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The Function of CDK5 in Metastasis

CDK5 在转移中的作用

基本信息

批准号：
9764841
负责人：
Peter Sicinski
金额：
$ 44.13万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9764841
关键词：
Ablation Acute Affect Animals Biological CDK5 gene Cancer Model Cancer Patient Cancer cell line Cell Line Cell Proliferation Cells Collection Complex Cyclin-Dependent Kinase 5 Cyclins Development Disease Engineering Funding Genetic Goals Grant Growth Human In Vitro Knock-in Mouse Knock-out Knockout Mice Lead Link Melanoma Cell Mesenchymal Mesenchymal Cell Neoplasm Metastatic Melanoma Molecular Mouse Strains Mus Names Neoplasm Metastasis Nervous system structure Neurites Neuronal Differentiation Neurons Organ Patients Phenocopy Phosphorylation Phosphotransferases Play Primary Neoplasm Process Proteins Role Side Testing Tissue Microarray Transcript Transmembrane Transport Treatment Efficacy Tumor Cell Migration Tumor stage Vimentin Work Xenograft procedure analog axon guidance axonal guidance cancer cell cancer therapy cancer type cell motility cell type follow-up in vivo inhibitor/antagonist lymph nodes melanoma metastatic process migration mouse model neoplastic cell new therapeutic target novel novel therapeutic intervention novel therapeutics outcome forecast patient oriented preclinical study prevent protein expression synaptogenesis therapeutic target tumor tumor progression tumorigenesis

项目摘要

This application focuses on the cyclin-dependent kinase 5 (CDK5). The overarching goal of this proposal is to test whether inhibition of CDK5 kinase might represent an effective therapeutic strategy in treatment of metastatic melanomas. In our study, we will utilize human cancer cell lines as well as mouse cancer models. Our work may lead to a novel therapeutic approach for cancer patients centered on CDK5 inhibition. Despite its name, CDK5 is not regulated by cyclins. CDK5 is inactive in its monomeric form, and its kinase activity is triggered by interaction with non-cyclin proteins termed p35 and p39. During normal development, CDK5-p35 and CDK5-p39 kinases are active in the nervous system. CDK5-p35/p39 kinases were shown to regulate a wide range of neuronal functions, including terminal differentiation, synapse formation and plasticity, axon guidance, neurite outgrowth, membrane transport and neuronal migration, through phosphorylation of various neuronal substrates. Growing evidence indicates that CDK5 plays an important role in tumorigenesis. Several studies documented that human cancer cells express CDK5 and p35/p39, and contain catalytically active CDK5-p35/p39 complexes. High expression of CDK5 in tumors was shown to confer overall poor prognosis. The exact molecular function of CDK5 in tumor cells is not fully understood. It has been postulated that CDK5 affects cell proliferation, or regulates tumor cell migration, or survival, with different studies ascribing activating or inhibitory roles for CDK5 in these processes. In our study, we decided to focus on melanoma, as this tumor type expressed particularly high CDK5 levels. We obtained preliminary evidence that CDK5 plays an important role in tumor cell invasiveness and metastasis. We obtained preliminary results about the molecular role played by CDK5 in the metastatic spread of tumor cells. We also developed a novel mouse strain that allows us to switch off CDK5 activity in vivo. In the work proposed in this application, we will extend these findings. In Specific Aim 1, we will utilize our strain of mice that allows an acute shutdown of CDK5, along with a well- established mouse model of melanoma, to further study the role of CDK5 in melanoma metastasis in vivo. In Aim 2, we will follow up on our preliminary results, and we will determine the exact molecular function played by CDK5 in melanoma metastasis. Lastly, in a translational Aim 3, we will perform a pre-clinical study to test whether inhibition of CDK5 kinase would block the metastatic spread of human melanomas, using a large collection of human patient-derived xenografts (PDX). The expected overall impact of this proposal is that it will elucidate the molecular function of CDK5 in melanoma cells, and will lead to novel targeted therapeutic strategies centered on CDK5 inhibition.

此应用重点关注细胞周期蛋白依赖性激酶 5 (CDK5)。该提案的总体目标是测试 CDK5 激酶的抑制是否可能代表治疗以下疾病的有效治疗策略：转移性黑色素瘤。在我们的研究中，我们将利用人类癌细胞系和小鼠癌症模型。我们的工作可能会为癌症患者带来一种以 CDK5 抑制为中心的新治疗方法。尽管正如其名，CDK5 不受细胞周期蛋白调节。 CDK5 的单体形式无活性，其激酶活性为由与称为 p35 和 p39 的非细胞周期蛋白相互作用触发。在正常发育过程中，CDK5-p35 CDK5-p39 激酶在神经系统中活跃。 CDK5-p35/p39 激酶被证明可以调节广泛的神经元功能，包括终末分化、突触形成和可塑性、轴突通过各种磷酸化，引导、神经突生长、膜运输和神经元迁移神经元底物。越来越多的证据表明CDK5在肿瘤发生中发挥着重要作用。一些研究表明，人类癌细胞表达 CDK5 和 p35/p39，并含有催化活性 CDK5-p35/p39 复合物。 CDK5 在肿瘤中的高表达表明总体预后较差。 CDK5 在肿瘤细胞中的确切分子功能尚不完全清楚。据推测 CDK5 影响细胞增殖，或调节肿瘤细胞迁移或存活，不同的研究认为激活或 CDK5 在这些过程中的抑制作用。在我们的研究中，我们决定关注黑色素瘤，因为这种肿瘤类型表达特别高的 CDK5 水平。我们获得了 CDK5 发挥重要作用的初步证据在肿瘤细胞侵袭和转移中发挥作用。我们获得了有关分子作用的初步结果 CDK5 在肿瘤细胞的转移扩散中发挥作用。我们还开发了一种新的小鼠品系，可以我们关闭体内CDK5活性。在本申请提出的工作中，我们将扩展这些发现。在具体目标 1，我们将利用我们的小鼠品系，使 CDK5 急性关闭，并具有良好的建立小鼠黑色素瘤模型，进一步研究CDK5在黑色素瘤体内转移中的作用。在目标2，我们将跟进我们的初步结果，我们将确定所发挥的确切分子功能 CDK5 在黑色素瘤转移中的作用。最后，在转化目标 3 中，我们将进行临床前研究来测试抑制 CDK5 激酶是否会阻止人类黑色素瘤的转移扩散，使用大量人类患者来源的异种移植物（PDX）的收集。该提案的预期总体影响是将阐明 CDK5 在黑色素瘤细胞中的分子功能，并将带来新的靶向治疗策略以 CDK5 抑制为中心。