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Archive

November 2008

New treatments for D842V mutations

Effective treatments for metastatic GIST were born in 2000 when Gleevec transformed the management of GIST. Treatment with Gleevec resulted in substantial benefit for 85 percent of GIST patients, up dramatically from the historical benefit rate of about 5 percent.

The 15 percent of patients that do not respond to Gleevec are made up of several groups, including some with wildtype GIST (no detectable mutation in KIT or PDGFRA, the two genes most commonly mutated in GIST). The other major group of patients that tend to not respond to Gleevec are patients with the most common PDGFRA mutation, a PDGFRAD842V mutation in exon 18. This mutation is also insensitive to treatment with Sutent. Patients with PDGFRAD842V mutations make up about four to five percent of all GIST patients.

Maria Debiec-Rychter, M.D, Ph.D., of the Catholic University of Leuven, Belgium and her colleagues, have recently identified two drugs that inhibit the PDGFRAD842V mutation and represent promising new treatments for patients with this mutation. Barbara Dewaele was the first author of the paper which was recently published in Clinical Cancer Research. Debiec-Rychter is a member of the LRG research team and this work was partially funded by the Life Raft Group.

The Leuven team found that dasatinib and IPI-504 were both effective inhibitors of PDGFRAD842V mutations in laboratory experiments. These experiments included tests against Ba/F3 cells (cells engineered to test specific mutations) and actual tumor cells taken from a patient with the PDGFRAD842V mutation.

Dasatinib has been extremely effective for Gleevec-resistant chronic myelogenous leukemia (CML) and it is approved for that purpose in the U.S. and other countries. Dasatinib is manufactured by Bristol-Myers Squibb and the trade name in the U.S. is Sprycel; while in trials, it is/was called BMS-354825. After a slow start in phase I trials that included 18 GIST patients, there is renewed interest in dasatinib for GIST, at least in some unexplored populations. There is an open phase II trial in Switzerland for GIST patients that have never had Gleevec (first-line treatment or “Gleevec-naive”). Gleevec-resistant GIST patients are also eligible for a phase II trial of dasatinib in advanced sarcomas in the United States.

IPI-504 also effectively inhibited the PDGFRAD842V mutation in the lab by a different mechanism than dasatinib. While dasatinib blocks the PDGFRA signal without damaging the PDGFRA protein, IPI-504 treatment results in the destruction of the PDGFRA protein. IPI- 504 is a HSP90 inhibitor manufactured by Infinity Pharmaceuticals. It is in phase III trials for GIST patients with resistance to Gleevec and Sutent.

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