Mechanisms of resistance to WEE1 inhibition in Myc driven medulloblastoma

项目摘要 髓母细胞瘤（MB）是儿童中最常见的恶性脑肿瘤， 表现出高度的异质性。MB的治疗包括化疗和 辐射往往导致长期发病。MYC驱动的甲基溴尤其具有高风险 长期存活率低的肿瘤。我们先前将WEE 1确定为MYC驱动的 MB. WEE 1调节MYC驱动的复制应激和高通量化学筛选 鉴定了与吉西他滨的高度协同作用。进一步的数据表明，MB肿瘤 变得对WEE 1抑制具有抗性，并且该机制由CDK 7介导。我们 假设CDK 7通过重编程使MB细胞对WEE 1抑制重新敏感 增强子景观改变代谢途径和抑制同源 重组DNA修复网络。至CDK 7 的抑制 抑制 MB 和 同源 靶向 方法 为 与WEE 1联合验证抑制 作为一种治疗策略，我们将探讨三个关键问题。1. CDK 7如何改变 增强子景观调节对WEE 1抑制的敏感性？2.是WEE 1的组合 CDK 7抑制在体内MB治疗有效吗？3.添加针对 重组介导的DNA修复增强CDK 7/WEE 1介导的治疗 在MB？这项工作的结果预计将产生重要的见解， 这可用于抑制高风险MB中的MYC功能， 治疗MYC驱动的MB，这是我们研究的长期目标。

PROJECT SUMMARY Medulloblastoma (MB) is the most prevalent malignant brain tumor in children and demonstrates high level of heterogeneity. Treatment for MB includes chemotherapy and radiation often resulting in long-term morbidity. MYC driven MB in particular are high risk tumors with poor long-term survival. We previously identified WEE1 as a target in MYC driven MB. WEE1 regulates MYC driven replication stress and high throughput chemical screening identified high degree of synergy with gemcitabine. Further data suggest that MB tumors become resistant to WEE 1 inhibition and that this mechanism is mediated by CDK7.. We hypothesize CDK7 re-sensitizes MB cells to WEE1 inhibition by reprograming the enhancer landscape to alter metabolic pathways and suppressing homologous recombination DNA repair networks. To CDK7 that inhibition of inhibition MB and homologous targeting approaches for validate inhibition in combination with WEE1 as a therapeutic strategy we will pursue three key questions. 1. How dose CDK7 alter enhancer landscape to modulate sensitivity to WEE1 inhibition? 2. Is combination of WEE1 CDK7 inhibition therapeutically effective in MB in vivo? 3. Can addition of agents that target recombination mediated DNA repair potentiate CDK7/WEE1 mediated therapeutic of MB? The results of this work are expected to yield important insights into that could be used to inhibit MYC function in high-risk MB, and provide a rationale the treatment of MYC driven MB, which represents the long-term goal of our research.