Professor Charles Sawyer explains that the CML clone makes mistakes in DNA replication and generates a diverse repertoire of mutations.

Charles Sawyer, M.D. is professor of medicine and director of the Prostate Cancer Program Area at U.C.L.A. Johnsson Comprehensive Cancer Center, and an investigator of the Howard Hughes Medical Institute. He works on therapies that target specific mutations in prostate cancer and chronic myeloid leukemia (CML). Here he describes his work developing a targeted therapy for CML patients with resistance to the anti-cancer drug Gleevec. “They come about most likely because in the process of growing, the CML clone makes mistakes in DNA replication and generates a diverse repertoire of mutations – most of which are probably irrelevant and just disappear but under the face of selective pressure of a drug, you get outgrowths. They get a growth advantage and they grow up. What's I think is clear is the drug itself is not causing mutations; it's not mutagenic. And when we look using very sensitive tools, it looks like the mutations are already there in most patients and so the die might be cast early on in the disease and it speaks to the need of having perhaps a cocktail of drugs to combat this much like the treatments for HIV virus is based. Well, I can give a number but the natural history of CML is actually a little different now in 2004 than it was four years ago because essentially everyone is now on Gleevec. But if you start on Gleevec in the late stage of the disease, 100% of patients have a resistance within about a year or two. If you start Gleevec at the beginning of the disease, about 15% have resistance within three years. We don't know beyond that what will happen but the curve seems to be continually dropping down gradually but there's no evidence that anyone's been cured with Gleevec and when we use PCR to look for residual CML cells in patients, even those that are doing fantastic, we still see residual cells by PCR. So, most of us believe that there's a reservoir of CML cells left escaping Gleevec, not necessarily expanding but just sitting there. And whether or not that reservoir will be a big problem in another five years of follow-up, we'll just have to see.”

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