Antibody hinders growth of Gleevec-resistant gastrointestinal tumors in lab tests

Public release date: 4-Feb-2013 [ | E-mail | Share ]

Contact: Krista Conger kristac@stanford.edu 650-725-5371 Stanford University Medical Center

STANFORD, Calif. - An antibody that binds to a molecule on the surface of a rare but deadly tumor of the gastrointestinal tract inhibits the growth of the cancer cells in mice, according to researchers at the Stanford University School of Medicine.

The effect remains even when the cancer cells have become resistant to other treatments, and the findings may one day provide a glimmer of hope for people with the cancer, known as gastrointestinal stromal tumor, or GIST. The scientists hope to move into human clinical trials of the antibody within two years.

The antibody's target is a receptor called KIT, which is often mutated in patients with the cancer. When mutated, KIT sends a continuous stream of messages into the cell urging it to grow uncontrollably. The Stanford researchers found that the antibody reduces the amount of KIT on the surface of the cancer cells and stimulates immune cells called macrophages to kill the rogue cells.

Currently, people with GIST are often treated first with surgery and then with the drug imatinib, marketed as Gleevec - a small molecule that also targets KIT. The treatment, which was approved for GIST in 2002, has been remarkably successful: It has increased the average survival time of many people with advanced disease from about 18 months to about five years. It was the first targeted small molecule inhibitor that proved effective against a solid tumor, but its effect is temporary.

"Gleevec, or imatinib, marked a paradigm shift in our understanding about cancer treatment and sparked much additional research into these inhibitors," said Matt van de Rijn, MD, PhD, professor of pathology. "However, a new mutation almost always occurs over time in KIT that renders the tumor insensitive to the drug. We've found that treatment of these resistant cells with an antibody targeting KIT slows the growth of human GIST cells in cell culture and in animals, and increases their chances of being removed by the immune system."

The researchers believe it may be possible that the anti-KIT antibody treatment could be used as an alternative to, or even in combination with, imatinib or other small-molecule or antibody-based therapies to provide better control of the cancer.

"We're moving from an era in which, historically, patients are often treated with a single agent or class of agents into a time when tumors might be treated with more than one approach from the moment of diagnosis," said van de Rijn.

He is a co-senior author of the study, which will be published online Feb. 4 in the Proceedings of the National Academy of Sciences. Irving Weissman, MD, director of Stanford's Institute for Stem Cell Biology and Regenerative Medicine, is the other co-senior author. Former graduate student Badreddin Edris, PhD, postdoctoral scholar Stephen Willingham, PhD, and graduate student Kipp Weiskopf share first authorship of the paper. Weissman is also a member of Stanford's Cancer Institute.

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Antibody hinders growth of Gleevec-resistant gastrointestinal tumors in lab tests