Role of PTEN and PI-3 Kinase in Medulloblastomagenesis

PTEN 和 PI-3 激酶在髓母细胞瘤发生中的作用

基本信息

批准号：
10681197
负责人：
DONALD DURDEN
金额：
$ 30.93万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-03 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10681197
关键词：
Address Adult Animal Model Applications Grants Blood - brain barrier anatomy Brain Cancer Control Caring Cell Compartmentation Cells Cerebellar Neoplasms Cerebellum Chemoresistance Chemotherapy and/or radiation Childhood Clinical Trials Cognitive deficits Cytoplasmic Granules Data Development Disease Down-Regulation Epigenetic Process Evaluation Exhibits Future Genetically Engineered Mouse Genomics Human In Vitro Intervention Knowledge Laboratories Libraries Malignant - descriptor Malignant Childhood Neoplasm Malignant Neoplasms Malignant neoplasm of brain Medical Membrane Glycoproteins MicroRNAs Mission Modeling Molecular Molecular Profiling Morbidity - disease rate Mus Mutation Neurocognitive Neurons PIK3CG gene PTEN gene Pathogenesis Pathway interactions Patients Pediatric Neoplasm Pharmacogenomics Phenotype Phosphatidylinositide 3-Kinase Inhibitor Protein Isoforms Proto-Oncogene Proteins c-akt Public Health Regulation Reporting Research Resistance Role SHH gene Sampling Signal Pathway Signal Transduction Sonic Hedgehog Pathway Subgroup Survivors System Testing Therapeutic Therapeutic Intervention Toxic effect Transgenic Mice Transgenic Organisms Tumor Suppressor Proteins United States National Institutes of Health Validation Work Xenograft procedure cancer stem cell cancer therapy chemoradiation chemotherapy clinically relevant design disability genetic analysis genomic signature in vivo inhibitor innovation kinase inhibitor medulloblastoma mouse genetics mouse model nerve stem cell novel patient derived xenograft model precursor cell recombinase resistance mechanism response smoothened signaling pathway stem cell biology stem-like cell targeted agent targeted treatment transcriptomics tumor tumor growth tumor initiation tumorigenesis

项目摘要

Medulloblastoma (MB) is a cancer arising within the cerebellum, and is the most common malignant brain tumor in children. Current care which relies on radiotherapy and chemotherapy, only cures 60% of patients, and has serious long-term neurocognitive sequelae in survivors, hence the unmet medical need to develop more efficacious, less toxic therapies for this disease. Malignant brain tumors including the sonic hedgehog (SHH) subgroup of MB are driven by tumor propagating cells (cancer stem cells; CSCs) expressing the cell surface glycoprotein CD15. A knowledge gap exist in that the molecular mechanisms controlling CSC and non CSC phenotypes are poorly delineated. The central hypothesis for this proposal is that the PI3K/PTEN signaling axis exerts control over the CSC phenotype in SHH MB and hence represents a target for therapeutic exploitation with PI3K inhibitors. Importantly, work from our laboratory has demonstrated that PTEN expression is suppressed in the CSC compartment of the Smo transgenic (SHH pathway) mouse model of MB. The clinical relevance of the PTEN deficient Smo transgene mouse model is highlighted by our finding that PTEN expression is lost in human MB, and the observation that PTEN loss correlates with poor survival in MB patients. Our grant proposal, guided by our preliminary data proposes 3 specific aims: 1) Determine if genetic alterations in PTEN or specific isoforms of PI3K are necessary and/or sufficient for SHH driven CSC phenotype and tumorigenesis 2) Utilize high throughput kinome library screens and genomic profiling of mouse and human MB CSCs and non CSCs to identify a molecular signature and synthetic lethality effects which will predict sensitivity or resistance to a PI-3K inhibitor. 3) Elucidate the epigenetic mechanism by which PTEN is regulated in the CSC compartment in human SHH PDX models and the SmoTg GEMM model; Focused on PTEN specific miRNA regulatory networks. We will use the Math1creER recombinase to generate the conditional deletion of PTEN, p110 and/or p110 in normal cerebellar granule neuronal precursor cells (GNPs) or in the CSC compartment and determine the effects on the development of MB and CSC phenotype. In Aim 2, we will expand upon our recent report demonstrating the activity of the PI3K inhibitor, BKM120 against CSCs to include synthetic lethality screens with other targeted agents and conventional chemotherapeutics. An innovative component of our application is the recent discovery of a novel miRNA network which epigenetically regulates PTEN in the CSC compartment which is associated with the CSC phenotype. This observation will be explored in our GEMMs , MB PDX models and in human MB tumor samples to determine the role of these miRNAs in the regulation of PTEN, PI3K and the CSC phenotypes including tumor initiating activity. The proposed work is significant in that it will: 1) establish a role for PTEN, p110 and p110 in CSC biology in MB 2) identify novel synthetic lethalities in combination with PI3K inhibition in MB CSCs and 3) elucidate a role for miRNA networks in the control of PTEN and CSC phenotypes.

