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Glee for Gleevec

By Sean Henahan, Access Excellence

Los Angeles, CA (6/21/01)- Rarely has the world of cancer research seen such enthusiasm as that surrounding the approval of new treatment called Gleevec. The new drug can be taken as a pill, has fewer side effects than standard chemotherapy, and appears to produce dramatic results in patients with certain types of cancer. Even a new report that some cancers may develop resistance to the treatment has not discouraged the research community, where the feeling is that new drugs can be developed that may improve upon the positive results seen with Gleevec while reducing side effects and resistance.

Gleevec (matinib mesylate, formerly known as STI571), was approved by the USFDA in May of this year for the treatment of chronic myelogenous leukemia (CML). Recent reports from medical conferences indicate the drug also benefits some patients with gastrointestinal stromal tumor or GIST. While clinicians are truly excited by the positive results they are seeing with this drug, what really thrills them is that this drug works quite differently than all the other cancer treatments than have come before.

The traditional approach to the treatment of various cancers has involved the use of toxic chemotherapeutic agents and/or radiation, both of which can be difficult to administer and are poorly tolerated by patients. That is because traditional treatments kill cancer cells by interrupting cellular processes in both cancerous and noncancerous tissues. The debilitating side effects of traditional chemotherapy include nausea, fatigue and temporary hair loss. Gleevec, in contrast, acts by blocking an enzyme found only in certain types of cancer cells. While side effects with Gleevec can include nausea, vomiting, fluid retention, muscle cramps and headache, patients generally tolerate the drug much better than standard treatments.

HOW IT WORKS

Gleevec was custom designed to treat CML. CML results through a chromosomal rearrangement that fuses two genes together. This produces an oncogene that encodes an enzyme, a form of tyrosine kinase known as BCR-ABL. Unchecked production of that enzyme leads to excessive levels of white blood cells in the blood and bone marrow. that disrupts the normal production of white blood cells. Gleevec works specifically to block the activity of that form of tyrosine kinase.

"For the first time, cancer researchers now have the necessary tools to probe the molecular anatomy of tumor cells in search of cancer-causing proteins. Gleevec offers proof that molecular targeting works in treating cancer, provided that the target is correctly chosen. The challenge now is we've got to find these targets," noted Richard Klausner, M.D., director of the National Cancer Institute.

Gleevec was the hot topic at the recent annual meeting of the American Society of Clinical Oncology. Researchers presented data from clinical studies confirming the utility of this drug in the treatment of chronic myelogenous leukemia. They also provided new data indicating the drug benefits some patients with GIST. Interestingly, it appeared that the drug inhibited a different form of tyrosine kinase than that seen in CML. This is particularly important, since GIST does not respond to standard chemotherapy or radiation treatment.

"This work is based on an understanding of the genetic mechanisms that characterize this type of cancer. Laboratory experiments predicted this medication might work in GIST, and we have been tremendously pleased with the clinical benefits which the majority of patients achieved in this trial." said researcher George Demetri, M.D., of Dana-Farber Cancer Institute.

"This research is important for two reasons. First, we may have a treatment option for a disease that does not currently respond to any known therapy- radiation or chemo. Second, this will hopefully serve as a pattern for how future solid tumor research may be successfully done," said Charles Blanke, MD, Associate Professor of Medicine at Oregon Health Sciences University, Portland.
Researchers also presented preliminary data indicating that Gleevec may prove useful as a treatment for other cancers, including small cell lung cancer, chronic myelomonocytic leukemia, and glioblastoma.

RESISTANCE?

One of the more frustrating problems in cancer therapy is that patients' cancerous cells can mutate and develop resistance to virtually any chemotherapeutic agent. While resistance has not been seen in CML patients with the early form of the disease, a new study in Science suggests that patients with more advanced form of CML may not fare as well. Dr. Mercedes E. Gorre and her colleagues at UCLA evaluated nine cases of patients with advanced disease who had developed resistance to Gleevec. They found that in each case resistance was associated with reactivation of the causal oncogene. In some cases the oncogene has mutated in such a way as to alter the enzyme's ability to bind to Gleevec. In other cases, the oncogene mutated to produce even higher levels of the enzyme.

The researchers are nonplused by this finding. Rather, they are optimistic, since a common mutation pattern was seen in many of the patients. That suggests that it will be possible to design a new compound to inhibit the mutant oncogene and overcome resistance.

THE LONG AND WINDING RESEARCH ROAD

The arrival of Gleevec highlights the long, incremental nature of cancer research. The road to FDA approval for Gleevec began way back in 1960 when researcher Peter Nowell reported that patients with chronic myelogenous leukemia consistently had an abnormally small chromosome 22. This alteration became known as the Philadelphia chromosome, and opened a new avenue of research. By 1973, new techniques allowed researchers to understand the elements of chromosomal translocation between chromosome 22 and chromosome 9. About ten years later researchers showed that the the abl proto-oncogene was located on chromosome 9 in non-CML patients and translocated to the Philadelphia chromosome in patients with CML. In the 1980s researchers determined that the abl oncogene was activated by this translocation. It then became clear that a fused protein product, called BCR-ABL, was associated with 95 percent of CML cases. Subsequent studies confirmed that bcr-abl by itself could cause leukemia in mice. Since that time scientists concentrated on developing ways to biochemically block BCR-ABL. The lead compound, STI571 made its way through the clinical trial process, and showed some remarkable results, with relatively mild side effects. The drug, now dubbed, Gleevec was approved this year.

Cancer researchers caution that long-term results of Gleevec therapy are still not known. Longer term follow-up will be necessary to better understand both the benefits and potential side effects of the drug. Meanwhile, many research groups are developing potential therapies based on tyrosine kinase inhibition. Compounds currently being investigated include the epidermal growth factor receptor, protein kinase C, and the vascular endothelial growth factor receptor.

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