Candidate Drug Shows Impressive Activity against Aggressive Melanoma in Mouse Model

A low molecular weight inhibitor of the V600E mutated form of the BRAF oncogene demonstrated potent antitumor activity in a preclinical trial of melanoma cells growing in culture and in a mouse xenograft model.

A paper published in the June 15, 2010, online edition of the journal Cancer Research by investigators at Hoffmann-La Roche, Inc., (Nutley, NJ, USA) and Plexxikon, Inc. (Berkeley, CA, USA) reported the preclinical characterization of the antitumor activity of the drug RG7204 (PLX4032) using established in vitro and in vivo models of malignant melanoma.

Results showed that the drug potently inhibited proliferation and mitogen-activated protein/extracellular signal-regulated kinase (ERK) and ERK phosphorylation in a panel of tumor cell lines, including melanoma cell lines expressing the BRAF-V600E mutation (at amino acid position number 600 on the BRAF protein, the normal valine is replaced by glutamic acid). About 60% of melanomas have the V600E mutation.

In contrast, RG7204 lacked activity in cell lines that expressed wild-type BRAF or non-V600 mutations. In several mouse tumor xenograft models of BRAF-V600E-expressing melanoma, RG7204 treatment caused partial or complete tumor regressions and improved animal survival, in a dose-dependent manner. There was no toxicity observed in any dose group in any of the in vivo models tested.

"Patients with advanced melanoma currently do not have a lot of options. There are some therapies, but the response rates are very low. Based on this promising preclinical data, we believe this compound merits further study in patients with advanced melanoma,” said contributing author Dr. David Heimbrook, global head of discovery oncology at Hoffmann-LaRoche.

Related Links:
Hoffmann-La Roche, Inc.
Plexxikon, Inc.