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

人黑色素瘤细胞中白细胞介素-8 （IL-8）的表达与其体内转移潜能相关。此外，UV-B照射原发性皮肤黑色素瘤可诱导裸鼠IL-8 mRNA和蛋白的产生，促进肿瘤生长和转移。此外，IL-8基因在原发性皮肤黑色素瘤中的异位表达导致体内肿瘤生长和转移增加。IL-8通过上调MMP-2的表达和活性发挥血管生成作用。这些观察结果表明，IL-8可能是黑色素瘤血管生成、肿瘤生长和转移的中介；此外，IL-8可能是恶性黑色素瘤免疫治疗的靶点。事实上，在裸鼠模型中，一种完全人源化的IL-8中和抗体（ABX-IL-8）作为一种单一模式可以抑制人类黑色素瘤的生长和转移。MCAM/MUC18是表达的粘附分子

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.