Integrating Transforming Approaches to Identify and Target New Vulnerabilities in Cancer

整合变革方法来识别和针对癌症的新弱点

• 批准号: 10457896
• 负责人: Kimberly Stegmaier
• 金额: $ 102.55万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-09 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10457896
• 关键词: Acute Myelocytic Leukemia; Address; Antigens; Biology; Chemicals; Chemistry; Clinical; Clinical Trials; Complex; Dependence; Disease; Enzymes; Ewings sarcoma; Genetic; Genome; Genomics; Glycogen Synthase Kinase 3; Laboratories; Malignant Childhood Neoplasm; Malignant Neoplasms; Mitochondria; Molecular; Neuroblastoma; Oxidoreductase; Pathogenesis; Patient Care; Patients; Positioning Attribute; Protein-Serine-Threonine Kinases; Research; Role; SYK gene; Technology; Testing; Translating; cohesin; experience; folic acid metabolism; functional genomics; genetic approach; high risk; high throughput screening; innovation; leukemia; member; multidisciplinary; new technology; new therapeutic target; novel strategies; programs; small molecule; small molecule inhibitor; success

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.

总结 在过去的十年里，以癌症为重点的发现以前所未有的速度发展， 技术.然而，对于许多恶性肿瘤，如急性髓性白血病（AML），疾病的生存期 保持不变，尽管对其基因组景观进行了更精细的描述。我的研究计划 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兴的 AML和其他由简单基因组定义的恶性肿瘤中的癌症依赖性，特别是儿科 癌的在这个建议中，我建立在我们过去的成功基础上：1）发明小分子药物的新方法， 发现2）应用最先进的化学和功能基因组筛选来鉴定新的治疗药物 白血病、尤文肉瘤和神经母细胞瘤的靶点，并将我们的发现转化为临床试验 对于患有这些疾病的患者。我未来的研究计划主要集中在AML上，目的是1） 部署遗传方法来验证候选癌症依赖性，2）发现和测试新的小- 癌症依赖性的分子抑制剂，和3）剖析每个靶点的机制及其在AML中的作用。 我将开始研究我们研究中出现的与高危AML亚型相关的靶点： 细胞质激酶脾酪氨酸激酶（SYK）;丝氨酸-苏氨酸激酶糖原合成酶激酶3 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（MTHFD 2）;和粘着蛋白复合物的成员：基质抗原2（STAG 2）。在一些 在某些情况下，如尤文肉瘤和STAG 2，我将把测试扩展到其他疾病的情况下， 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;拥有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， 成功完成本提案中所述的7年研究计划。