GIST specialist surgeon Dr. Ron DeMatteo, along with colleagues at Memorial Sloan-Kettering Cancer Center (MSKCC), has published a new paper in the April issue of Cancer Research with potentially important implications for the GIST community. “Pharmacological Inhibition of KIT Activates MET Signaling in Gastrointestinal Stromal Tumors” explores the science behind the MET receptor, a fairly new avenue of study in GIST research, and the efficacy of two drugs, crizotinib and cabozantinib, which leverage it.
Although the c-Kit receptor’s role in GIST has been well documented, DeMatteo’s group observed that treatment with imatinib (Gleevec) also activates a receptor called MET (also known as c-MET). This news is of special importance to those patients for whom imatinib is not (or is no longer) effective (i.e. imatinib-resistant), since MET is activated in imatinib-resistant cell lines as well.
The group discovered that employing a MET inhibitor such as crizotinib (used in some types of lung cancer), was toxic to the imatinib-resistant cell lines, and the combination of imatinib and crizotinib was more effective than imatinib alone in multiple pre-clinical models of GIST. Their conclusion was that “…MET activation occurs in GIST and upregulation of MET may contribute to imatinib-resistance in vivo. Furthermore, targeting MET is a promising strategy for the treatment of both imatinib-sensitive and –resistant GIST.” DeMatteo’s findings were verified over multiple tests on human specimens with advanced GIST as well as in a genetically engineered mouse model.
In addition to the MET inhibitor crizotinib, the MSKCC group also performed experiments with another drug, cabozantinib. Currently FDA-approved for medullary thyroid cancer, it not only inhibits MET, but is a potent KIT inhibitor as well. Cabozantinib (approved name-Cometriq) demonstrated profound anti-tumor effects in multiple preclinical models including both imatinib-sensitive and imatinib-resistant GISTs.
Relevance of study for GIST patients
When asked why this is of immediate relevance, Dr. DeMatteo stated, “We are trying to say that cabozantinib could be applied to human GIST right away, given how effective it was in our models. Ideally, we could start with a clinical trial, but off-label treatment is potentially possible and the drug is already FDA- approved for a form of thyroid cancer.”
While a cabozantinib clinical trial is already being planned in Europe for GIST patients, it could in theory be prescribed off-label for patients resistant to the three FDA-approved GIST drug therapies. Whether or not it would be covered by insurance is unclear at this point.
According to Dr. DeMatteo, “Because cabozantanib is so effective, we speculate that it may even be preferable to imatinib up front.” LRG Science Director, Jerry Call agrees, citing cabozantinib, in his opinion, as the most promising next drug for KIT mutation GISTers who are resistant to approved therapies. He provides the caveat, however, that to his knowledge the drug has yet to be tried in a GIST patient and therefore, there is only limited information available about potential side effects.
Following LRG Research Team member Dr.Maria Debiec-Rychter’s 2013 CTOS poster, DeMatteo’s article marks the second top-tier research group to publish encouraging results with cabozantinib. In their conclusions the authors noted, “Given that most patients who develop imatinib resistance eventually experience disease progression on the three currently approved tyrosine kinase inhibitors, imatinib, suntinib, and regorafenib, there is an urgent need for additional therapeutic options, and our findings have immediate clinical relevance.”