Experimental small molecule inhibitor shows promise as melanoma treatment option

TAK-33 inhibited and regressed tumor growth in melanoma cell lines and patient-derived xenograft models. This “robust” success in the lab, according to a study published in Nov. 5, 2014 in Molecular Cancer Therapeutics, justifies continued clinical development as a potential therapy for melanoma patients.

University of Colorado Cancer Center researchers studied melanoma samples, using patient-derived xenografts, which are human melanomas grown in mice. They reported anti-cancer activity in 10 of 11 tumor samples treated with TAK-733. Treated tumors shrunk from zero to 100 percent.

While TAK-733 is a second-generation inhibitor in patients with BRAF mutations, this study suggests drug activity in the cancer regardless of BRAF mutation status.

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Particularly interesting is the activity in BRAF WT (wild type) models, where current approved therapy such as vemurafenib has been reported not to be active.

"The importance of this molecule is that it's a next-generation and highly potent inhibitor of a known melanoma pathway. It was highly effective against melanoma and the method of our study – using patient-derived tumor samples grown in mice – makes us especially optimistic that we should see similar results in the human disease," study author John Tentler, PhD, associate professor in medicine at University of Colorado says in a University of Colorado Cancer Center press release.

According to the release, the FDA approved vemurafenib to treat BRAF-mutant melanoma in 2011. But while vemurafenib response rates are around 80 percent for patients with BRAF mutations, response duration often is limited to two to 18 months. In the study’s abstract, authors reported particular interest in TAK-733’s activity in BRAF WT models, where approved therapies, such as vemurafenib, have not been shown to be active.

"We're learning how to use existing drugs better, for example RAF along with MEK inhibitors to block both mutations and thus a common mechanism of resistance. But there is also room for improvement in the drugs themselves and we hope that TAK-733 could improve on the results of existing, approved MEK inhibitors," Tentler says in the release. "There's always a need for better, more potent molecules.”

Source: Micel LN, Tentler JJ, Tan AC, Selby HM, Brunkow KL, Robertson KM, Davis SL,Klauck PJ, Pitts TM, Gangolli E, Fabrey R, O'Connell SM, Vincent PW, Eckhardt SG. Antitumor Activity of the MEK Inhibitor TAK-733 Against Melanoma Cell Lines and Patient-Derived Tumor Explants. Mol Cancer Ther. 2014 Nov 5.