Targeting TAK1 in Neuroblastoma

神经母细胞瘤(NB)仍然是儿童最常见的颅外实体瘤。大多数人 高危NB患者对治疗有初步反应，但最终复发，这表明获得性药物 化疗过程中会出现耐药细胞的耐药或选择。这是一个重大的 需要治疗的障碍。了解介导化疗耐药的分子机制 而靶向这一途径中的关键分子是治愈这种疾病的关键。 核因子-B在肿瘤细胞中经常被激活，被认为是肿瘤发生的机制之一。 癌症化疗耐药。化疗药物和放射治疗可激活核因子-B。TAK1是 IKK和MAPK激活以及IL-6基因表达的关键激酶中间产物 多重刺激。最近，据报道，肿瘤和炎症细胞之间的相互作用起到了一定作用。 与临床转移性NB表型有关。已发现NB细胞中依赖Galectin-3的途径 上调人神经母细胞瘤微环境中的IL-6。IL-6在基质细胞和巨噬细胞中的表达 促进肿瘤微环境中的NB增殖。TAK1介导核因子-βB和MAPK的激活 对基因毒性应激的反应。鉴于核因子-B和MAPK的激活是两个主要的生存信号，我们 假设抑制TAK1的激活可能会破坏细胞死亡和细胞生存之间的平衡， 并使细胞对化疗敏感，导致细胞死亡。此外，TAK1抑制基质细胞和 肿瘤相关巨噬细胞可能阻断肿瘤诱导的IL-6表达并破坏其功能 肿瘤微环境中与NB细胞的相互作用。 在我们的初步研究中，我们发现一种小分子抑制剂(5Z-7-oxozeaenol)对TAK1的抑制作用 在体外和体内均能显著增强NB细胞对化疗的敏感性。的中心假说 本工作认为TAK1通过介导Nb之间的相互作用在Nb耐药中发挥重要作用 肿瘤微环境中含有间质细胞和肿瘤相关巨噬细胞的肿瘤细胞。这个 拟议的实验将使用原位和TH-MYCN转基因小鼠模型来验证这一假设 分析TAK1抑制剂对肿瘤化疗耐药及肿瘤微环境的影响。具体的 这一应用的目的是：1)确定TAK1抑制剂是否使肿瘤细胞对化疗敏感 异种原位移植和TH-MYCN转基因小鼠模型的建立；2)检测TAK1的作用 抑制肿瘤细胞与肿瘤微环境的相互作用。 拟议的项目将把TAK1确立为NB的治疗目标。此外，这种小分子抑制剂 TAK1激酶的表达可作为治疗高危NB患者的潜在辅助手段。长期目标 这项建议的目的是确定和验证用于治疗干预的潜在的可药物酶靶标。 这种对儿童具有破坏性的疾病。

Neuroblastoma (NB) continues to be the most common extracranial solid tumor in children. The majority of high-risk NB patients show an initial response to therapy but ultimately relapse, suggesting that acquired drug resistance or selection of therapy-resistant cells occurs with chemotherapy treatment. This presents a major obstacle for treatment. Understanding the molecular mechanisms that mediate resistance to chemotherapy and targeting key molecules in this pathway are pivotal for curing this disease. NF-¿B activation is frequently encountered in tumor cells and it is believed to be one of the mechanisms of cancer chemotherapy resistance. Chemotherapeutic agents and radiation therapy can activate NF-¿B. TAK1 is a pivotal kinase intermediate for IKK and MAPK activations, as well as IL-6 gene expression in response to multiple stimuli. Recently, interactions between tumor and inflammatory cells have been reported to contribute to the clinical metastatic NB phenotype. A galectin-3-dependent pathway in NB cells has been found to upregulate IL-6 in the microenvironment of human NB. IL-6 expression in stromal cells and macrophages promotes NB proliferation in tumor microenvironment. TAK1 mediates NF-¿B and MAPK activations in response to genotoxic stresses. Given that NF-¿B and MAPK activations are two major survival signals, we hypothesize that inhibition of TAK1 activation may disrupt the balance between cell-death and cell-survival, and sensitize cells to chemotherapy resulting in cell death. Furthermore, TAK1 inhibition in stromal cells and tumor-associated macrophages may block tumor-induced IL-6 expression and disrupt their functional interaction with NB cells in tumor microenvironment. In our preliminary studies, we have found that TAK1 inhibition by a small molecule inhibitor (5Z-7-oxozeaenol) significantly enhances the sensitivity of NB cells to chemotherapy in vitro and in vivo. The central hypothesis of this work is that TAK1 plays an important role in chemoresistance of NB by mediating the interaction of NB tumor cells with stromal cells and tumor-associated macrophages in the tumor microenvironment. The proposed experiments will test this hypothesis by using an orthotopic and TH-MYCN transgenic mouse models to analyze the effect of TAK1 inhibitor on tumor chemoresistance and tumor microenvironment. The specific aims for this application are: 1) to determine whether TAK1 inhibitor sensitizes NB cells to chemotherapy in both orthotopic xenograft and TH-MYCN transgenic mouse models of NB; 2) to determine the effect of TAK1 inhibition on the interaction of NB cells and tumor microenvironment in these models. The proposed project, will establish TAK1 as a therapeutic target in NB. Furthermore, this small molecule inhibitor of TAK1 kinase may serve as a potential adjunct in the treatment of high-risk NB patients. The long-term goal of this proposal is to identify and validate potential druggable enzymatic targets for therapeutic intervention of this devastating disease in children.