Study in New England Journal of Medicine shows targeted protein is central to GIST growth
Researchers are confident they have proven that a deadly, untreatable gastrointestinal cancer is triggered by one protein that can be stopped with the drug Gleevec. More than half of patients suffering from gastrointestinal stromal tumors (GIST) have gone into remission on Gleevec, and another quarter of patients have seen their disease stopped in its tracks, according to an article to be published in the New England Journal of Medicine on Aug. 15.
The study, conducted at four sites in the U.S. and Finland, including Portland, looked at 147 GIST patients who had failed surgical or chemotherapy treatment for the disease and began taking Gleevec. Within weeks to months, 53.7 percent of patients had a partial response, including shrinkage of tumors, and another 27.9 percent of patients had no further progression of the disease.
"In essence, three-quarters of patients in this study were doing better, a remarkable result considering that this type of cancer typically ravishes the body very quickly and kills patients within months," said co-principal investigator Charles Blanke, M.D., associate professor of medicine in the Oregon Health & Science University School of Medicine and the Portland Veterans Affairs Medical Center.
Researchers say these results demonstrate that in many cases GIST is driven by a single abnormal protein, KIT, which is shut down by Gleevec.
"Just as this drug shut down the single abnormal protein in chronic myelogenous leukemia (CML) and proved to be a remarkable treatment for that disease, we think the same thing is happening with GIST," said Michael Heinrich, M.D., associate professor in the OHSU School of Medicine and PVAMC.
Heinrich was one of the scientists who deduced that Gleevec, which shuts down the BCR-ABL protein in CML, might also work effectively against KIT, a structurally similar protein. In laboratory experiments, the theory worked, so Heinrich enlisted the help of Blanke to test the drug on GIST patients who express KIT in their tumors.
"It worked better than we could have predicted," said Blanke. "This is exciting news, not just because these results validate the theory of targeted therapy, but because these patients have no other options. Not only are we seeing shrinkage in size and quantity of tumors, but patients are feeling better than they have in many months."
GIST affects about 5,000-10,000 Americans a year, striking any of the organs in the entire length of the gastrointestinal tract or its lining. These tumors are prone to spread to other organs and, once spread, they often are unresponsive to chemotherapy or irradiation and are invariably fatal. Clinical trials for GIST using Gleevec began in July 2000 at OHSU, Dana-Farber Cancer Institute in Boston, Fox Chase Cancer Center in Philadelphia and Helsinki University Central Hospital in Finland. Scientific studies were carried out at PVAMC in Portland, with the assistance of Christopher Corless, M.D., Ph.D.
Gleevec was approved by the Food and Drug Administration in record time for chronic- and acute-phase CML treatment in May 2001. The FDA approved the drug for treatment of GIST in February 2002. Gleevec is being tested on several other diseases that express proteins thought to be blocked by its activity. This week's New England Journal of Medicine cites four cases of a rare bone marrow condition called myeloproliferative disorder that were treated using Gleevec.
"We have always thought of Gleevec as a paradigm to develop other targeted drugs for cancer treatment," said Brian Druker, M.D., JELD-WEN Chair of Leukemia Research at the OHSU Cancer Institute, who collaborated with scientists at pharmaceutical company Novartis to develop Gleevec. "It's amazing to see this same drug succeed at treating other diseases, and we hope that this will become the rule rather than the exception."