BIOLOGY AND THERAPEUTIC TARGETING OF IL-8 AND MUC18/MCAM

点击翻译按钮获取中文摘要

Expression of interleukin-8 (IL-8) by human melanoma cells correlates with their metastatic potential in vivo. Moreover, UV-B irradiation of primary cutaneous melanoma induces IL-8 mRNA and protein production and increases both tumor growth and metastasis in nude mice. In addition, ectopic expression of the IL-8 gene into primary cutaneous melanoma resulted in an increase in tumor growth and metastasis in vivo. IL-8 exerts its angiogenic effect through up-regulation of MMP-2 expression and activity. These observations suggest that IL-8 could be a mediator of angiogenesis, tumor growth and metastasis in melanoma; furthermore, IL-8 may be a target for immunotherapy against malignant melanoma. Indeed, a fully-humanized neutralizing antibody to IL-8 (ABX-IL-8) administered as a single modality inhibits growth and metastasis of human melanoma in a nude mice model. MCAM/MUC18 is an adhesion molecule expressed on advanced primary and metastatic melanoma cells which contributes to acquisition of metastatic phenotype through up-regulation of MMP-2 and increased extravasation. A fully-humanized anti-MUC18 antibody (ABX-MA1) inhibits growth, angiogenesis and metastasis of human melanoma cells in a nude mouse model. Because treatment of melanoma cells with the chemotherapeutic agent DTIC causes upregulation of IL-8; we hypothesize that ABX-IL8 will potentiate the clinically beneficial cytotoxic effect of DTIC. In addition, we hypothesize that a treatment strategy inhibiting both IL-8 and MUC18 may be clinically beneficial. To address these hypotheses, we propose the following specific aims: . Evaluate the effect of ABX-IL8 in combination with dacarbazine (DTIC) on growth, angiogenesis and metastasis of human melanoma in an animal model and determine the mechanism by which IL-8 regulates MMP-2 expression in melanoma cells . Determine if the combination of MUC18 blockade plus DTIC is superior to MUC18 blockade alone in inhibition of melanoma growth and metastasis in an animal model . Evaluate the effect of combined IL-8 and MUC18 blockade on melanoma growth and metastasis in an animal model . Evaluate effects of IL-8 and/or MUC18 blockade with or without DTIC chemotherapy on angiogenesis and apoptosis in tissue specimens and clinical outcome in patients with stage III melanoma These studies will elucidate the potential of IL-8 and/or of MUC18 regulation as part of the new modalities to treat patients with melanoma, as well as to understand the role of IL-8 and/or MUC18 in progression.