CAMKV Kinase Signaling in Neuroblastoma

神经母细胞瘤中的 CAMKV 激酶信号转导

• 批准号: 10630951
• 负责人: JIANHUA YANG
• 金额: $ 43.73万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10630951
• 关键词: Animal Model; Biological Markers; CREB1 gene; Ca(2+)-Calmodulin Dependent Protein Kinase; Calcium; Cell Line; Cell Proliferation; Cephalic; Cessation of life; Chemoresistance; Child; Clustered Regularly Interspaced Short Palindromic Repeats; Defect; Development; Disease; Disease Outcome; Dose; Family; Goals; Growth; Inhibition of Cell Proliferation; K 252a; Knock-out; Knockout Mice; MYCN gene; Malignant - descriptor; Malignant Childhood Neoplasm; Malignant Neoplasms; Mediator; Molecular; Neuroblastoma; Oncogenic; Patient-Focused Outcomes; Pediatric Neoplasm; Phosphorylation; Phosphotransferases; Play; Protein-Serine-Threonine Kinases; Proteins; Recurrence; Refractory; Regimen; Regulation; Research; Research Proposals; Role; Sampling; Serine; Signal Pathway; Signal Transduction; Solid Neoplasm; Somatic Mutation; Stimulus; Testing; Therapeutic; Transgenic Mice; Transgenic Model; Transgenic Organisms; Tumor Promotion; Vesicle; Work; Xenograft procedure; biological heterogeneity; chemotherapeutic agent; clinical heterogeneity; conditional knockout; design; experimental study; high risk; improved; in vivo; inhibitor; innovation; knock-down; member; mouse development; mouse model; neuroblastoma cell; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; overexpression; pre-clinical; screening; small molecule inhibitor; therapy design; transcription factor; tumor; tumor growth; tumorigenesis

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.

神经母细胞瘤（NB）是儿童最常见的颅外恶性实体瘤。高风险NB 仍然是一种不治之症。由于 NB 中复发性体细胞突变的发生相对较少， 致癌信号转导的失调可能导致 NB 肿瘤发生。该提案将追求 通过定义 CaM 激酶样囊泡相关 (CAMKV) 在 NB 发育中的作用来实现这一目标 检查 CAMKV 激酶抑制在小鼠模型中治疗 NB 的治疗潜力。在我们的 初步研究，我们发现CAMKV在结构上是钙/钙调蛋白依赖性细胞的成员 蛋白激酶家族，在 NB 肿瘤样本中非常特异地过表达，其高表达预示着 患者预后不佳。此外，CAMKV 在 NB 细胞中充当活性 CREB ​​激酶。击倒 CAMKV 表达导致 NB 细胞系细胞增殖缺陷并降低磷酸 CREB ​​水平 已测试。此外，我们还鉴定出 K252a 和 OTSSP167 作为 CAMKV 抑制剂，可有效抑制细胞 几种 NB 细胞系在培养物中的增殖和异种移植小鼠模型中的肿瘤生长。有趣的是， 我们最近生成的 Camkv 基因敲除小鼠具有活力且具有生育能力。 我们的长期目标是为高危 NB 儿童开发新型靶向疗法。的目标 该应用旨在了解 CAMKV 在 NB 肿瘤发展中的作用并展示 CAMKV 作为 NB 治疗的生物标志物和激酶靶标。这项工作的中心假设是 CAMKV 在 NB 发育中发挥重要作用，是 NB 的分子激酶靶标。拟议的实验 将通过剖析 NB 细胞中 CAMKV 信号传导的功能并确定 CAMKV 对异种移植小鼠模型中 NB 肿瘤生长的抑制作用。我们还将使用最近生成的 Camkv 敲除小鼠以确定 CAMKV 在 Th-MYCN 转基因小鼠模型中 NB 发育中的作用。这 该项目的具体目标是：1）确定CAMKV在NB中的调节和功能机制 细胞； 2) 确定CAMKV在肿瘤小鼠模型NB发育中的作用； 3）确定 CAMKV 体内抑制的治疗潜力。这一贡献意义重大，因为它将证明 CAMKV 激酶在 NB 发展中的关键作用，并证明 CAMKV 激酶抑制是一种潜在的 治疗 NB 并克服体内化疗耐药性的策略。此外，揭示监管 CAMKV 激酶信号传导将为基于 CAMKV 的难治性高风险治疗设计提供蓝图 注意。拟议的研究具有创新性，因为它是第一项专门揭示和针对 用于设计 NB 疗法并专门研究小分子对 CAMKV 抑制的 CAMKV 信号传导 抑制剂作为克服化疗耐药性的机制。该项目将牢固地建立CAMKV- 基于治疗作为难治性高危 NB 的新型治疗策略。

项目成果

FOXK2 amplification and overexpression promotes breast cancer development and chemoresistance.

FOXK2 扩增和过度表达可促进乳腺癌的发展和化疗耐药性。

• DOI: 10.1101/2023.05.28.542643
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Yu,Yang;Cao,Wen-Ming;Cheng,Feng;Shi,Zhongcheng;Han,Lili;Yi,Jin-Ling;daSilva,EdaiseM;Dopeso,Higinio;Chen,Hui;Yang,Jianhua;Wang,Xiaosong;Zhang,Chunchao;Zhang,Hong
• 通讯作者: Zhang,Hong