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

• 批准号: 10337202
• 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
• 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/10337202
• 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; 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

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.

项目摘要/摘要 小儿急性淋巴细胞白血病的治疗率（全部）在最后的 几十年来，所有这些都是儿童与癌症相关死亡的第二大原因。在那里继续 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， 特别是患有复发或难治性疾病的人。 T-ALL是一种对药物的反应的疾病 靶向代谢，包括甲氨蝶呤和天冬酰胺酶，它们构成了T-ALL治疗的骨干。 因此，我假设靶向代谢的新颖方法在T-All中可能特别相关。我 筛选了一系列白血病细胞系针对亚甲基四氢叶酸的小分子抑制剂 脱氢酶2（MTHFD2）和丝氨酸羟基转移酶2（SHMT2），线粒体的酶 一个碳叶酸途径，我发现T-All细胞对这些抑制剂高度敏感，更是如此 比其他白血病细胞系。该建议旨在使用MTHFD2和SHMT2的小分子抑制剂， 以及对这些酶的遗传抑制，体外和体内，研究SHMT2的机械作用 T-ALL发病机理中的MTHFD2。该项目的最终目标是为患者开发新的疗法 与T-All。 我是一名儿科肿瘤学家，正在寻求K08在金伯利·斯蒂格玛尔（Kimberly Stegmaier）博士的指导时间的支持 DFCI的实验室，与麻省理工学院的Matthew Vander博士一起担任联合学者。我的长期职业目标是 使用基因组和化学方法成为独立的学术医师科学家 急性白血病中的代谢脆弱性，以治疗干预。我先前的研究 经验已经确立了我在功能基因组，分子和细胞生物学以及药物测试方面的技能 应用于急性髓样白血病和T-All。我现在有好处，可以建立必要的专业知识 通过关键指导的K08，癌症代谢，转化医学和发育疗法 奖。达纳 - 法伯癌症研究所（DFCI）/马萨诸塞州波士顿儿童医院 技术（麻省理工学院）和麻省理工学院和哈佛大学的广泛研究所是国际认可的研究计划 在造血，代谢和癌细胞生物学领域的许多专家研究人员中， 其他的。小儿肿瘤学的DFCI分师在培训年轻医师的著名记录中 科学家在小儿癌症研究中的领导作用。我聚集了一项出色的指导和 咨询委员会由Nika Danial博士，Jon Aster博士和Lewis Silverman博士组成，他们将指导我 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，成为成功的转化癌的独立研究者 代谢。

项目成果

Targeting EZH2 for the treatment of hepatosplenic T-cell lymphoma.

靶向 EZH2 治疗肝脾 T 细胞淋巴瘤。

• DOI: 10.1182/bloodadvances.2019001256
• 发表时间: 2020
• 期刊: Blood advances
• 影响因子: 7.5
• 作者: Pikman,Yana;Conway,AmySaur;Robichaud,AmandaL;Kitara,Samuel;Church,AlannaJ;Kennedy,AlyssaL;Silverman,LewisB;Billett,AmyL;Weinstock,DavidM;Harris,MarianH;Stegmaier,Kimberly
• 通讯作者: Stegmaier,Kimberly

Hypoxic, glycolytic metabolism is a vulnerability of B-acute lymphoblastic leukemia-initiating cells.

• DOI: 10.1016/j.celrep.2022.110752
• 发表时间: 2022-04-26
• 期刊: CELL REPORTS
• 影响因子: 8.8
• 作者: Morris, Vivian;Wang, Dahai;Li, Zhiheng;Marion, William;Hughes, Travis;Sousa, Patricia;Harada, Taku;Sui, Shannan Ho;Naumenko, Sergey;Kalfon, Jeremie;Sensharma, Prerana;Falchetti, Marcelo;da Silva, Renan Vinicius;Candelli, Tito;Schneider, Pauline;Margaritis, Thanasis;Holstege, Frank C. P.;Pikman, Yana;Harris, Marian;Stam, Ronald W.;Orkin, Stuart H.;Koehler, Angela N.;Shalek, Alex K.;North, Trista E.;Pimkin, Maxim;Daley, George Q.;da Rocha, Edroaldo Lummertz;Rowe, R. Grant
• 通讯作者: Rowe, R. Grant

Unleashing Cell-Intrinsic Inflammation as a Strategy to Kill AML Blasts.

• DOI: 10.1158/2159-8290.cd-21-0956
• 发表时间: 2022-07-06
• 期刊: Cancer discovery
• 影响因子: 28.2

Treatment of recurrent pediatric myelodysplastic syndrome post hematopoietic stem cell transplantation.

• DOI: 10.1002/ccr3.8190
• 发表时间: 2023-11
• 期刊: Clinical case reports
• 影响因子: 0.7

The Folate Cycle Enzyme MTHFR Is a Critical Regulator of Cell Response to MYC-Targeting Therapies.

• DOI: 10.1158/2159-8290.cd-19-0970
• 发表时间: 2020-12
• 期刊: Cancer discovery
• 影响因子: 28.2
• 作者: Su A;Ling F;Vaganay C;Sodaro G;Benaksas C;Dal Bello R;Forget A;Pardieu B;Lin KH;Rutter JC;Bassil CF;Fortin G;Pasanisi J;Antony-Debré I;Alexe G;Benoist JF;Pruvost A;Pikman Y;Qi J;Schlageter MH;Micol JB;Roti G;Cluzeau T;Dombret H;Preudhomme C;Fenouille N;Benajiba L;Golan HM;Stegmaier K;Lobry C;Wood KC;Itzykson R;Puissant A
• 通讯作者: Puissant A