Integrating Transforming Approaches to Identify and Target New Vulnerabilities in Cancer

摘要 在过去的十年里，通过颠覆性的技术，人们以前所未有的速度发现了癌症 技术。然而，对于许多恶性肿瘤，如急性髓系白血病(AML)，疾病的存活率 保持不变，尽管对其基因组图景进行了更细粒度的描述。我的研究项目寻求 应用功能基因组学和化学生物学的新方法来验证和翻译新出现的 急性髓系白血病和其他由简单基因组定义的恶性肿瘤的癌症相关性，特别是儿科 癌症。在这个提议中，我将在我们过去成功发明小分子新方法的基础上再接再厉 发现2)应用最先进的化学和功能基因组筛选来确定新的治疗方法 白血病、尤文肉瘤和神经母细胞瘤的靶点，以及将我们的发现转化为临床试验 对于患有这些疾病的患者。主要关注急性髓系白血病，我未来的研究计划寻求1) 部署遗传方法来验证候选癌症相关性，2)发现和测试新的小型- 癌症依赖性的分子抑制物，以及3)剖析每个靶点的机制及其在AML中的作用。 我将从我们的研究中出现的与高危AML亚型相关的靶点开始研究： 胞浆蛋白激酶--脾酪氨酸激酶；丝氨酸-苏氨酸激酶糖原合成酶-3 α(GSK-3α)，一种参与叶酸代谢的线粒体酶，亚甲基四氢叶酸 脱氢酶2(MTHFD2)；以及粘附素复合体的一个成员：基质抗原2(STAG2)。在一些 例如尤文肉瘤和STAG2，我将把检测扩展到其他目标疾病背景下 相关的，我的实验室有专业知识。在分子发病机制和护理方面具有深厚的专业知识 AML患者；领导高度多学科团队的经验，专注于高通量筛查 这种疾病和丰富的化学、生物学和临床合作者网络，我处于独特的地位 成功完成本方案所述的7年研究计划。

SUMMARY The last decade has seen an unparalleled pace of cancer-focused discovery enabled by disruptive technologies. However, for many malignancies, such as acute myeloid leukemia (AML), survival of the disease remains unchanged despite a more granular description of its genomic landscape. My research program seeks to apply new approaches in functional genomics and chemical biology to validate and translate emerging cancer dependencies in AML and other malignancies defined by simple genomes, particularly pediatric cancers. In this proposal, I build upon our past success in 1) inventing new approaches to small-molecule discovery 2) applying state-of-the-art chemical and functional genomic screens to identify new therapeutic targets in leukemia, Ewing sarcoma, and neuroblastoma, and in 3) translating our discoveries to clinical trials for patients suffering from these diseases. Primarily focusing on AML, my future research program seeks to 1) deploy genetic approaches to validate candidate cancer dependencies, 2) discover and test new small- molecule inhibitors of cancer dependencies, and 3) dissect the mechanisms of each target and its role in AML. I will begin with the study of targets that have emerged in our research as relevant in high-risk AML subtypes: the cytoplasmic kinase spleen tyrosine kinase (SYK); a serine-threonine kinase glycogen synthase kinase 3 alpha (GSK-3α), a mitochondrial enzyme involved in folate metabolism, methylenetetrahydrofolate dehydrogenase 2 (MTHFD2); and a member of the cohesin complex: stromal antigen 2 (STAG2). In some cases, such as Ewing sarcoma and STAG2, I will extend testing to other disease contexts where the target is relevant and my laboratory has expertise. With deep expertise in the molecular pathogenesis and care of patients with AML; experience leading highly multi-disciplinary teams focused on high-throughput screening for this disease and a rich network of chemistry, biology, and clinical collaborators, I am uniquely positioned to succeed in the 7 year research plan delineated in this proposal.