Mechanisms of PPM1D in medulloblastoma tumorigenesis and invasion

PPM1D在髓母细胞瘤发生和侵袭中的机制

• 批准号: 8421691
• 负责人: Robert Craig Castellino
• 金额: $ 32.37万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8421691
• 关键词: 17q; AMD3100; Adult; Affect; CXCR4 gene; Cell membrane; Cells; Child; Childhood; Childhood Brain Neoplasm; Cilia; Clinical; Clinical Trials; Cytogenetics; Data; Diagnosis; Disease-Free Survival; Drug Combinations; Erinaceidae; Exhibits; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; Gene Expression; Generations; Genes; Genetic; Goals; Growth; Health; Human; Knock-out; Lead; Lesion; Ligands; MDM2 gene; Malignant - descriptor; Malignant neoplasm of brain; Mediating; Mediator of activation protein; Metastatic Neoplasm to the Leptomeninges; Modeling; Molecular; Molecular Target; Mus; Neoplasm Metastasis; Neurons; Neurosurgeon; Oncogenes; Oncologist; PPM1D gene; Pathologist; Patients; Pharmaceutical Preparations; Pharmacology; Phosphoric Monoester Hydrolases; Positioning Attribute; Protein Isoforms; Proto-Oncogene Proteins c-akt; Relative (related person); Research Personnel; Role; Signal Pathway; Signal Transduction; Subgroup; Survival Rate; Survivors; TP53 gene; Therapeutic; Tissues; Transcript; Tumor Pathology; arm; chemokine; functional genomics; improved; in vivo; in vivo Model; innovation; interdisciplinary approach; knock-down; medulloblastoma; molecular marker; mouse model; neuro-oncology; new therapeutic target; novel; overexpression; precursor cell; prevent; public health relevance; small molecule; smoothened signaling pathway; therapeutic target; therapy development; trafficking; tumor; tumor growth; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): The PPM1D (WIP1) gene is overexpressed in over 50% of medulloblastomas and in 3 of the 4 recently described medulloblastoma molecular subgroups. Our preliminary data shows that WIP1 overexpression is also associated with tumor metastasis and poor progression-free and overall survival. The long-term goal of this application is to identify mechanisms and predictors of tumor progression and metastasis in order to develop therapies that will improve the survival of patients with WIP1-overexpressing medulloblastoma. We have found that WIP1 overexpressing medulloblastomas exhibit a unique cross-talk with Sonic Hedgehog (SHH) signaling and the chemokine G-protein-coupled receptor CXCR4 that is poorly characterized. Our central hypothesis is that WIP1 overexpression alters expression or activation of components of the SHH signaling cascade and results in aberrant localization or activation of CXCR4, causing increased growth, invasion, and metastasis of WIP1-overexpressing medulloblastoma cells. Using an innovative multidisciplinary approach that combines genetics and pharmacology, we will determine (1) the mechanisms of cross-talk between SHH and WIP1 signaling in MB tumorigenesis, (2) the mechanisms of MB invasion mediated by WIP1, and (3) the efficacy of targeting WIP1 along with agents that target SHH and CXCR4 signaling in mouse models of medulloblastoma to improve the treatment of aggressive medulloblastomas. Access to multiple models of WIP1 overexpression and multiple human medulloblastoma tissue sets places us in a unique position to discover novel therapeutic targets. Ultimately, this study will benefit human health by identifying new molecular targets and novel drug combinations in WIP1-overexpressing medulloblastomas. Understanding the molecular mechanisms associated with WIP1 overexpression will ultimately lead to improved, less toxic therapeutic strategies and improved survival rates in children diagnosed with brain cancer.

描述(申请人提供)：PPM1D(Wip1)基因在超过50%的髓母细胞瘤和最近描述的4个髓母细胞瘤分子亚群中的3个中高表达。我们的初步数据显示，Wip1的过度表达也与肿瘤转移以及较差的无进展和总体生存率有关。这项应用的长期目标是确定肿瘤进展和转移的机制和预测因素，以便开发能够提高Wip1过表达髓母细胞瘤患者的存活率的治疗方法。我们发现Wip1过表达的髓母细胞瘤表现出与Sonic Hedgehog(SHH)信号和趋化因子G蛋白偶联受体CXCR4的独特的串扰，而CXCR4的特性很差。我们的中心假设是，Wip1的过表达改变了SHH信号级联的表达或激活，导致CXCR4的异常定位或激活，导致Wip1过表达的髓母细胞瘤细胞的生长、侵袭和转移增加。采用遗传学和药理学相结合的创新多学科方法，我们将确定(1)SHH和Wip1信号在MB肿瘤发生中的串扰机制，(2)Wip1介导的MB侵袭机制，以及(3)靶向Wip1以及靶向SHH和CXCR4信号的药物在髓母细胞瘤小鼠模型中的有效性，以提高侵袭性髓母细胞瘤的治疗效果。获得多种模型的Wip1过表达和多种人类髓母细胞瘤组织集使我们处于发现新的治疗靶点的独特地位。最终，这项研究将通过在Wip1过表达的髓母细胞瘤中识别新的分子靶点和新的药物组合来造福人类健康。了解与Wip1过度表达相关的分子机制最终将导致改善、毒性较低的治疗策略，并提高被诊断为脑癌的儿童的存活率。