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.

人黑色素瘤细胞表达白介素 8 (IL-8) 与其体内转移潜力相关。此外，原发性皮肤黑色素瘤的 UV-B 照射可诱导 IL-8 mRNA 和蛋白质的产生，并增加裸鼠中肿瘤的生长和转移。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的增加。 IL-8 通过上调 MMP-2 表达和活性发挥其血管生成作用。这些观察结果表明，IL-8 可能是黑色素瘤中血管生成、肿瘤生长和转移的介质。此外，IL-8可能是针对恶性黑色素瘤的免疫治疗的靶点。事实上，以单一方式施用的全人源化 IL-8 中和抗体 (ABX-IL-8) 可抑制裸鼠模型中人黑色素瘤的生长和转移。 MCAM/MUC18 是一种表达的粘附分子 对晚期原发性和转移性黑色素瘤细胞的作用，通过上调 MMP-2 和增加外渗，有助于获得转移表型。全人源化抗 MUC18 抗体 (ABX-MA1) 可抑制裸鼠模型中人黑色素瘤细胞的生长、血管生成和转移。因为用化疗剂 DTIC 治疗黑色素瘤细胞会导致 IL-8 上调；我们假设 ABX-IL8 将增强 DTIC 的临床有益细胞毒性作用。此外，我们假设抑制 IL-8 和 MUC18 的治疗策略可能在临床上有益。为了解决这些假设，我们提出以下具体目标： 。 在动物模型中评估 ABX-IL8 联合达卡巴嗪 (DTIC) 对人黑色素瘤生长、血管生成和转移的影响，并确定 IL-8 调节黑色素瘤细胞中 MMP-2 表达的机制 。 确定 MUC18 阻断加 DTIC 的组合在抑制动物模型中黑色素瘤生长和转移方面是否优于单独使用 MUC18 阻断 。 评估联合 IL-8 和 MUC18 阻断对动物模型中黑色素瘤生长和转移的影响 。 评估 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中血管生成和细胞凋亡以及临床结果的影响 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，并了解 IL-8 和/或 MUC18 在进展中的作用。