Targeting IKK beta and aurora kinases in melanoma

目前黑色素瘤的流行主要影响我们退伍军人中的老年男性和女性，原因是 年龄、日照和化学物质暴露。黑色素瘤进展过程中极光激酶A和B的扩增 和/或解除对核因子-B的调控导致非整倍体，促进细胞增殖，逃避凋亡， 促进炎症介质的产生和肿瘤进展。我们有初步数据显示 当极光A激酶被阻断时，一些人黑色素瘤的异种移植瘤的生长受到抑制，而 来自其他黑色素瘤病变的异种移植对IKK抑制剂有反应。我们假设这个构成要素 IKK和/或极光激酶(AIK)的激活可促进黑色素瘤的进展和 抑制这些途径将会抑制肿瘤的生长。此外，我们假设人类黑色素瘤 基因表达谱可以预测哪些肿瘤对AIK抑制剂有反应，哪些肿瘤对IKK有反应 抑制剂。这个项目有三个特定的目标：1)表征极光激酶A，B， C黑色素瘤进展过程中的组织芯片免疫组织化学分析 确定IKK/AIK激酶的过度表达如何影响黑素细胞和肿瘤生长；2)确定 是否同时抑制IKK和AIK通路对治疗黑色素瘤更有效 通过单独靶向每个单独的激酶并确定抑制IKK和AIK如何影响 抗肿瘤宿主防御；3)表征人类黑色素瘤肿瘤的基因表达谱 对AIK或IKK？抑制剂有反应或无反应。利用组织的免疫组织化学分析 微阵列我们将检测极光激酶和nevi的磷酸化(relA/p65)的表达模式， 肿瘤进展过程中的发育不良痣、原发和转移性黑色素瘤病变。我们将利用一个诱导器 体外改变黑素细胞和黑色素瘤细胞AURA和IKK表达的表达系统 确定这两条通路过度激活的后果。我们将研究以下方面的回应 在小鼠异种移植模型中，黑色素瘤对IKK、AIKs及其组合的抑制作用。最后， 使用基因表达微阵列分析，我们将确定区分 药物应答者与非应答者。从这项提案中得出的数据将为更好地 为黑色素瘤患者设计临床试验，这将对我们的退伍军人群体产生积极影响。

The current melanoma "epidemic" is primarily affecting older men and women in our Veteran population due to age, sun and chemical exposure. During melanoma tumor progression amplification of aurora kinases A and B and/or the deregulation of NF-¿B lead to aneuploidy, enhanced cell proliferation, escape from apoptosis, enhanced production of inflammatory mediators and tumor progression. We have preliminary data showing that xenografts of some human melanoma tumors are growth inhibited when aurora A kinase is blocked, while xenografts from other melanoma lesions respond to an IKK¿ inhibitor. We hypothesize that constitutive activation of IKK¿ and/or aurora kinase (AIK) amplification can contribute to melanoma tumor progression and that inhibition of these pathways will inhibit tumor growth. Moreover, we hypothesize that human melanoma gene expression profiles can predict which tumors will respond to AIK inhibitors and which will respond to IKK¿ inhibitors. There are three specific aims for this project: 1) to characterize the expression of aurora kinase A, B, C during melanoma tumor progression using immunohistochemical analysis of tissue microarrays and to determine how the over-expression of IKK/ AIK kinases affect melanocytes and tumor growth; 2) to determine whether inhibiting both IKK and AIK pathways may prove to be more efficacious for treatment of melanoma tumors than by targeting each individual kinase alone and to determine how inhibition of IKK and AIK affect the anti-tumor host defense; 3) to characterize the gene expression profiles for human melanoma tumors that respond or do not respond to AIK or IKK¿ inhibitors. Using immunohistochemical analyses of tissue microarrays we will examine the expression pattern of aurora kinases and phosphorylated (RelA/p65) of nevi, dysplastic nevi, primary and metastatic melanoma lesions during tumor progression. We will utilize an inducible expression system to alter the expression of AurA and IKK¿ in melanocytes and melanoma cells in vitro to determine the consequences of over-activation of these two pathways. We will examine the response of melanoma tumors to inhibitors of IKK¿, AIKs, and combinations thereof in a murine xenograft model. Finally, using gene expression microarray analysis, we will determine the expression profiles that distinguish between drug responders versus non-responders. The data derived from this proposal will provide key insights for better design of clinical trials for melanoma patients which should positively impact our Veteran population.