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

IL-8 和 MUC18/MCAM 的生物学和治疗靶向

• 批准号: 6993431
• 负责人: MENASHE BARELI
• 金额: $ 17.61万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-09 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6993431
• 关键词: angiogenesis; antineoplastics; athymic mouse; cell adhesion molecules; combination therapy; cytotoxicity; dacarbazine; disease /disorder model; human subject; interleukin 8; melanoma; metalloendopeptidases; metastasis; neoplasm /cancer chemotherapy; neoplasm /cancer immunotherapy; neoplasm /cancer pharmacology; neoplastic process; neutralizing antibody; nonhuman therapy evaluation; patient oriented research; pharmacokinetics; small molecule

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.

白介素8(IL-8)的表达与黑色素瘤细胞体内转移潜能相关。此外，UV-B辐射可诱导原发皮肤黑色素瘤IL-8mRNA和蛋白的产生，增加裸鼠体内肿瘤的生长和转移。此外，IL-8基因在原发皮肤黑色素瘤中的异位表达导致了体内肿瘤生长和转移的增加。IL-8通过上调基质金属蛋白酶-2的表达和活性发挥其血管生成作用。这些观察结果表明，IL-8可能是黑色素瘤血管生成、肿瘤生长和转移的介质；此外，IL-8可能是抗恶性黑色素瘤免疫治疗的靶点。事实上，一种完全人源化的IL-8中和抗体(ABX-IL-8)作为一种单一的方式注射，可以在裸鼠模型中抑制人黑色素瘤的生长和转移。MCAM/MUC18是一种表达的黏附分子 在晚期原发和转移性黑色素瘤细胞上，通过上调基质金属蛋白酶-2和增加渗出，有助于获得转移表型。一种完全人源化的抗MUC18抗体(ABX-MA1)在裸鼠模型中抑制人黑色素瘤细胞的生长、血管生成和转移。因为用化疗药物DTIC处理黑色素瘤细胞会引起IL-8的上调；我们假设ABX-IL8将增强DTIC的临床有益的细胞毒作用。此外，我们假设同时抑制IL-8和MUC18的治疗策略可能在临床上是有益的。为了解决这些假设，我们提出了以下具体目标： 。评价ABX-IL8联合达卡巴肼(DTIC)对人黑色素瘤生长、血管生成和转移的影响，并探讨IL-8调节黑色素瘤细胞基质金属蛋白酶-2表达的机制 。在动物模型中确定MUC18阻滞剂联合DTIC是否优于单独应用MUC18阻滞剂 。IL-8和MUC18联合阻断对黑色素瘤生长和转移的影响 。评价IL-8和/或MUC18阻断联合或不联合DTIC化疗对III期黑色素瘤患者组织标本血管生成、细胞凋亡及临床预后的影响 这些研究将阐明IL-8和/或MUC18调节作为治疗黑色素瘤患者新方法的一部分的潜力，以及了解IL-8和/或MUC18在进展中的作用。