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

项目概要/摘要 虽然儿童急性淋巴细胞白血病（ALL）的治愈率在过去几年中有了显着提高， 几十年来，ALL仍然是儿童癌症相关死亡的第二大原因。依然 对于T细胞急性淋巴细胞白血病（T-ALL）患者的有效疗法的未满足的需求， 特别是那些复发性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，这是T-ALL治疗的支柱。 因此，我假设靶向代谢的新方法可能与T-ALL特别相关。我 筛选了一组白血病细胞系对抗亚甲基四氢叶酸的小分子抑制剂 线粒体脱氢酶2（MTHFD 2）和丝氨酸羟甲基转移酶2（SHMT 2），线粒体的酶， 一碳叶酸途径，我发现T-ALL细胞对这些抑制剂高度敏感， 比其他白血病细胞系更好。本发明的目的是利用MTHFD 2和SHMT 2的小分子抑制剂， 以及这些酶的遗传抑制，在体外和体内，研究SHMT 2的机制作用。 和MTHFD 2在T-ALL发病机制中的作用。该项目的最终目标是为患者开发新的疗法 关于T-ALL 我是一名儿科肿瘤学家，正在寻求K 08在Kimberly Stegmaier博士的指导时间的支持。 DFCI实验室，麻省理工学院的Matthew Vander海登博士作为共同导师。我的长期职业目标是 成为一个独立的学术物理学家，科学家，使用基因组和化学方法来识别 急性白血病的代谢脆弱性，着眼于治疗干预。我之前的研究 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经验使我具备了一定的技能 适用于急性髓细胞白血病和T-ALL。我现在有能力建立必要的专业知识， 癌症代谢，转化医学和发展治疗学，通过关键的指导K 08 奖丹娜-法伯癌症研究所（DFCI）/波士顿儿童医院，马萨诸塞州 技术（MIT）和麻省理工学院和哈佛的布罗德研究所是国际公认的研究项目 与造血，代谢和癌细胞生物学领域的许多专家研究人员一起， 他人DFCI儿科肿瘤科在培训年轻医生方面有着杰出的记录- 科学家在儿科癌症研究中的领导作用。我召集了一个优秀的导师， 顾问委员会，由Nika Danial博士，Jon Aster博士和刘易斯西尔弗曼博士组成，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，成为一个成功的独立研究者在转化癌 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.