Targeting mitochondrial one carbon folate metabolism for novel T-cell acute lymphoblastic leukemia therapy

项目摘要/摘要 虽然儿童急性淋巴细胞白血病(ALL)的治愈率在过去的几年里有了显著的提高 几十年来，ALL仍然是儿童癌症相关死亡的第二大原因。那里还在继续 T细胞急性淋巴细胞白血病(T-ALL)患者对有效治疗的需求尚未得到满足， 尤其是那些复发或难治性疾病的患者。T-ALL是一种通常对药物有反应的疾病 靶向代谢，包括甲氨蝶呤和天冬酰胺酶，它们构成了T-ALL治疗的支柱。 因此，我推测靶向新陈代谢的新方法可能与T-ALL特别相关。我 亚甲基四氢叶酸小分子抑制剂对白血病细胞系的筛选 线粒体的脱氢酶2(MTHFD2)和丝氨酸羟甲基转移酶2(SHMT2) 一条碳叶酸途径，我发现T-ALL细胞对这些抑制剂高度敏感，尤其是 而不是其他白血病细胞系。该提案旨在使用小分子抑制剂MTHFD2和SHMT2， 以及在体外和体内对这些酶的遗传抑制，以研究SHMT2的机制作用 MTHFD2在T-ALL发病中的作用。该项目的最终目标是为患者开发新的治疗方法。 和T-All一起。 我是一名儿科肿瘤学家，正在为金伯利·斯泰格迈尔医生的指导时间寻求K08支持 DFCI的实验室，麻省理工学院的马修·范德·海登博士作为共同导师。我的长期职业目标是 成为一名独立的学术医生和科学家，使用基因组和化学方法来鉴定 急性白血病的代谢脆弱性，着眼于治疗干预。我之前的研究 经验奠定了我在功能基因组学、分子和细胞生物学以及药物测试方面的技能 适用于急性髓系白血病和T-ALL。我现在已经做好准备，可以在以下方面建立必要的专业知识 通过关键导师K08的癌症代谢、转化医学和发展疗法 获奖。达纳-法伯癌症研究所(DFCI)/波士顿儿童医院，麻省理工学院 麻省理工学院和美国麻省理工学院和哈佛大学都是国际公认的研究项目 在造血、新陈代谢和癌细胞生物学领域拥有多名专家研究人员，其中 其他。DFCI儿科肿瘤科在培训年轻医生方面有着卓越的记录- 在儿科癌症研究中发挥领导作用的科学家。我已经组织了一个很好的指导和 顾问委员会，由Nika Danial博士、Jon Aster博士和Lewis Silverman博士组成，他们将指导我的 研究和培训经验。有了结构化的指导、教育和研究计划，我将 获得必要的专业知识，成为一名成功的转化性癌症独立研究者 新陈代谢。

Project summary/Abstract While cure rates for pediatric acute lymphoblastic leukemia (ALL) have improved dramatically over the last several decades, ALL remains the second leading cause of cancer-related death in children. There continues to be an unmet need for effective therapies for patients with T-cell acute lymphoblastic leukemia (T-ALL), particularly those with relapsed or refractory disease. T-ALL is a disease generally responsive to drugs targeting metabolism, including methotrexate and asparaginase, which form the backbone of T-ALL therapy. Thus, I hypothesize that novel approaches to targeting metabolism may be particularly relevant in T-ALL. I screened a panel of leukemia cell lines against small-molecule inhibitors of methylene tetrahydrofolate dehydrogenase 2 (MTHFD2) and serine hydroxymethyltransferase 2 (SHMT2), enzymes of the mitochondrial one carbon folate pathway, and I discovered that T-ALL cells are highly sensitive to these inhibitors, more so than other leukemia cell lines. This proposal aims to use the small molecule inhibitors of MTHFD2 and SHMT2, as well as genetic suppression of these enzymes, in vitro and in vivo, to study the mechanistic role of SHMT2 and MTHFD2 in T-ALL pathogenesis. The ultimate goal of the project is to develop novel therapies for patients with T-ALL. I am a pediatric oncologist who is seeking K08 support for mentored time in Dr. Kimberly Stegmaier's laboratory at DFCI, with Dr. Matthew Vander Heiden at MIT as a co-mentor. My long-term career goal is to become an independent academic physician-scientist, using genomic and chemical approaches to identify metabolic vulnerabilities in acute leukemia with an eye toward therapeutic intervention. My prior research experiences have established my skills in functional genomics, molecular and cellular biology and drug testing applied to acute myeloid leukemia and T-ALL. I am now well positioned to establish the necessary expertise in cancer metabolism, translational medicine and developmental therapeutics through the critical mentored K08 award. The Dana-Farber Cancer Institute (DFCI)/Boston Children's Hospital, Massachusetts Institute of Technology (MIT) and the Broad Institute of MIT and Harvard are internationally recognized research programs with a number of expert researchers in the areas of hematopoiesis, metabolism and cancer cell biology, among others. The DFCI Division of Pediatric Oncology has a distinguished record of training young physician- scientists for leadership roles in pediatric cancer research. I have assembled an excellent mentoring and advisory committee, consisting of Dr. Nika Danial, Dr. Jon Aster, and Dr. Lewis Silverman, who will guide my research and training experiences. With the structured mentoring, educational, and research plans, I will acquire the necessary expertise to become a successful independent investigator in translational cancer metabolism.