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Solid tumors

BRAF; smoothened (SMO)

Studies in patient samples and cell culture suggest BRAF and SMO inhibitors could be useful for treating ameloblastomas, which are rare, typically benign tumors that form in the jaw. Whole-transcriptome sequencing of ameloblastoma samples from 28 patients showed that 11 had SMO mutations and 13 had BRAF mutations, all of which were primarily activating mutations. In an immortalized mouse ameloblast-lineage cell line that expressed one of the identified activating mutations in Smo, the hedgehog pathway inhibitor Trisenox arsenic trioxide decreased hedgehog pathway activity compared with vehicle. In a human ameloblastoma cell line that expressed one of the identified activating mutations in BRAF, the BRAF inhibitor Zelboraf vemurafenib blocked proliferation with an IC50 value of 0.19 mM. Next steps could include developing animal models of ameloblastoma and using them to evaluate drugs that inhibit the hedgehog pathway or BRAF.
Teva Pharmaceutical Industries Ltd., H. Lundbeck A/S and Nippon Shinyaku Co. Ltd. market Trisenox to treat acute promyelocytic leukemia (APL).
Roche, Daiichi Sankyo Co. Ltd. and Chugai Pharmaceutical Co. Ltd. market Zelboraf to treat melanoma.

SciBX 7(25); doi:10.1038/scibx.2014.735
Published online June 26, 2014

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Sweeney, R.T. et al. Nat. Genet.; published online May 25, 2014;
Contact: Robert B. West, Stanford University Medical Center, Stanford, Calif.