Remodeling the translatome in N-myc mediated medulloblastoma and its therapeutic implications

髓母细胞瘤是儿童最常见的恶性脑肿瘤。手术后，放射治疗和 化疗后，总的五年生存率为60%-70%。幸存者表现出严重的身体和认知障碍， 通常不能独立生活。髓母细胞瘤存在于四个不同的分子亚群(WNT，SHH， 第3组、第4组)。一个无法治愈的SHH驱动的肿瘤亚群显示MYCN转录放大 因素。我们如何在髓母细胞瘤中靶向N-myc？N-myc调节蛋白质合成的能力与 与其致癌潜力以及与mTOR丝氨酸-苏氨酸激酶的相互作用有关。我们假设N- MYC劫持了mTOR丝氨酸苏氨酸激酶调节的翻译机制来驱动转化； 靶向翻译控制代表了N-myc驱动的癌症的一种治疗策略。用人 核糖体图谱技术，我们令人惊讶地发现，除了作为蛋白质的全球调节因子的作用 合成，N-myc与mTOR相互作用，调节属于折叠机械的13个mRNAs的翻译， 对于N-myc驱动的髓母细胞瘤具有重要的功能。N-myc引导 翻译这些特定的mRNAs亚集来驱动肿瘤的发生，以及这些潜在的漏洞是否 能否被利用来开发靶向治疗仍然是悬而未决的问题。在这项提案中，我们将 从机械上剖析N-myc如何劫持其致癌活性的翻译机制。使用小说 我们将分别评估eIF4E和eIF4A在我们的N-myc驱动的 转基因小鼠(GEM)模型。我们还将测试针对eIF4A和eIF4E的新药， 分析GEM模型和患者来源的原位异种移植。这些目标的成功实现将 描述N-myc如何与mTOR相互作用以调节关键的翻译靶子集，并阐明 N-myc驱动的髓母细胞瘤的药物机制。

Medulloblastoma is the most common malignant pediatric brain tumor. After surgery, radiation and chemotherapy, five-year survival is 60-70% overall. Survivors show severe physical and cognitive disabilities, often unable to live independently. Medulloblastoma exists in four distinct molecular subgroups (WNT, SHH, Group3, Group 4). An incurable subgroup of SHH driven tumors show amplification of the MYCN transcription factor. How can we target N-myc in medulloblastoma? N-myc’s ability to regulate protein synthesis is tied both to its oncogenic potential and to interactions with the mTOR serine-threonine kinase. We hypothesize that N- myc hijacks the translational machinery regulated by the mTOR serine threonine kinase to drive transformation; and that targeting translation control represents a therapeutic strategy for N-myc driven cancers. Employing ribosome profiling technology, we surprisingly found that in addition to roles as a global regulator of protein synthesis, N-myc interacts with mTOR to regulate translation of 13 mRNAs belonging to the folding machinery, functionally important for N-myc driven medulloblastoma. The mechanisms by which N-myc directs the translation of these specific subsets of mRNAs to drive tumorigenesis and whether these potential vulnerabilities can be leveraged to develop targeted therapies remain outstanding questions. In this proposal, we will mechanistically dissect how N-myc hijacks the translational machinery for its oncogenic activity. Using novel genetic approaches, we will separately evaluate the importance of eIF4E and eIF4A in our N-myc driven genetically engineered mouse (GEM) models. We will also test new clinical drugs against eIF4A and eIF4E, analyzing GEM models, and patient derived orthotopic xenografts. Successful completion of these aims will delineate how N-myc interacts with mTOR to regulate key subsets of translational targets, and elucidates druggable mechanisms in N-myc driven medulloblastoma.