Increasing Effects of Interferons for Melanoma

干扰素对黑色素瘤的作用增强

• 批准号: 6434665
• 负责人: ERNEST C BORDEN
• 金额: $ 32.93万
• 依托单位: CLEVELAND CLINIC FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-01-07 至 2005-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6434665
• 关键词: apoptosis; functional /structural genomics; gene induction /repression; human subject; human therapy evaluation; interferon alpha; interferon beta; ligands; melanoma; metastasis; microarray technology; neoplasm /cancer genetics; neoplasm /cancer immunotherapy; neoplasm /cancer pharmacology; nuclear factor kappa beta; patient oriented research

New therapies to eliminate melanoma must be identified both for the high-risk patient after surgery and for metastatic disease. Interferons (IFNs) have therapeutic activity in both clinical settings but little expansion has occurred in understanding of mechanisms underlying clinical effectiveness in melanoma -- or indeed other malignancies. Underlying clinical antitumor effects must be the potent and pleiotropic gene modulatory effects that occur at a transcriptional level. Utilizing oligonucleotide array analysis, over 100 genes that are induced by IFNs in a melanoma cell line have been identified. On an equimolar basis these genes are induced to a substantially greater extent by IFN-beta than by IFN-alpha2. Based upon the hypothesis that the antitumor effects of IFNs in melanoma may result from direct effects on tumor cells, apoptosis, an understudied effect of IFNs, is a focus of our studies. Induction of apoptosis, coupled with array studies, led to the protein TRAIL (TNF-Related Apoptosis Inducing Ligand) as a mechanism that in part accounts for melanoma cell death. In sensitive melanoma cell lines, IFN-beta, but not IFN-alpha2, induces caspase dependent apoptosis that was associated with TRAIL. Resistant melanoma cell lines are characterized by lack of proliferative inhibition or apoptosis induction by either IFN- alpha2 or IFN-beta and lack of TRAIL induction. The data further suggest that apoptosis induction is negatively influenced by NFkappaB (Nuclear Factor kappa B) activation by TRAIL. With a goal of understanding of IFNs as antitumor cytokines and using melanoma as a model, our working hypothesis is that genes and functional mechanisms, yet to be identified, contribute substantially to the antitumor effects of IFNs. Our estimates based upon genome size suggest that greater than 500 interferon- stimulated genes (ISGs) remain to be identified. The goals of the proposal are: 1) By assessment of sensitive and resistant melanomas to identify new genes that may contribute to mediating apoptosis response and resistance in response to IFNs, 2) To define and confirm functional effects of the newly identified ISG, TRAIL, on IFN-induced apoptosis, 3) To determine how NF- kappaB or other induced anti-apoptotic pathways influence actions of IFNs and TRAIL, and 4) As an effective inducer of of apoptosis in mice and of TRAIL, to conduct a Phase II trial of IFN-beta to identify disease response in metastatic melanoma. The data should contribute to understanding of IFNs effects in melanoma but also other neoplasms and to a beginning understanding of the therapeutic potential of TRAIL.

必须为手术后的高危患者和转移性疾病确定消除黑色素瘤的新疗法。干扰素(IFN)在两种临床环境中都具有治疗活性，但对黑色素瘤或其他恶性肿瘤临床疗效的潜在机制的了解几乎没有扩大。潜在的临床抗肿瘤作用必须是发生在转录水平上的强大的、多效性的基因调控效应。利用寡核苷酸阵列分析，已在黑色素瘤细胞系中鉴定出100多个由IFN诱导的基因。在等摩尔的基础上，干扰素-β比干扰素-α2诱导这些基因的程度要大得多。基于干扰素在黑色素瘤中的抗肿瘤作用可能源于对肿瘤细胞的直接作用的假设，我们的研究重点之一是凋亡，这是干扰素的一个未被充分研究的作用。诱导细胞凋亡，再加上阵列研究，导致了TRAIL(肿瘤坏死因子相关的凋亡诱导配体)蛋白，作为黑色素瘤细胞死亡的部分原因。在敏感的黑色素瘤细胞系中，干扰素-β而不是干扰素-α2诱导caspase依赖的细胞凋亡，这与TRAIL相关。耐药黑色素瘤细胞株的特点是缺乏增殖抑制或诱导凋亡的干扰素-α2或干扰素-β和缺乏TRAIL的诱导。这些数据进一步表明，TRAIL对NFkappaB(核因子kappa B)的激活对细胞凋亡的诱导有负面影响。为了理解干扰素作为抗肿瘤细胞因子，并以黑色素瘤为模型，我们的工作假设是，基因和功能机制尚未确定，对干扰素的抗肿瘤作用有很大贡献。我们基于基因组大小的估计表明，仍有500多个干扰素刺激基因(ISG)有待识别。该建议的目标是：1)通过评估敏感和耐药的黑色素瘤，以确定可能有助于介导IFNS诱导的细胞凋亡的新基因；2)确定和确认新发现的ISG，TRAIL，对干扰素诱导的细胞凋亡的功能效应；3)确定核因子-kappaB或其他诱导的抗凋亡通路如何影响IFNS和TRAIL的作用；以及4)作为小鼠细胞凋亡的有效诱导剂，进行干扰素-β的II期试验，以确定转移性黑色素瘤的疾病反应。这些数据应该有助于理解IFN在黑色素瘤和其他肿瘤中的作用，并有助于开始了解TRAIL的治疗潜力。