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: 9212111
• 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/9212111
• 关键词: 17q; AMD3100; Adult; Affect; CXCR4 Receptors; CXCR4 gene; Cell membrane; Cells; Child; Childhood; Childhood Malignant Brain Tumor; Cilia; Clinical; Clinical Trials; Cytogenetics; Data; Diagnosis; Disease-Free Survival; Exhibits; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; Gene Expression; Generations; Genetic; Goals; Growth; Health; Human; Knock-out; Lead; Lesion; Ligands; MDM2 gene; 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; Pharmacology; Phosphoric Monoester Hydrolases; Positioning Attribute; Protein Isoforms; Proto-Oncogene Proteins c-akt; Research Personnel; Role; SHH gene; 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 drug combination; novel therapeutics; overexpression; precursor cell; prevent; public health relevance; small molecule; smoothened signaling pathway; targeted agent; targeted treatment; 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（由申请人提供）：PPM1D (WIP1) 基因在超过 50% 的髓母细胞瘤以及最近描述的 4 个髓母细胞瘤分子亚群中的 3 个中过表达。我们的初步数据表明，WIP1 过度表达还与肿瘤转移以及较差的无进展生存期和总生存期相关。该应用的长期目标是确定肿瘤进展和转移的机制和预测因子，以便开发能够提高 WIP1 过表达髓母细胞瘤患者生存率的疗法。我们发现过表达 WIP1 的髓母细胞瘤表现出与 Sonic Hedgehog (SHH) 信号传导和趋化因子 G 蛋白偶联受体 CXCR4 之间的独特串扰，但目前尚不清楚。我们的中心假设是，WIP1 过表达会改变 SHH 信号级联各成分的表达或激活，导致 CXCR4 异常定位或激活，从而导致 WIP1 过表达髓母细胞瘤细胞的生长、侵袭和转移增加。利用结合遗传学和药理学的创新多学科方法，我们将确定 (1) MB 肿瘤发生中 SHH 和 WIP1 信号传导之间的串扰机制，(2) WIP1 介导的 MB 侵袭机制，以及 (3) 疗效在髓母细胞瘤小鼠模型中，靶向 WIP1 以及靶向 SHH 和 CXCR4 信号传导的药物，以改善侵袭性髓母细胞瘤的治疗。获得 WIP1 过表达的多种模型和多种人髓母细胞瘤组织集使我们处于发现新治疗靶点的独特地位。最终，这项研究将通过在 WIP1 过度表达的髓母细胞瘤中确定新的分子靶点和新的药物组合，从而造福人类健康。了解与 WIP1 过度表达相关的分子机制最终将导致改进、毒性较小的治疗策略，并提高被诊断患有脑癌的儿童的生存率。

项目成果

The rationale for targeted therapies in medulloblastoma.

髓母细胞瘤靶向治疗的基本原理。

• DOI: 10.1093/neuonc/not147
• 发表时间: 2024-09-13
• 期刊: Neuro-oncology
• 影响因子: 15.9
• 作者: T. MacDonald;D. Aguilera;R. Castellino
• 通讯作者: R. Castellino

Response to bevacizumab, irinotecan, and temozolomide in children with relapsed medulloblastoma: a multi-institutional experience.

复发性髓母细胞瘤儿童对贝伐单抗、伊立替康和替莫唑胺的反应：多机构经验。

• 发表时间: 2013-04
• 作者: Aguilera, Dolly;Mazewski, Claire;Fangusaro, Jason;MacDonald, Tobey J;McNall;Hayes, Laura L;Kim, Sungjin;Castellino, Robert C
• 通讯作者: Castellino, Robert C

Response of subependymal giant cell astrocytoma with spinal cord metastasis to everolimus.

伴脊髓转移的室管膜下巨细胞星形细胞瘤对依维莫司的反应。

• 发表时间: 2014-10
• 作者: Aguilera, Dolly;Flamini, Robert;Mazewski, Claire;Schniederjan, Matthew;Hayes, Laura;Boydston, William;Castellino, Robert C;MacDonald, Tobey J
• 通讯作者: MacDonald, Tobey J

Novel therapeutic targets in pediatric neural tumors

小儿神经肿瘤的新治疗靶点

• 发表时间: 2018-02-16
• 作者: J. Milosevic