Gleevec is a beacon of sorts, a herald of the new era of molecular medicine. It was one of the first cancer drugs to target a specific molecular cause of cancer, rather than more general features such as dividing cells. Gleevec binds to the active form of BCR-ABL, a hyperactive kinase produced by a chromosomal translocation, the so-called Philadelphia chromosome, at which parts of chromosome 9 and 22 trade places.

Gleevec, made by Novartis AG, of Basel, Switzerland, is approved for use in two cancers: chronic myeloid leukemia (CML) and gastrointestinal stromal tumors, a form of stomach cancer. Research published in the Dec. 1, 2004, issue of the Journal of Clinical Oncology shows that Gleevec is a promising treatment for AIDS-related Kaposi's sarcoma, too.

But Gleevec also is a reminder that molecular medicine does not equal panacea. Many CML patients have either Gleevec-resistant forms of the disease from the outset or develop such resistance after a few years of treatment. In fact, because CML is characterized by a rapidly dividing cell population, patients ultimately have mixed populations of leukemic bone marrow cells with different mutations, and "development of resistance is essentially inevitable," Stephen Burley, chief scientific officer of Structural GenomiX, told BioWorld Today.

In that sense, CML is analogous to rapidly replicating viruses, such as HIV, that also favor the development of resistance if treated with only one drug.

From The Pages Of Science Into The Clinic

In the July 16, 2004, issue of Science, researchers from the University of California at Los Angeles School of Medicine and Bristol-Myers Squibb Co. published experiments in animal models and in bone marrow cells of CML patients showing that a new compound, BMS-354825, was effective in combating Gleevec-resistant CML. (See BioWorld Today, July 19, 2004.)

Now, in research presented at the recent American Society of Hematology (ASH) annual meeting, scientists from the University of California at Los Angeles and the MD Anderson Cancer Center in Houston have followed up that publication with encouraging Phase I data.

They investigated both the hematological response (a reduced production of leukemic cells, which correlates with reduced clinical symptoms) and the cytogenetic response (which investigates chromosomal abnormalities, specifically the continued presence of the Philadelphia chromosome in the leukocyte population). Thirty-six patients with relatively early stage CML and 29 patients in the more-advanced phases of the disease were studied.

About 85 percent of patients with relatively early stage CML, and roughly 75 percent to 80 percent of patients in the more advanced phases, showed a hematological response. Cytogenetic data were not available for all patients, but slightly more than a quarter of early stage and slightly more than half of late-stage patients for whom data were available showed a cytogenetic response.

BMS-354825 appears to be successful at targeting Gleevec-resistant mutants because it is somewhat less specific than Gleevec itself - an ironic twist, given the underlying philosophy that drove Gleevec's development, and molecular medicine in general, is that molecular targeting will lead to better efficacy at reduced toxicity.

The BCR-ABL tyrosine kinase has two different shapes, depending on whether it is in an active or inactive state. Gleevec binds to BCR-ABL only when it is in its off position; many mutations that lead to Gleevec resistance prevent the protein from relaxing into the off position in the first place. BMS-354825 casts a wider net - it inhibits five proteins, including BCR-ABL in both its off and on forms.

While BMS-354825 and other agents appear to be successful in dealing with many mutations that confer Gleevec resistance, one particular mutation that has proved intractable to date has been T315I. The mutant is a particularly nasty combination: It confers resistance to Gleevec that cannot be overcome through the use of higher doses, and it has proved hard to develop other agents that are effective against it.

Next Up: Targeting The T315I Mutant

But scientists at San Diego-based Structural GenomiX might have developed an inhibitor that is effective against the T315I mutant.

"We believe that the optimal way to approach CML is a combination chemotherapy with multiple inhibitors that target both wild-type and mutant forms of the BCR-ABL kinase," Structural GenomiX's Burley said. "And we made the judgment that the [mutation] you have to hit is T315I, because it renders cells absolutely resistant to Gleevec."

Structural GenomiX used its drug discovery technologies, including X-ray crystal structures of wild-type and T315I mutants, to identify lead compounds that are active against both forms of the BCR-ABL kinase. One of those compounds now is in preclinical development, and Structural GenomiX hopes to file an investigational new drug application by late 2005. Structural GenomiX has not published any data on the inhibitor, but academic scientists, including scientific advisory board member Brian Druker, of Oregon Health Sciences University, and Frank Giles, of MD Anderson Cancer Center, presented data on the compound at this year's ASH meeting.

No Comments