ABCB5 is a multidrug resistance transporter recently shown to be preferentially expressed by cells ofmelanocytic lineage and to be responsible for conferring resistance to chemotherapy in vitro. For example,inhibition of ABCB5 renders normally resistant melanoma cells susceptible to doxorubicin. Subsequent workhas shown that ABCB5 expression 1) marks melanoma cells of stem cell phenotype and function; 2)correlates with tumorigenic growth of melanoma cells in vivo; and 3) is more abundant in human malignantmelanoma than in benign melanocytic nevi. In tandem with fundamental approaches to further establishingABCB5 as an identifier of melanoma stem cells (MF, separately funded), we here propose to explore theclinical relevance of ABCB5 as a biomarker of melanoma progression, prognosis, and outcome, as well as todemonstrate the therapeutic efficacy of ABCB5 targeting in a relevant animal model of human malignantmelanoma. The technologies that will be employed to accomplish these goals range from tissue microarraysto detailed analysis of primary human melanomas supported by prognostic and outcome data to a SCIDmouse bioassay in which melanomas develop in xenografted human skin in a manner that recapitulatesnaturally-occurring disease and in which ABCB5+ tumor cells may be therapeutically targeted. In sum, theseapproaches will determine the clinical relevance and therapeutic importance of this novel biomarker, andshould pave the way to eventual clinical therapeutic trials focused on targeting of ABCB5* melanoma stemcells.
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