MYCN, mTOR and translation control in medulloblastoma

髓母细胞瘤中的 MYCN、mTOR 和翻译控制

基本信息

批准号：
8801526
负责人：
Davide Ruggero
金额：
$ 63.22万
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/8801526
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 Genetic Genetically Engineered Mouse 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 high risk human FRAP1 protein inhibitor/antagonist insight kinase inhibitor mTOR protein medulloblastoma mouse model new technology novel pre-clinical progenitor programs public health relevance research study stem 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）：髓母细胞瘤是儿童最常见的恶性脑肿瘤。侵略性分子亚组的生物学知识不足，靶向疗法很少。 SHH驱动的肿瘤的高风险亚组还显示了MYCN原型癌基因的扩增，而4个肿瘤显示MYCN的水平升高或扩增。我们如何靶向髓母细胞瘤中的MYCN？我们假设MYCN与翻译机构合作以驱动髓母细胞瘤的转化，并抑制 MTOR激酶代表了MYCN/SHH共同驱动和4组髓母细胞瘤的关键治疗策略。在前列腺和造血肿瘤中，MYC通过与雷帕霉素（MTOR）哺乳动物靶标的转化设备相互作用来驱动肿瘤发生，这是翻译的主要调节剂。 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信号。一类新的MTOR激酶抑制剂通过MTORC1效应子破坏信号传导，而临床变构粘合剂（雷帕霉素和类似物）仅破坏S6K。这些机械上不同的活性具有巨大的治疗意义，如我们的第4组髓母细胞瘤模型mTOR激酶抑制剂，但没有雷帕霉素，表现出疗效。重要的是，我们在髓母细胞发育过程中发现了MYCN和MTOR之间的串扰。我们的初步数据表明，在MYCN和MTOR之间，在这种联系中，EIF4E在肿瘤发生中的关键作用。这些观察结果表明S6K是可分配的，而MYC/MYCN驱动的髓母细胞瘤需要EIF4E。在此提案中，我们将确定MyCN如何劫持转化设备的致癌活性（A1）。我们最近在遗传上开发了不同的高风险组4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的误表达驱动了肿瘤。使用独特的遗传方法，我们将分别评估S6K和EIF4E在MYCN/SHH和4组GEM模型（A2）中的重要性。最后，我们将使用MTOR的临床抑制剂评估S6K（MTOR的变构抑制剂）和EIF4E（mTOR激酶抑制剂）作为治疗靶标，分析细胞系，GEM模型和患者衍生的异种植物（PDX-a3）。成功的完成阐明了MYCN驱动的髓母细胞瘤中的基本目标机制。