Targeting TAK1 in Neuroblastoma

神经母细胞瘤（NB）仍然是儿童颅外最常见的实体瘤。大多数 高风险NB患者对治疗显示初始反应，但最终复发，表明获得性药物 耐药性或选择治疗耐药性细胞与化疗治疗一起发生。这是一个重大的 治疗的障碍。了解介导化疗耐药性的分子机制 而针对这一通路中的关键分子是治愈这种疾病的关键。 NF-B活化在肿瘤细胞中经常遇到，并且被认为是肿瘤细胞凋亡的机制之一。 癌症化疗耐药性化疗药物和放射治疗可以激活NF-B。TAK 1是 IKK和MAPK激活的关键激酶中间体，以及响应于 多重刺激最近，肿瘤和炎症细胞之间的相互作用已被报道有助于 临床转移性NB表型。已经发现NB细胞中的半乳糖凝集素-3依赖性途径 上调人NB微环境中的IL-6。基质细胞和巨噬细胞中IL-6的表达 促进肿瘤微环境中NB的增殖。TAK 1介导NF-B和MAPK活化， 基因毒性应激反应。鉴于NF-B和MAPK激活是两个主要的生存信号，我们 假设抑制TAK 1活化可能破坏细胞死亡和细胞存活之间平衡， 并使细胞对化疗敏感，导致细胞死亡。此外，在基质细胞中的TAK 1抑制和 肿瘤相关巨噬细胞可能阻断肿瘤诱导的IL-6表达， 与肿瘤微环境中NB细胞的相互作用。 在我们的初步研究中，我们发现小分子抑制剂（5 Z-7-oxozeaenol）抑制TAK 1， 在体外和体内显著增强NB细胞对化疗的敏感性。的中心假设 TAK 1通过介导NB与化疗药物的相互作用，在NB的耐药性中起重要作用 肿瘤微环境中的肿瘤细胞与基质细胞和肿瘤相关巨噬细胞。的 本实验将通过原位和TH-MYCN转基因小鼠模型来验证这一假设 分析TAK 1抑制剂对肿瘤耐药及肿瘤微环境的影响。具体 本申请的目的是：1）确定TAK 1抑制剂是否使NB细胞对化疗敏感， NB的原位异种移植和TH-MYCN转基因小鼠模型; 2）确定TAK 1 在这些模型中抑制NB细胞与肿瘤微环境的相互作用。 拟议的项目将确立TAK 1作为NB的治疗靶点。此外，这种小分子抑制剂 TAK 1激酶可能作为一种潜在的辅助治疗高危NB患者。远景目标 该提案的目的是鉴定和验证用于治疗干预的潜在可药物化酶靶点， 这种毁灭性的疾病。

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.