Increasing Effects of Interferons for Melanoma

干扰素对黑色素瘤的作用增强

• 批准号: 6923734
• 负责人: ERNEST C BORDEN
• 金额: $ 34.04万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 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 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6923734
• 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.

新的治疗方法，以消除黑色素瘤必须确定为高风险患者术后和转移性疾病。 干扰素（IFN）在两种临床环境中都具有治疗活性，但在了解黑色素瘤或其他恶性肿瘤临床有效性的机制方面几乎没有扩展。 潜在的临床抗肿瘤作用必须是在转录水平上发生的强效和多效性基因调节作用。利用寡核苷酸阵列分析，在黑色素瘤细胞系中已经鉴定了超过100个由IFN诱导的基因。 在等摩尔的基础上，这些基因被IFN-β诱导的程度远大于IFN-α 2。 基于IFN对黑色素瘤的抗肿瘤作用可能是直接作用于肿瘤细胞的假设，IFN的一种未充分研究的作用--细胞凋亡是我们研究的焦点。细胞凋亡的诱导，再加上阵列研究，导致蛋白质TRAIL（TNF相关的细胞凋亡诱导配体）作为一种机制，部分占黑色素瘤细胞死亡。 在敏感的黑色素瘤细胞系中，IFN-β而不是IFN-α 2诱导与TRAIL相关的半胱天冬酶依赖性细胞凋亡。 抗性黑色素瘤细胞系的特征在于缺乏IFN-α 2或IFN-β的增殖抑制或凋亡诱导以及缺乏TRAIL诱导。 数据进一步表明，凋亡诱导受到TRAIL激活NF κ B（核因子κ B）的负面影响。以了解干扰素作为抗肿瘤细胞因子的目标，并使用黑色素瘤作为模型，我们的工作假设是，基因和功能机制，尚未确定，大大有助于干扰素的抗肿瘤作用。 我们基于基因组大小的估计表明，仍有超过500个干扰素刺激基因（ISG）有待鉴定。 该提案的目标是：1）通过评估敏感性和抗性黑色素瘤以鉴定可能有助于介导细胞凋亡应答和应答IFN的抗性的新基因，2）定义和确认新鉴定的ISG、TRAIL对IFN诱导的细胞凋亡的功能作用，3）确定NF-κ B或其他诱导的抗细胞凋亡途径如何影响IFN和TRAIL的作用，和4）作为小鼠中细胞凋亡和TRAIL的有效诱导剂，进行IFN-β的II期试验以鉴定转移性黑素瘤中的疾病反应。 这些数据应有助于了解干扰素在黑色素瘤中的作用，也有助于了解其他肿瘤，并有助于开始了解TRAIL的治疗潜力。

项目成果

Interferon stimulated gene 15 constitutively produced by melanoma cells induces e-cadherin expression on human dendritic cells.

• 发表时间: 2002-06
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: E. Padovan;L. Terracciano;U. Certa;B. Jacobs;A. Reschner;M. Bolli;G. Spagnoli;E. Borden;M. Heberer