Targeting Wee1 in Myc driven Medulloblasoma

 描述(申请人提供)：脑瘤是美国儿童最常见的肿瘤死亡原因，髓母细胞瘤是最常见的儿童恶性脑瘤，每年诊断超过500例。虽然对标准风险患者的治疗结果有所改善，但Myc癌基因过度表达的高危患者仍然表现不佳。此外，与治疗相关的发病率仍然很高，特别是在非常年轻的患者中。因此，迫切需要更有效的治疗方法来 抗击高Myc表达的髓母细胞瘤。利用整合的基因组分析，我们最近确定WEE1激酶是髓母细胞瘤的潜在治疗靶点。我们证明WEE1在髓母细胞瘤患者样本中过表达，并且抑制WEE1在体外和体内抑制髓母细胞瘤细胞的生长。特别是，Myc过表达的细胞对WEE1抑制更敏感。然而，WEE1如何促进髓母细胞瘤的发生尚不清楚。此外，Myc驱动的髓母细胞瘤是否可以用目前临床上使用的WEE1抑制剂治疗尚不清楚。因此，这项建议的目的是确定WEE1在髓母细胞瘤中的活性机制，并提供临床前验证WEE1抑制作为Myc驱动的髓母细胞瘤的治疗方法。我们假设WEE1通过保护细胞免受Myc癌基因诱导的复制应激，并促进DNA损伤修复来响应DNA复制靶向化疗药物，从而提高髓母细胞瘤细胞的存活率。为了解决这一假设，目标一的研究将通过检测WEE1在表达WEE1的髓母细胞瘤细胞中的表达的影响，检测WEE1如何与Myc在转化人神经干细胞方面的合作，以及评估Myc表达与WEE1抑制的合成致死性相互作用来确定WEE1在髓母细胞瘤发生中的作用。目的二研究目前正在临床开发的WEE1特异性抑制剂MK1775在体内抑制WEE1的疗效和耐受性。目的三利用全基因组RNAi技术和高通量的激酶抑制剂系统，鉴定在髓母细胞瘤中介导WEE1抑制的合成致死率的决定因素。拟议的研究将确定WEE1如何调控髓母细胞瘤的发生，并通过提供科学理论基础和临床前研究，将WEE1确立为髓母细胞瘤的新治疗靶点。 早期临床研究所需的数据。这些研究的完成有望通过引入WEE1抑制的新治疗策略来影响髓母细胞瘤的治疗。

 DESCRIPTION (provided by applicant): Brain tumors are the most common cause of oncological death in American children, and medulloblastoma is the most common malignant childhood brain tumor, with over 500 cases diagnosed each year. While therapy for standard-risk patients has resulted in improved outcomes, high-risk patients with Myc oncogene overexpression still do poorly. In addition, there remains significant therapy-related morbidity, particularly in very young patients. Thus, there is a critical need for more effective therapies to combat high Myc expressing medulloblastoma. Using integrated genomic analysis we have recently identified the WEE1 kinase as a potential therapeutic target in medulloblastoma. We demonstrated that WEE1 is over expressed in medulloblastoma patient samples and that inhibition of WEE1 suppresses medulloblastoma cell growth in vitro and in vivo. In particular Myc overexpressing cells are more sensitive to WEE1 inhibition. However how WEE1 enhances medulloblastoma tumorigenesis is unknown. Further whether Myc driven medulloblastoma can be treated with current clinical inhibitors of WEE1 is not known. Thus the objectives of this proposal are to determine the mechanism of WEE1 activity in medulloblastoma and to provide pre-clinical validation of WEE1 inhibition as a therapeutic approach in Myc driven medulloblastoma. We hypothesize that WEE1 enhances medulloblastoma cell survival by protecting cells from Myc oncogene induced replicative stress and promoting DNA damage repair in response to DNA replication targeted chemotherapeutics. To address the hypothesis the studies in aim one will determine the role of WEE1 in medulloblastoma tumorigenesis by examining the impact of WEE1 expression in Myc expressing medulloblastoma cells, examining how WEE1 co-operates with Myc in transforming human neural stem cells and evaluating the synthetic lethal interaction of Myc expression with WEE1 inhibition. Aim two is designed to establish the therapeutic efficacy and tolerability of WEE1 inhibition in vivo using a specific WEE1 inhibitor, MK 1775, that is currently in clinical development. Aim three will identify determinants that mediate synthetic lethality with WEE1 inhibition in medulloblastoma using genome wide RNAi technology and kinase inhibitor high throughput systems. The proposed studies will define how WEE1 regulates medulloblastoma tumorigenesis and establish WEE1 as a novel therapeutic target in medulloblastoma by providing the scientific rationale and preclinical data required for early phase clinical studies. Completion of these studies is expected to impact medulloblastoma therapy by resulting in novel therapeutic strategies incorporating WEE1 inhibition.