MYCN, mTOR and translation control in 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。侵袭性分子亚组的生物学知之甚少，靶向治疗也很少。SHH驱动肿瘤的高风险亚组也显示MYCN原癌基因扩增，而4个肿瘤显示MYCN水平增加或扩增。我们如何在髓母细胞瘤中靶向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MYCN的表达可能是一个重要的机制。 mTOR激酶代表了MYCN/SHH共同驱动的和第4组成神经管细胞瘤的关键治疗策略。在前列腺和造血系统肿瘤中，MYC通过与哺乳动物雷帕霉素靶蛋白（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（mTORC 1）通过核糖体蛋白S6激酶（S6 K）和翻译起始因子eIF 4 E发出信号。一类新的mTOR激酶抑制剂通过mTORC 1效应物破坏信号传导，而临床变构结合剂（雷帕霉素及其类似物）仅破坏S6 K。这些机制上不同的活性具有巨大的治疗意义，因为在我们的第4组髓母细胞瘤模型中，mTOR激酶抑制剂而不是雷帕霉素显示出功效。重要的是，我们发现在髓母细胞瘤发展过程中MYCN和mTOR之间存在串扰。我们的初步数据表明，eIF 4 E在MYCN和mTOR之间的这种联系中在肿瘤发生中起着关键作用。这些观察结果表明，S6 K是EIF 4 E，而eIF 4 E是MYC/MYCN驱动的髓母细胞瘤所必需的。在这个提议中，我们将确定MYCN如何劫持其致癌活性的翻译装置（A1）。我们最近从基因上 在高危组4和MYCN驱动的SHH依赖性髓母细胞瘤的工程小鼠（GEM）模型中，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S6 K和eIF 4 E在我们的MYCN/SHH和第4组GEM模型中的重要性（A2）。最后，我们将使用mTOR的临床抑制剂来评估S6 K（mTOR的变构抑制剂）和eIF 4 E（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。

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.