髓母细胞瘤 (MB) 是一种发生在小脑内的癌症，是最常见的脑恶性肿瘤儿童肿瘤目前依靠放疗和化疗的治疗只能治愈 60% 的患者，并且幸存者会产生严重的长期神经认知后遗症，因此开发的医疗需求未得到满足针对这种疾病的更有效、毒性更小的疗法。 (SHH) MB 亚组由表达该细胞的肿瘤增殖细胞（癌症干细胞；CSC）驱动表面糖蛋白 CD15 的知识差距在于控制 CSC 和非 CSC 的分子机制。 CSC 表型的描述很差。该提议的中心假设是 PI3K/PTEN。信号轴对 SHH MB 中的 CSC 表型进行控制，因此代表了治疗的靶点重要的是，我们实验室的工作证明了 PTEN。 MB 的 Smo 转基因（SHH 途径）小鼠模型的 CSC 区室中的表达受到抑制。我们的发现强调了 PTEN 缺陷 Smo 转基因小鼠模型的临床相关性： PTEN 表达在人类 MB 中缺失，并且观察到 PTEN 表达缺失与 MB 中生存率低相关我们的拨款提案以我们的初步数据提案为指导，有 3 个具体目标：1) 确定是否遗传。 PTEN 或 PI3K 特定亚型的改变对于 SHH 驱动的 CSC 表型是必要和/或充分的 2) 利用高通量激酶组库筛选和小鼠和肿瘤发生的基因组分析人类 MB CSC 和非 CSC 来识别分子特征和合成致死效应，这将预测对 PI-3K 抑制剂的敏感性或耐药性 3) 阐明 PTEN 的表观遗传机制。在人类 SHH PDX 模型和 SmoTg GEMM 模型中的 CSC 区室中受到调节；我们将使用 Math1creER 重组酶来生成 PTEN 特定 miRNA 调控网络。正常小脑颗粒神经元前体细胞中 PTEN、p110 和/或 p110 的条件性缺失 (GNP) 或 CSC 区室，并确定对 MB 和 CSC 表型发育的影响。在目标 2 中，我们将扩展最近的报告，展示 PI3K 抑制剂 BKM120 的活性针对 CSC，包括使用其他靶向药物和常规药物进行合成致死筛选我们应用的一个创新部分是最近发现的一种新型 miRNA。在与 CSC 相关的 CSC 区室中表观遗传调节 PTEN 的网络这一观察结果将在我们的 GEMM、MB PDX 模型和人类 MB 肿瘤中进行探索。样本以确定这些 miRNA 在 PTEN、PI3K 和 CSC 表型调节中的作用包括肿瘤起始活性。拟议的工作意义重大，因为它将：1）确定 PTEN 的作用， MB 2) 中 CSC 生物学中的 p110 和 p110 与 PI3K 抑制相结合，确定新的合成致死率 MB CSC 中的作用以及 3) 阐明 miRNA 网络在控制 PTEN 和 CSC 表型中的作用。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Vascular Permeability and Remodelling Coincide with Inflammatory and Reparative Processes after Joint Bleeding in Factor VIII-Deficient Mice.

DOI：
10.1055/s-0038-1641755
发表时间：
2018-06
期刊：
Thrombosis and haemostasis
影响因子：
6.7
作者：
Cooke EJ;Zhou JY;Wyseure T;Joshi S;Bhat V;Durden DL;Mosnier LO;von Drygalski A
通讯作者：
von Drygalski A