Editors' ChoiceCancer

Targeting Melanoma: Endothelin B Receptor Makes an Encore

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Science Translational Medicine  09 Feb 2011:
Vol. 3, Issue 69, pp. 69ec17
DOI: 10.1126/scitranslmed.3002178

Melanoma is an aggressive cancer and, as such, is a frequent target of new therapies, including new small-molecule inhibitors, immunotherapies, and antisense-directed agents. In a recent paper by Asundi et al., the authors evaluated the potential therapeutic utility of targeting the endothelin B receptor (ENDRB), which was identified as an overexpressed mRNA in melanoma cells. (ENDRB is expressed at low levels in normal tissue.) The authors first reduced the expression of ENDRB with shRNA, but only saw a small effect on tumor growth in mouse xenograft models. However, targeting this cell-surface molecule with a monoclonal antibody resulted in its rapid endocytosis and internalization into melanoma cells. The authors then coupled the antibody to the antimitotic agent monomethylauristatin E (MMAE) and administered this conjugate to human melanoma cell lines in vitro, as well as to their xenograft mice. Both treatments resulted in a dramatic reduction in tumor survival. Interest in ENDRB—known to be important in the proliferation and migration of melanoma cells from the neural crest—is not new: Prior studies have evaluated the ability of small-molecule inhibitors or dual-receptor antagonists to target ENDRB without success. However, the potential utility of a new selective antibody combined with MMAE may prove to be the magic bullet. As human melanomas appear to express even more ENDRB than the preclinical model examined in this paper, these results may point to another intriguing therapy for the treatment of melanoma.

J. Asundi et al., An antibody-drug conjugate targeting the endothelin B receptor for the treatment of melanoma. Clin. Cancer Res. 18 January 2011 (10.1158/1078-0432). [Abstract]

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