From The University of Chicago and Loyola University Chicago, Chicago, Illinois; the University of Texas M. D. Anderson Cancer Center, Houston, Texas; and the National Institute on Aging, National Institutes of Health, Bethesda, Maryland
Authors disclosures of potential conflicts of interest are found at the end of this article.
Address reprint requests to Thomas F. Gajewski, MD, PhD, The University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637; e-mail: tgajewsk{at}medicine.bsd.uchicago.edu
Overview: Although significant focus in the development of targeted therapies for melanoma has centered upon the Ras/Raf/mitogen-activated protein (MAP) kinase casade, early clinical trial results using agents that target this pathway have been disappointing. Continued study of melanoma biology has revealed additional features of metastatic melanoma that could explain aggressive tumor behavior and therapeutic resistance. Fortunately, characterization of these molecular alterations has pointed toward new potential therapeutic targets for this disease. Two broad categories of target are discussed in this review: metabolic enzymes expressed in the tumor microenvironment, and developmental signaling pathways active in aggressive melanomas. Strategies are being developed to interfere with these signals that are poised for translation into the clinic.