Imatinib shows promise against idiopathic hypereosinophilic syndrome, allowing researchers to recognize that the disease is a cancer and that it is due to a DNA deletion resulting in an activated tyrosine kinase enzyme, according to an article in the March 27th issue of the New England Journal of Medicine.

American researchers at a major cancer center chose imatinib because it had already shown promise against chronic myelogenous leukemia and there was early evidence (published in the Lancet in May 2002, after the current study began) suggesting that the pathogenesis of hypereosinophilic syndrome might be similar to that of the chronic leukemia.

Of 11 patients given imatinib, 9 responded positively to treatment and 8 have remained free of disease, with the longest follow-up currently at 18 months.

“Our research addresses the question of why patients with hypereosinophilic syndrome respond so well to imatinib,” said Gary Gilliland, M.D., Ph.D., senior author. “We have shown that a small deletion of DNA in the blood cells of patients [with hypereosinophilic syndrome] fuses two genes together, creating a novel cancer-causing gene that is inhibited by imatinib. This fusion explains the clinical response these patients have to imatinib and demonstrates that hypereosinophilic syndrome is a form of cancer.”

Gilliland and Richard Stone, M.D., another coauthor, noted that the syndrome is rare, with an annual incidence of less than 1 in 100,000 people. It almost always affects men.

However, Stone said that the rarity of the condition does not dilute the broader implications of the findings. “The creation of a cancer-causing gene by a small deletion of DNA is a novel genetic mechanism that may be present in many other tumors if we look for it. As we learn more about the genetics of cancer, we should be able to develop other targeted therapies like imatinib.”

Previous work with chronic myelogenous leukemia had shown that DNA exchange between two chromosomes results in a persistently activated signaling protein (an enzyme in the tyrosine kinase family) and that the excessive activity is the basis for carcinogenesis. In the current study, the research group identified a small deletion from chromosome 4 that fuses 2 genes, producing a unique tyrosine kinase enzyme that is also persistently activated.

Imatinib has been shown to inhibit 5 signaling proteins in the tyrosine kinase family. Data from the Human Genome Projects indicates that there are 96 tyrosine kinase enzymes, which raises the possibility that other cancers may be caused by mutations in different genes.

“We are seeing a tiny fraction because we have Gleevec [imatinib] as a tool,” said Gilliland. “This is important because we can make inhibitors to all of the 96 tyrosine kinases in the human genome.”