Studies of Drug Resistance May Lead to Individual Therapy for Rare Cancers

DURHAM, N.C., July 2 /PRNewswire/ -- For patients with a rare form of cancer called "gastrointestinal stromal tumor" (GIST), therapy with the drug imatinib (Gleevec(R)) has revolutionized treatment. However, the cancer may continue to grow despite imatinib: immediately in some patients, or after an initial response in others. An article in the June issue of The Oncologist looks at recent research into the reasons for this imatinib resistance -- including results that may open the way to individualized treatment for GIST in the near future.

Based on new discoveries, "[S]everal strategies are already in use for patients with imatinib-refractory disease and it can be expected that other active systemic treatments will be developed on the basis of this improved insight," concludes the article by Dr. Stefan Sleijfer and colleagues of Erasmus University Medical Center, Rotterdam, The Netherlands.

Gastrointestinal stromal tumors are rare cancers of the gastrointestinal tract. If detected early, GIST can be treated by surgery. In the past, more advanced cases of GIST were treated by standard chemotherapy. However, the response was not as good as in patients with other types of cancer.

In recent years, imatinib has been introduced as a new approach to treatment for advanced GIST. (Imatinib is also used to treat patients with chronic myelogenous leukemia.) It has been shown that the growth of GIST is driven by the receptor c-Kit, which depends on an enzyme called tyrosine kinase to exert its function. Imatinib blocks the tyrosine kinase of c-Kit. With standard chemotherapy, only about half of patients were alive one year after diagnosis. With imatinib, one-half of the patients are still alive more than five years later.

"However, it appears that many, if not all, patients with advanced GISTs eventually experience progressive disease during imatinib treatment," Dr. Sleijfer and colleagues write. Studies suggest that there are actually two kinds of progression. Ten to fifteen percent of patients have "early progression" -- they never really have a good response to imatinib. In most cases, this form of imatinib resistance appears to be related to certain mutations involving the tyrosine kinase pathway of c-Kit.

Other patients have "late progression" -- at first the cancer shrinks in response to imatinib, but later progresses despite treatment. The most common cause seems to be the development of new mutations that make the cancer less sensitive to imatinib. Other mechanisms of late resistance also occur, and more are likely to be identified in the future.

Trials have evaluated alternative treatments for imatinib-resistant GIST, whether early or late. Some patients will respond to a higher dose of imatinib; others can be switched to other drugs targeting the tyrosine kinase pathway. Still other strategies are currently being studied.

With the discovery that specific patterns of imatinib resistance are related to specific mutations, GIST could become one of the first types of cancers for which truly individualized treatment can be given. "In particular, the insight that c-Kit mutants differ in their sensitivity to different doses of drugs or to different compounds will contribute to this," Dr. Sleijfer and coauthors write.

The logical first step would be testing for the specific c-Kit mutations present in GISTs, before the start of treatment. This would help to identify patients likely to have a better or worse response to initial imatinib treatment. In the future, different treatment approaches could be designed according to the patient's specific pattern of mutations. Already, higher doses of imatinib are being used for patients with certain c-Kit mutations -- the effects on overall survival remain to be seen.

Although much more research will be needed, mutation testing might allow treatment to be tailored to the individual patient -- not just the dose, but also the drug used. Dr. Sleijfer and colleagues write, "One of the major challenges in oncology is individualization of treatment, and GIST may be one of the first diseases in which this could become a reality."

The new article, entitled, "Improved Insight into Resistance Mechanisms to Imatinib in Gastrointestinal Stromal Tumors: A Basis for Novel Approaches and Individualization of Treatment," is available online at http://www.theoncologist.com/ and in print in the June issue of "The Oncologist."

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