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.

人黑色素瘤细胞对白介素8（IL-8）的表达与其体内转移潜力相关。此外，原发性黑色素瘤的UV-B辐射会诱导IL-8 mRNA和蛋白质产生，并增加裸鼠的肿瘤生长和转移。另外，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可以是黑色素瘤中血管生成，肿瘤生长和转移的介体。此外，IL-8可能是针对恶性黑色素瘤的免疫疗法的靶标。实际上，作为单一模态给药的对IL-8（ABX-IL-8）的完全人性化的中和抗体抑制了裸鼠模型中人类黑色素瘤的生长和转移。 MCAM/MUC18是表达的粘附分子 在先进的原发性和转移性黑色素瘤细胞上，这有助于通过上调MMP-2并增加外渗。完全人性化的抗MUC18抗体（ABX-MA1）在裸小鼠模型中抑制人黑色素瘤细胞的生长，血管生成和转移。因为用化学治疗剂DTIT治疗黑色素瘤细胞会导致IL-8上调；我们假设ABX-IL8将增强DTIT的临床有益细胞毒性作用。此外，我们假设抑制IL-8和MUC18的治疗策略在临床上可能是有益的。为了解决这些假设，我们提出以下具体目的： 。 评估ABX-IL8与Dacarbazine（DTIT）在动物模型中人类黑色素瘤的生长，血管生成和转移的影响，并确定IL-8调节MMP-2在黑色素瘤细胞中的机制 。 确定在动物模型中，在抑制黑色素瘤生长和转移方面，MUC18封锁和DTIT的组合是否仅优于MUC18封锁 。 评估IL-8和MUC18封锁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阻断具有或不使用DTIT化学疗法对组织标本的血管生成和凋亡的影响，以及III期黑素瘤患者的临床结果 这些研究将阐明IL-8和/或MUC18调节的潜力，这是治疗黑色素瘤患者的新方式的一部分，以及了解IL-8和/或MUC18在进展中的作用。