The Utility of WDR5 WIN Site Inhibitors in Rhabdoid Tumors

项目总结/摘要 横纹肌样瘤（RT）是一种罕见的侵袭性儿童癌症，死亡率极高。 大多数患有RT的儿童将在诊断后18个月内死亡。目前还没有标准的护理 对于这些儿童来说，美国每年诊断出的RT病例不到25例， 针对这种癌症的新治疗策略的研究很少。然而，尽管它具有侵略性， RT具有异常简单的遗传特征，因为它是由单个基因SMARCB 1的丢失驱动的，SMARCB 1 编码SWI/SNF染色质重塑复合物的SNF 5组分。最近的研究表明， SNF 5缺失导致RT，部分是通过激活MYC，一种癌蛋白转录因子， 致瘤功能推而广之，抗MYC疗法在治疗RT方面可能具有巨大的价值。 它本身被广泛认为是不可药用的，这意味着如果 成功的，将最有可能集中在辅助因素MYC使用的功能。一种MYC辅因子， 正在开发的是WDR 5，它有助于MYC在“蛋白质合成”时向染色质的募集 这些基因刺激生物量积累，这是MYC致癌库的关键部分。 重要的是，WDR 5-MYC相互作用的遗传破坏降低了PSG的转录，并促进了细胞的增殖。 体内肿瘤消退。WDR 5“WIN位点”抑制剂快速全面地取代WDR 5， 染色质，并因此选择性地降低PSG处的MYC水平。这些发现预测， 抑制剂也可用于治疗RT。本项目的目标是了解RT细胞的反应 WIN位点抑制剂和鉴定赋予敏感性或抗性的重要调节剂。表征 特异性目标1将联合收割机结合基因组和细胞方法 鉴定WDR 5和MYC染色质结合以及转录的变化，以告知机制， 所述WIN位点抑制剂促进RT细胞中的生长抑制和细胞死亡。在具体目标2中， 基因组CRIPSR筛选和协同筛选将确定赋予敏感性或抗性的基因， 确定提高WIN位点抑制剂疗效的药物。这项工作的完成将揭示RT如何 细胞响应WIN位点阻断，并为RT和潜在的其他MYC提供新的治疗策略， 驱动肿瘤。一个严格的研究项目，一个特殊的导师，和刺激的组合 在范德比尔特的研究环境将产生出色的培训经验。项目和培训计划 这份提案中的详细内容将使我具备成为一名有影响力的独立癌症研究人员的工具。

PROJECT SUMMARY/ABSTRACT Rhabdoid tumors (RT) are rare and aggressive childhood cancers with exceptionally high rates of mortality. Most children suffering with RT will die within 18 months of diagnosis. There is currently no standard of care for these children and—with fewer than 25 cases of RT diagnosed in the U.S. each year—the likelihood of developing new treatment strategies for this cancer are low. Despite its aggressive characteristics, however, RT has an unusually simple genetic profile in that it is driven by loss of a single gene, SMARCB1, which encodes the SNF5 component of the SWI/SNF chromatin remodeling complex. Recent work has shown that SNF5 loss leads to RT, in part, by activating MYC, an oncoprotein transcription factor with extensive pro- tumorigenic functions. By extension, anti-MYC therapies could have immense value in treating RT. But MYC itself is widely considered to be undruggable, meaning that pharmacological strategies to target MYC, if successful, will most likely focus on the co-factors MYC uses to function. A MYC cofactor for which inhibitors are being developed is WDR5, which facilitates the recruitment of MYC to chromatin at "protein synthesis genes" (PSGs) that stimulate biomass accumulation, a critical part of the oncogenic repertoire of MYC. Importantly, genetic disruption of the WDR5-MYC interaction decreases transcription of PSGs and promotes tumor regression in vivo. WDR5 "WIN site" inhibitors quickly and comprehensively displace WDR5 from chromatin and as a result, selectively reduce MYC levels at PSGs. These findings predict that WIN site inhibitors could also be used for treating RT. The goal of this project is to understand the response of RT cells to WIN site inhibitors and to identify important modulators conferring sensitivity or resistance. To characterize the response to WIN site inhibition in RT cells, Specific Aim 1 will combine genomic and cellular approaches to identify changes in WDR5 and MYC chromatin association and in transcription to inform mechanisms by which WIN site inhibitors promote growth inhibition and cell death in RT cells. In Specific Aim 2, whole genome CRIPSR screens and synergy screens will define genes that confer sensitivity or resistance and identify drugs that improve the efficacy of WIN site inhibitors. Completion of this work will uncover how RT cells respond to WIN site blockade and inform new treatment strategies for RT and potentially other MYC- driven tumors. The combination of a rigorous research project, an exceptional mentor, and the stimulating research environment at Vanderbilt will yield an outstanding training experience. The project and training plan detailed in this proposal will equip me with the tools to become an impactful independent cancer researcher.