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The Next Step in GIST: When 'Miracle' Drugs Stop Working

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Posted: 8/31/2004

COLUMBUS, Ohio – Patients who can’t take or who no longer respond to what was once called a “miracle” drug for cancer may be helped by a new therapy that aims to scramble key signals that fuel tumors’ growth. The drug, called SU11248, may offer hope to patients with gastrointestinal stromal tumor (GIST) who were initially taking imatinib mesylate, or Gleevec.

Doctor Manisha Shah
Manisha H Shah, M.D.

When Gleevec was first introduced in 2001, it made headlines all over the world because it appeared to bring at least one form of cancer – chronic myelogenous leukemia (CML) – to its knees. If taken early enough in the development of CML, Gleevec can lead to remission in a matter of weeks, and while some scientists feel it may eventually prove to be curative, it is too soon to tell.

Scientists also discovered Gleevec can be stunningly effective for some patients with GIST – slow growing, often overlooked cancers that often take root in the connective tissue around the stomach or bowel and are resistant to chemotherapy or radiation.

Gleevec is useful in treating both CML and GIST because it blocks the activity of certain proteins and growth factors (tyrosine kinases) that misfire in both forms of the disease.

“Initially, gastrointestinal tumors are often mistaken for something else,” says Dr. Manisha Shah, an oncologist in The Ohio State University Comprehensive Cancer Center. “Patients with GIST usually don’t have any early symptoms and surgery gets ruled out because the cancer has often spread by the time they first see their doctors. That’s why we were so pleased to see that Gleevec could virtually melt away these gigantic tumors in some patients.”

Despite Gleevec’s initial success, however, some patients with CML or GIST are finding that after a while, the drug stops helping them. Their cancers change, creating new mutations that enable them to withstand even the most effective therapies. This phenomenon, called chemoresistance, is forcing scientists at Ohio State and elsewhere to re-evaluate the limitations of molecularly targeted therapy and work quickly to develop treatments, like SU11248.

“Chemoresistance is one of the most frustrating problems we encounter in treating almost every kind of cancer,” says Dr. William Blum, an oncologist who specializes in leukemia at The Ohio State University Arthur G. James Cancer Hospital and Richard J. Solove Research Institute. He says new agents like SU11248, and others, may be the next step in dealing with evolving mutations that render cancer cells chemoresistant.

Patients with GIST at The James enrolled in a phase III trial evaluating SU11248 are randomized into either a treatment group or a control group. It is a double-blind study, meaning that neither the participants nor their physicians know who is getting SU11248 and who is taking a placebo. Patients on the study take one pill a day, and researchers will evaluate them to see if the drug can shrink their tumors or delay the time until the cancer spreads.

SU11248 can help block the development of new blood vessels to feed the growth of new tumors and slow tumor growth by interfering with important growth signals.

Results from an earlier trial found SU11248 beneficial to just over half of those in the study, but their tumor shrinkage was not substantial enough to merit approval of the drug based on an uncontrolled trial. In addition, roughly a third of the patients experienced significant side effects, like diarrhea, fatigue and low blood counts.

Shah says this new study, which is much larger and also includes a control group, should offer clearer and more useful data about any benefits SU11248 may offer patients with Gleevec-resistant GIST. The trial is open at dozens of major cancer centers around the world; investigators are hoping to identify at least 350 patients who would be appropriate for the study

GIST is a relatively rare cancer, accounting for only 5,000 new cases in the United States each year.

The study is sponsored by Pfizer.

The Ohio State University Comprehensive Cancer Center is a network of interdisciplinary research programs with over 200 investigators in 13 colleges across the OSU campus, the Arthur G. James Cancer Hospital and Richard J. Solove Research Institute and Children’s Hospital, in Columbus. OSUCCC members conduct research on the prevention, detection, diagnosis and treatment of cancer, generating over $95 million annually in external funding.

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Michelle Gailiun
Medical Center Communications

Cancer; Clinical/Translational Research; James Cancer Hospital; OSU Medical Center; Treatment Options