Diversity Supplement for MYCN, mTOR and translation control in medulloblastoma

髓母细胞瘤中 MYCN、mTOR 和翻译控制的多样性补充

基本信息

批准号：
9067800
负责人：
Davide Ruggero
金额：
$ 1.82万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9067800
关键词：
Active Sites Affect Alleles Automobile Driving Biology CCI-779 Cell Line Child Clinical Clinical Trials Complex Data Development Drug usage Gap Junctions Genetically Engineered Mouse Health Hematopoietic Neoplasms MYCN gene Malignant neoplasm of brain Measures Modeling Modification Molecular Mus N-Myc Protein Oncogenic Output Pathway interactions Patients Peptide Initiation Factors Phosphorylation Phosphotransferases Prostatic Neoplasms Proto-Oncogenes Ribosomal Protein S6 Kinase Ribosomes Role SHH gene Signal Transduction Sirolimus Subgroup Testing Therapeutic Time Tissues Translations Transplantation Tumor Burden Xenograft procedure genetic approach high risk human FRAP1 protein inhibitor/antagonist insight kinase inhibitor mTOR protein medulloblastoma mouse model new technology novel pre-clinical progenitor programs research study stem targeted treatment therapeutic target tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Medulloblastoma is the most common malignant brain tumor in children. Aggressive molecular subgroups have poorly understood biology and few targeted therapies. A high risk subgroup of SHH driven-tumors also shows amplification of the MYCN proto-oncogene, while 4 tumors demonstrate increased levels or amplification of MYCN. How can we target MYCN in medulloblastoma? We hypothesize that MYCN cooperates with the translational apparatus to drive transformation in medulloblastoma, and that inhibition of the mTOR kinase represents a critical therapeutic strategy for both MYCN/SHH co-driven, and Group 4 medulloblastoma. In both prostate and hematopoietic tumors, MYC drives tumorigenesis through interacting with the translational apparatus downstream of the mammalian target of rapamycin (mTOR) a master regulator of translation. The mTOR complex 1 (mTORC1) signals through Ribosomal Protein S6 kinase (S6K) and the translation initiation factor eIF4E. A new class of mTOR kinase inhibitors disrupts signaling through both mTORC1 effectors, whereas clinical allosteric binders (rapamycin and analogues) disrupt only S6K. These mechanistically distinct activities have enormous therapeutic implications, as in our Group 4 medulloblastoma model, mTOR kinase inhibitors, but not rapamycin, show efficacy. Importantly, we found cross-talk between MYCN and mTOR during medulloblastoma development. Our preliminary data point to a critical role for eIF4E in tumorigenesis at this nexus between MYCN and mTOR. These observations suggest that S6K is dispensable, whereas eIF4E is required for MYC/MYCN-driven medulloblastoma. In this proposal, we will determine how MYCN hijacks the translational apparatus for its oncogenic activity (A1). We recently developed distinct genetically engineered mouse (GEM) models for high-risk Group 4 and MYCN driven SHH-dependent medulloblastoma, in which mis-expression of MYCN drives oncogenesis. Using unique genetic approaches, we will separately evaluate the importance of S6K and eIF4E in our MYCN/SHH and Group 4 GEM models (A2). Finally, we will use clinical inhibitors of mTOR to evaluate S6K (allosteric inhibitors of mTOR) and eIF4E (mTOR kinase inhibitors) as therapeutic targets, analyzing cell lines, GEM models, and patient derived xenografts (PDX--A3). Successful completion elucidates fundamental targetable mechanisms in MYCN-driven medulloblastoma.

描述（由申请人提供）：髓母细胞瘤是儿童中最常见的恶性脑肿瘤。攻击性分子亚群对生物学知之甚少，也很少有针对性的治疗方法。 SHH 驱动肿瘤的高风险亚组也显示出 MYCN 原癌基因的扩增，而 4 个肿瘤则显示出 MYCN 水平增加或扩增。我们如何靶向髓母细胞瘤中的 MYCN？我们假设 MYCN 与翻译装置合作驱动髓母细胞瘤的转化，并且抑制 mTOR 激酶代表了 MYCN/SHH 共同驱动的 4 类髓母细胞瘤的关键治疗策略。在前列腺肿瘤和造血系统肿瘤中，MYC 通过与哺乳动物雷帕霉素靶点 (mTOR)（翻译的主要调节因子）下游的翻译装置相互作用来驱动肿瘤发生。 mTOR 复合物 1 (mTORC1) 通过核糖体蛋白 S6 激酶 (S6K) 和翻译起始因子 eIF4E 发出信号。一类新型 mTOR 激酶抑制剂可破坏两个 mTORC1 效应器的信号传导，而临床变构结合剂（雷帕霉素和类似物）仅破坏 S6K。这些机制上不同的活性具有巨大的治疗意义，正如在我们的第 4 组髓母细胞瘤模型中，mTOR 激酶抑制剂（而非雷帕霉素）显示出疗效。重要的是，我们发现在髓母细胞瘤发育过程中 MYCN 和 mTOR 之间存在串扰。我们的初步数据表明，eIF4E 在 MYCN 和 mTOR 之间的关系的肿瘤发生中发挥着关键作用。这些观察结果表明，S6K 是可有可无的，而 eIF4E 是 MYC/MYCN 驱动的髓母细胞瘤所必需的。在本提案中，我们将确定 MYCN 如何劫持翻译装置的致癌活性 (A1)。我们最近开发了独特的基因用于高风险 4 组和 MYCN 驱动的 SHH 依赖性髓母细胞瘤的工程小鼠 (GEM) 模型，其中 MYCN 的错误表达驱动肿瘤发生。使用独特的遗传方法，我们将分别评估 S6K 和 eIF4E 在我们的 MYCN/SHH 和 Group 4 GEM 模型 (A2) 中的重要性。最后，我们将使用mTOR的临床抑制剂来评估S6K（mTOR变构抑制剂）和eIF4E（mTOR激酶抑制剂）作为治疗靶点，分析细胞系、GEM模型和患者来源的异种移植物（PDX--A3）。成功完成阐明了 MYCN 驱动的髓母细胞瘤的基本靶向机制。