CAMKV Kinase Signaling in Neuroblastoma

神经母细胞瘤是儿童最常见的颅外恶性实体瘤。高危NB型 仍然是一种不治之症。由于NB中反复发生的体细胞突变相对较少， 癌基因信号转导的失调可能参与了NB的发生发展。这项提案将继续 通过定义CaM激酶样泡相关蛋白(CAMKV)在NB发生和发展中的作用来实现这一目标 研究CAMKV激酶抑制对小鼠神经营养不良的治疗潜力。在我们的 初步研究发现，CAMKV在结构上属于钙/钙调蛋白依赖型成员 蛋白激酶家族，在NB肿瘤样本中特异性地过表达，其高表达预示着 病人结局不佳。此外，在NB细胞中，CAMKV是一种活性CREB蛋白。击倒 CAMKV表达导致NB细胞增殖缺陷和磷酸化CREB水平降低 测试过。此外，我们确定K252a和OTSSP167是有效抑制细胞的CAMKV抑制剂 几种NB细胞系在培养中的增殖和异种移植小鼠模型中的肿瘤生长。有趣的是， 我们最近产生的Camkv基因敲除小鼠是活的和有生育能力的。 我们的长期目标是为患有高危NB的儿童开发新的靶向疗法。的目标是 这项应用是为了了解CAMKV在NB肿瘤发生中的作用，并展示CAMKV在NB肿瘤发生中的作用 CAMKV作为NB治疗的生物标记物和激酶靶点。 在NB的发育中起着重要的作用，并且是NB的一个分子激酶靶点。拟议中的实验 我将通过解剖CAMKV信号在NB细胞中的功能并确定 CAMKV对小鼠移植瘤生长的抑制作用我们还将使用最近生成的Camkv 在Th-MYCN转基因小鼠模型中确定CAMKV在NB发育中的作用。这个 本项目的具体目标是：1)确定CAMKV在NB中的调节和功能的机制 细胞；2)确定CAMKV在肿瘤小鼠模型中的作用；3)确定CAMKV在肿瘤小鼠模型中的作用 体内抑制CAMKV的治疗潜力。这一贡献意义重大，因为它将证明 CAMKV激酶在NB发育中的关键作用及证明抑制CAMKV激酶是一种潜在的途径 治疗NB和克服体内化疗耐药的策略。此外，揭开规则， CAMKV信号转导将为基于CAMKV的难治性高危患者的治疗设计提供蓝图 注意：这项拟议的研究具有创新性，因为它是第一项专门揭示和针对 CAMKV信号通路用于设计NB治疗药物和特异性研究小分子对CAMKV的抑制作用 作为克服化疗耐药性的一种机制的抑制剂。该项目将坚定地建立CAMKV- 基础治疗作为难治性高危神经母细胞瘤的一种新的治疗策略。

Neuroblastoma (NB) is the most common extracranial malignant solid tumor in children. High-risk NB remains an incurable disease. Since recurrent somatic mutations in NB occur with relative paucity, dysregulation of oncogenic signal transduction may contribute to NB tumorigenesis. This proposal will pursue that goal by defining the role of CaM kinase-like vesicle-associated (CAMKV) in NB development and examining the therapeutic potential of CAMKV kinase inhibition for treating NB in mouse models. In our preliminary studies, we have found that CAMKV, structurally a member of the calcium/calmodulin-dependent protein kinase family, is quite specifically overexpressed in NB tumor samples, and its high expression predicts poor patient outcome. Furthermore, CAMKV acts as an active CREB kinase in NB cells. Knockdown of CAMKV expression caused a cell proliferation defect and decreased phospho-CREB level in the NB cell lines tested. In addition, we identified K252a and OTSSP167 as CAMKV inhibitors that potently inhibited cell proliferation of several NB cell lines in culture and tumor growth in the xenograft mouse model. Interestingly, our recently generated Camkv knockout mice are viable and fertile. Our long term goal is to develop novel targeted therapies for children with high-risk NB. The objective of this application is to understand the role of CAMKV in NB tumor development and demonstrate the utility of CAMKV as a biomarker and kinase target for NB therapy.The central hypothesis of this work is that CAMKV plays an important role in NB development and is a molecular kinase target in NB. The proposed experiments will test this hypothesis by dissecting the function of CAMKV signaling in NB cells and determining the effect of CAMKV inhibition on NB tumor growth in xenograft mouse models. We will also use recently generated Camkv knockout mice to define the role of CAMKV in NB development in the Th-MYCN transgenic mouse model. The specific aims for this project are: 1) To determine the mechanism of CAMKV regulation and function in NB cells; 2) To determine the role of CAMKV in NB development in tumor mouse models; 3) To determine the therapeutic potential of CAMKV inhibition in vivo. This contribution is significant because it will demonstrate the critical role of CAMKV kinase in NB development and prove that CAMKV kinase inhibition is a potential strategy to treat NB and overcome chemotherapy resistance in vivo. Furthermore, uncovering the regulation of CAMKV kinase signaling will generate a blueprint for CAMKV-based design of treatment for refractory high-risk NB. The proposed research is innovative since it is the first study to specifically uncover and target the CAMKV signaling for designing NB therapeutics and to specifically study CAMKV inhibition by small molecule inhibitors as a mechanism for overcoming chemotherapy resistance. This project will firmly establish CAMKV- based therapy as a novel therapeutic strategy for refractory high-risk NB.