Insight & Intelligence

More »

GEN News Highlights

More »
November 13, 2008

Genetic Variations in GI Tumors Determine Which Medications Are Efficacious

  • Scientists at Oregon Health & Science University Knight Cancer Institute  report further evidence that patients have different responses to medications depending on the specific makeup of their cancer. The research team, working specifically with gastrointestinal stromal tumors (GISTs), found that genetic variations in patients’ disease determine which medications will be most effective in treating the condition.

    Although the vast majority of GISTs respond well to Gleevec (imatinib), the FDA-approved first line of treatment for GIST, over time tumors may become resistant and regrow. To combat this problem, Sutent (sunitinib), a second drug tested in clinical studies and shown to be active in treating Gleevec-resistant GIST, is administered to patients. Pfizer, the maker of Sutent, was one of the sponsors of this study through the Portland VA Research Foundation.

    Gleevec targets mutations of the KIT or PDGFRA enzymes. KIT mutations are found in 80–85% of tumors. PDGFRA mutations are found in about 5% of tumors. No mutations of KIT or PDGFRA are found in the remaining 10–15% of wild-type tumors.

    The team first analyzed tumor specimens from almost 400 GIST patients who were treated with Gleevec. The presence and type of mutation predicted their response to Gleevec: patients with a certain type of KIT mutation—KIT exon 11, which is present in 70% of GIST patients—had the best response to Gleevec. The next-best response was by wild-type GISTs and then GIST with KIT exon 9 mutations. Exon 9-mutant GIST was more affected when patients received double the usual daily dose of Gleevec. In contrast, patients with other types of GIST did equally well on the standard daily dose of Gleevec.

    Like Gleevec, Sutent targets KIT and PDGFRA enzymes. However, unlike Gleevec, Sutent can also block blood vessel formation in GISTs. To better understand how Sutent works, investigators analyzed tumor samples from 78 subjects treated with Sutent as part of a Phase I/II study. Trial participants whose tumors had KIT exon 9-mutations or wild-type tumors survived better during Sutent treatment when compared with patients whose tumors had KIT exon 11-mutant tumors. The research group found that Sutent was more potent than Gleevec for inhibiting the aberrant KIT enzyme activity in KIT exon 9-mutant and wild-type tumors.

    In addition, the scientists established that a common cause of Gleevec-resistance in GIST is the development of new mutations that block the ability of Gleevec to inhibit the rogue KIT enzyme. In a test tube system, Sutent can inhibit some but not all of these resistance mutations.

    These results appear in the Journal of Clinical Oncology.