Targeting Wee1 in Myc driven Medulloblasoma

 描述（由申请人提供）：脑肿瘤是美国儿童肿瘤死亡的最常见原因，髓母细胞瘤是最常见的恶性儿童脑肿瘤，每年诊断出500多例。虽然标准风险患者的治疗改善了预后，但Myc癌基因过表达的高危患者仍然表现不佳。此外，仍然存在显著的治疗相关发病率，特别是在非常年轻的患者中。因此，迫切需要更有效的疗法， 对抗高Myc表达的髓母细胞瘤。利用整合的基因组分析，我们最近确定了WEE 1激酶作为髓母细胞瘤的潜在治疗靶点。我们证明了WEE 1在髓母细胞瘤患者样本中过表达，并且WEE 1的抑制在体外和体内抑制髓母细胞瘤细胞生长。特别是Myc过表达细胞对WEE1抑制更敏感。然而，WEE 1如何增强髓母细胞瘤肿瘤发生尚不清楚。此外，Myc驱动的髓母细胞瘤是否可以用目前临床上WEE 1的抑制剂治疗尚不清楚。因此，本提案的目的是确定神经管母细胞瘤中WEE 1活性的机制，并提供WEE 1抑制作为Myc驱动的神经管母细胞瘤治疗方法的临床前验证。我们推测WEE 1通过保护细胞免受Myc癌基因诱导的复制应激和促进DNA复制靶向化疗药物引起的DNA损伤修复来增强髓母细胞瘤细胞的存活。为了解决这一假设，目的一的研究将通过检查WEE 1在表达Myc的髓母细胞瘤细胞中表达的影响，检查WEE 1如何与Myc在转化人神经干细胞中合作，并评估Myc表达与WEE 1抑制的合成致死相互作用，来确定WEE 1在髓母细胞瘤肿瘤发生中的作用。目的二是确定使用目前正在临床开发的特异性WEE 1抑制剂MK 1775在体内抑制WEE 1的治疗功效和耐受性。目的三是利用全基因组RNAi技术和激酶抑制剂高通量系统，确定神经管母细胞瘤中WEE 1抑制介导合成致死的决定因素。这些研究将明确WEE 1如何调节髓母细胞瘤的发生，并通过提供科学依据和临床前研究，将WEE 1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WEE 1抑制的新治疗策略来影响髓母细胞瘤治疗。

 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.