A new target has been found for wild-type and pediatric GIST. GISTs without mutations in either of the two genes commonly mutated in GIST typically respond poorly to Gleevec. Andrew Godwin, Ph.D. of Fox Chase Cancer Center and other researchers appear to have found a major driving force in these tumors. Dr. Godwin presented his findings at the 2008 American Society of Clinical Oncology (ASCO) meeting in Chicago on Saturday, May 31. In addition, Dr. Godwin’s work is scheduled to be published in the Proceedings of the National Academy of Sciences (PNAS) on June 1, 2008.
Effective targeted therapies such as Gleevec rely on blocking pathways that are critical to a specific cancer. Gleevec inhibits the aberrant signaling caused by KIT and PDGFRA gene mutations (although some mutations are resistant to Gleevec). KIT mutations are involved in about 80 percent of GISTs and PDGFRA mutations are the driving force in another five to eight percent of GISTs. The other ten to 15 percent of GISTs without KIT or PDGFRA mutations are called “wild-type GISTs”.
Mutations that alter a proteins shape and function are one cause of abnormal signaling in cancer cells, but they are not the only cause. Sometimes cancer cells have too much (or too little) of a protein (over expression). Godwin and his colleagues at Fox Chase have found that wild-type GISTs have extra copies of the insulin-like growth factor 1 receptor (IGF1R) gene and they make way too much of the IGF1R protein.
Two groups; Cristina Antonescu, M.D., and colleagues of Memorial Sloan-Kettering Cancer Center and Godwin and colleagues have both shown that IGF1R is also over expressed in pediatric GIST (another type of “wildtype GIST”).
In an interview with Michael Smith of Medpage Today, Dr. Godwin said, “Our real excitement is that we think this might be the oncogenic driving force” behind wild-type GIST. “We’re talking to companies right now about possible clinical trials,” Dr. Godwin told Medpage today.
Godwin’s team tested an IGF1R inhibitor, NVP-AEW541 (Novartis) against Gleevec-sensitive and Gleevec-resistant GIST tumor cells and found that it induced a cytotoxic response as a single agent and a strong cytotoxic response in combination with Gleevec.
In an audio interview on the Medpage Today website, Godwin said that Fox Chase currently tests for KIT and PDGFRA mutations and is setting up assays to be used in the clinic to measure the level of IGF1R in GIST.
Although Godwin found that IGF1R was highly over expressed in wild-type GIST versus GISTs with mutations in KIT or PDGFRA, he did note in his ASCO presentation that IGR1R was, in general, activated in GISTs. C. Braconi and colleagues have shown that the IGF1 receptor (IGF1R) and two IGF growth factors (ligands), IGF1 and IGF2 can be over expressed in some GISTs and that higher levels of IGF1 and IGF2 correlated with shorter times to recurrence after resection of primary tumors. This raises the question of whether or not anti-IGF1R therapy might be useful in GISTs with KIT or PDGFRA mutations as well.
In a paper published in Clinical Cancer Research on May 15, 2008, Dr. Cristina Antonescu reaffirmed her earlier finding that IGF1R was over expressed in pediatric GIST providing additional support for anti-IGR1R therapy for wild-type and pediatric GIST. In addition, Dr. Antonescu tested several of the most popular KIT inhibitors against cells that were engineered to be dependent on wild-type KIT. In this screen of the five more popular KIT inhibitors, Gleevec was found to be the least effective at inhibiting wild-type KIT (see Table). Although the KIT gene is not mutated in wild-type GIST, the KIT protein is known to be strongly activated and to date has still been the primary target in wildtype GIST, including pediatric GIST. It remains to be seen whether therapy that targets both KIT and IGF1R will be needed to control wild-type GISTs.
The new findings and the possibility of new clinical trials provide new hope for both children and adults with wildtype GIST.