw a lot of patients with this disease; at that time (15 years ago) it was a death sentence, although it could be held at bay for some years. He was struck by its high incidence in ranchers and farmers in the Texas panhandle. Exposure to pesticides and other farm chemicals was long suggested as a risk factor. Recent work provides an explanation: these chemicals are epimutagens, myeloma appears to be an “epigenetic cancer” and it can be successfully treated with drugs that block methylation of cancer-causing genes.

Pomalidomide and lenalidomide are FDA-approved derivatives of thalidomide. They are slight modifications of the original thalidomide molecule, which achieved beneficial results, but also caused unpleasant side effects. When given to patients with multiple myeloma, they block the methylation of the gene p21^WAF . This proceeds through a modification of the chromatin structure of this region, so when unmethylated, the p21^WAF gene product is synthesized. The end result is a self-destructive cascade resulting in the death of the tumor cells. These drugs have been so successful that they have kept myeloma patients alive for years, as reported recently by NPR (http://www.npr.org/blogs/health/2013/02/18/172098789/targeted-cancer-drugs-keep-myeloma-patients-up-and-running).

That’s the good news. The bad news is that the cost of a yearly regime of treatment will run to about $140,000, making it one of the most expensive cancer treatments available. However, a check of the internet reveals that the original parent compound, thalidomide, can be obtained in Mexico from Serrai Laboratories for $3.60 a day, a considerable savings.

So the picture of cause and effect looks clear. Pesticides and other epimutagenic compounds methylate suicide genes, shutting them off, so cells lose control of divison. This results in cancers such as myeloma which can be destroyed by reactivating suicide pathways through demethylation.

In the years to come we will see this as a recurrent theme in the origins and treatment of many different cancers.  

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