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

• 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
• 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

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）是在小脑内引起的癌症，是最常见的恶性大脑 儿童肿瘤。依靠放疗和化学疗法的当前护理，仅治愈60％的患者， 并且在生存中具有严重的长期神经认知后遗症，因此未满足的医学需要发展 对这种疾病的更有效，毒性较小。包括声波刺猬在内的恶性脑肿瘤 （SHH）Mb的亚组由表达细胞的肿瘤传播细胞（癌细胞； CSC）驱动 表面糖蛋白CD15。存在一个知识差距，因为控制CSC和非分子机制 CSC表型的描述不佳。该提议的中心假设是PI3K/PTEN 信号轴对SHH MB中的CSC表型执行控制，因此代表了治疗的目标。 用PI3K抑制剂开发。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隔室抑制了表达。 我们的发现强调了PTEN缺乏SMO转基因小鼠模型的临床相关性 PTEN表达在人类MB中丢失，并且观察到PTEN损失与MB的存活率差有关 患者。我们的赠款提案，在我们的初步数据建议的指导下3个特定目的：1）确定遗传是否是否 PI3K的PTEN或特定同工型的改变是必需的，并且/或对于SHH驱动的CSC表型足够 和肿瘤发生2）使用高吞吐量Kinome库筛选以及小鼠的基因组分析和 人类MB CSC和非CSC识别分子特征和合成的致死性效应 预测对PI-3K抑制剂的敏感性或抗性。 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室中受到调节；专注于 PTEN特定的miRNA调节网络。我们将使用Math1creer重组酶生成 正常小脑颗粒神经元细胞中PTEN，P110和/或P110的有条件缺失 （GNP）或CSC隔室中，并确定对MB和CSC表型发展的影响。 在AIM 2中，我们将扩展我们最近的报告，证明了PI3K抑制剂的活性BKM120 针对CSC，包括与其他靶向药物的合成致死性筛选和常规 化学治疗学。我们应用的创新组成部分是最近发现的新型miRNA 与CSC相关的CSC隔室中PTEN的表观遗传调节的网络 表型。该观察结果将在我们的GEMM，MB PDX模型和人类MB肿瘤中进行探讨 确定这些miRNA在PTEN，PI3K和CSC表型调节中的作用的样品 包括肿瘤启动活性。拟议的工作很重要，因为它将：1）为PTEN确定角色， MB中的CSC生物学中的P110和P110识别新型合成致死性与PI3K抑制 在MB CSC和3）中阐明了miRNA网络在控制PTEN和CSC表型中的作用。

项目成果

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