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

靶向线粒体一碳叶酸代谢用于新型 T 细胞急性淋巴细胞白血病治疗

基本信息

批准号：
10082440
负责人：
Yana Pikman
金额：
$ 17.71万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-02-15 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10082440
关键词：
Acute Lymphocytic Leukemia Acute Myelocytic Leukemia Acute T Cell Leukemia Acute leukemia Address Adult Advisory Committees Apoptosis Area Award B-Cell Acute Lymphoblastic Leukemia Biological Assay Boston Cancer Etiology Carbon Cell Cycle Cell Line Cell Maintenance Cellular biology Chemicals Child Childhood Acute Lymphocytic Leukemia Childhood Precursor T Lymphoblastic Leukemia Dana-Farber Cancer Institute Dependence Developmental Therapeutics Program Dihydrofolate Reductase Disease Drug Targeting Enzymes Equilibrium Eye Folic Acid Gene Expression Profile Genetic Suppression Genomics Glycine Glycine Hydroxymethyltransferase Goals Hematopoiesis Homeostasis Hydroxyl Radical Immunotherapy In Vitro Institutes International Laboratories Leadership Leukemic Cell Maintenance Malignant Childhood Neoplasm Malignant Neoplasms Massachusetts Mentors Metabolic Metabolism Methotrexate Methyltransferase Mitochondria Modeling Molecular and Cellular Biology Newly Diagnosed Non-Malignant Normal Cell Oxidation-Reduction Oxidoreductase Pathogenesis Pathway interactions Patients Pediatric Hospitals Pediatric Oncologist Pediatric Oncology Physicians Play Positioning Attribute Production Prognosis Proteins Proteome Recurrent disease Refractory Disease Reporting Research Research Personnel Research Training Role Sampling Scientist Serine Structure Succinates Supplementation T-Lymphocyte Technology Testing Therapeutic Therapeutic Intervention Time Training Treatment Protocols Vertebral column acute T-cell lymphoblastic leukemia cell acute myeloid leukemia cell alpha ketoglutarate anticancer research asparaginase blastomere structure cancer cell carbene career cell transformation childhood cancer mortality differential expression drug testing effective therapy experience folic acid metabolism functional genomics genetic approach improved in vivo in vivo Model inhibitor/antagonist leukemia treatment member new therapeutic target novel novel strategies novel therapeutics preclinical study programs skills small hairpin RNA small molecule inhibitor therapeutic target translational medicine tumor metabolism

项目摘要

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.

项目概要/摘要虽然儿童急性淋巴细胞白血病 (ALL) 的治愈率比过去显着提高几十年来，ALL 仍然是儿童癌症相关死亡的第二大原因。还有继续 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，特别是患有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，我推测靶向代谢的新方法可能与 T-ALL 特别相关。我筛选了一组针对亚甲基四氢叶酸小分子抑制剂的白血病细胞系脱氢酶 2 (MTHFD2) 和丝氨酸羟甲基转移酶 2 (SHMT2)，线粒体酶一种碳叶酸途径，我发现 T-ALL 细胞对这些抑制剂高度敏感，更是如此优于其他白血病细胞系。本提案旨在利用MTHFD2和SHMT2的小分子抑制剂，以及这些酶的体外和体内基因抑制，以研究 SHMT2 的机制作用和 MTHFD2 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疗法与 T-ALL 一起。我是一名儿科肿瘤科医生，正在 Kimberly Stegmaier 博士的指导下寻求 K08 支持 DFCI 实验室，麻省理工学院的 Matthew Vander Heiden 博士担任联合导师。我的长期职业目标是成为一名独立的学术医师科学家，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粒细胞白血病和T-ALL。我现在处于有利地位，可以在以下领域建立必要的专业知识：通过关键指导的 K08 进行癌症代谢、转化医学和发育治疗奖。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（MIT）和麻省理工学院和哈佛大学的博德研究所是国际公认的研究项目拥有造血、代谢和癌细胞生物学领域的多位专家研究人员，其中其他的。 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发挥领导作用。我聚集了优秀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研究和培训经验。通过结构化的指导、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癌症独立研究者代谢。