Patients with chronic myeloid leukemia (CML) who no longer respond to Gleevec are being enrolled in a Phase I trial of a new compound designed to overcome the problem of resistance.

The researchers who helped develop the compound said that if the new drug proves to be safe and effective in the clinic, patients with CML might in the future be treated with both drugs - and eventually with a cocktail of compounds similar to that used to treat diseases such as tuberculosis and HIV.

Neil Shah, assistant professor of hematology and oncology at the University of California at Los Angeles, told BioWorld Today: "We hope that this new drug will be as effective as imatinib [Gleevec], and as well tolerated. We expect that it will minimize the number of potential escape mechanisms that the disease can use to overcome imatinib."

Although cancers can be complex, he said, all cancers rely on one particular pathway to drive them. "The good news from this work is that when cancer cells become resistant to an inhibitor of that pathway, they don't seem to accomplish this by switching to an alternative pathway," Shah said. "This means that if we continue to hammer away at the critical pathway, we will eventually be able to have answers for all the tricks up the cancer's metaphorical sleeve."

The July 16, 2004, issue of Science reported preliminary studies of the new compound, called BMS-354825, in cells and an animal model. The paper is titled "Overriding Imatinib Resistance with a Novel ABL Kinase Inhibitor."

About 75,000 people worldwide are diagnosed with CML each year. In the disease, the genes BCR and ABL are fused together by a chromosomal translocation. Imatinib inhibits the resulting protein, which has a tyrosine kinase function: It plays a role in a cell-signaling pathway implicated in tumor development. The drug is highly specific, because the fusion protein is present only in the leukemic cells.

However, 10 percent to 15 percent of early phase CML patients treated with imatinib have become resistant to the drug after several years of therapy, and the number of patients developing resistance appears to be growing with longer-term follow-up. Furthermore, virtually all patients with advanced CML become resistant to imatinib within 18 months.

Shah and colleagues at UCLA, along with Charles Sawyers at the Howard Hughes Medical Institute and collaborators at Bristol-Myers Squibb Oncology in Princeton, N.J., investigated the mechanism of the resistance.

They knew from work carried out in 2000 by John Kuriyan, also of the Howard Hughes Medical Institute, that imatinib worked by binding to the Abl protein when it was in its "off" position. In 2002, a paper by Shah, Sawyers and Kuriyan in Cancer Cell reported that they had identified 15 different mutations in the BCR-ABL gene that caused resistance to imatinib.

Structural studies by Kuriyan showed that only a subset of patients had mutations at the precise point where imatinib would bind to the fusion protein to inhibit it. Instead, most patients had mutations that prevented the kinase from getting into its "off" position.

That suggested to Sawyers that a drug that binds the kinase when it is in the "on" position might be able to overcome the problem of resistance. Bristol-Myers Squibb already were developing a drug that would have that sort of function, and the two groups began their collaboration.

The Science paper reports how BMS-354825 can inhibit the proliferation of bone marrow progenitor cells that are positive for BCR-ABL from patients who are resistant to imatinib. The authors write that the results from those studies on human tissue samples indicate how BMS-354825 can select "for growth of rare normal progenitors present in these leukemic marrow samples."

When the investigators gave BMS-354825 to a mouse model of CML, the animals remained healthy after two weeks of therapy regardless of whether they carried cells containing mutant (imatinib-resistant) BCR-ABL or non-mutant BCR-ABL. Such mice treated with a control substance, by contrast, met criteria for euthanasia within 15 days. One mutant that is highly resistant to imatinib also appears to be resistant to the new compound.

Shah said: "BMS-354825 is the first compound that has been extensively tested against a panel of imatinib-resistant mutations, and it has impressive activity against 14 out of 15 such mutants. We have great hopes that this compound will be successful in treating CML patients whose disease has grown resistant to imatinib."

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