Exploring a new therapeutic approach through targeting epigenetic enzymes in ALL

通过针对 ALL 的表观遗传酶探索新的治疗方法

• 批准号: 9150647
• 负责人: Panagiotis Ntziachristos
• 金额: $ 24.9万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9150647
• 关键词: Acute Lymphocytic Leukemia; Acute T Cell Leukemia; Adult Acute Lymphocytic Leukemia; Adverse effects; Affect; Animals; Apoptosis; Architecture; Area; Award; Binding; Binding Sites; Biochemical; Bioinformatics; Bone Marrow Transplantation; Cells; Central Nervous System Prophylaxis; Chemicals; Child; Childhood; Childhood Hematopoietic Neoplasm; Childhood Leukemia; Chromatin; Chromatin Modeling; Collaborations; Complex; Coupled; Cranial Irradiation; Data; Data Analyses; Death Rate; Defect; Diagnosis; Discipline; Disease; Disease Progression; Disease remission; Drug Targeting; Education; Endocrine Gland Neoplasms; Enhancers; Environment; Enzymes; Epigenetic Process; Family; Fluorescent in Situ Hybridization; Fumarates; Future; Gene Expression; Gene Family; Genes; Genetic; Genetic Models for Cancer; Goals; Grant; Growth; Health; Histones; Human; Intrathecal Chemotherapy; Knowledge; Lead; Link; Lysine; Maintenance; Malignant Neoplasms; Maps; Mass Spectrum Analysis; Mediastinal Mass; Mediating; Mediator of activation protein; Medical center; Mentors; Metabolic; Metabolic Pathway; Metabolism; Methylation; Modeling; Molecular; Monitor; Mus; Mutation; Myeloid Leukemia; NOTCH1 gene; Neuraxis; New York; Normal Cell; Nuclear; Oncogene Activation; Oncogenes; Oncogenic; Outcome; Oxidative Phosphorylation; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Phase; Physiological; Plague; Play; Polycomb; Principal Investigator; Process; Proteins; Recruitment Activity; Recurrent disease; Regulator Genes; Relapse; Research; Respiratory distress; Risk; Role; Sampling; Succinate Dehydrogenase; Succinates; T-Cell Leukemia; T-Lymphocyte; Technical Expertise; Techniques; Testing; Therapeutic; Time; Tissues; Toxic effect; Training; Tumor Suppressor Proteins; Universities; White Blood Cell Count procedure; Writing; base; cancer type; career; chemotherapy; chromosome conformation capture; clinically relevant; design; epigenetic drug; experience; gastrointestinal; high risk; human disease; improved; in vitro Model; in vivo; inhibitor/antagonist; innovation; irradiation; killings; leukemia; leukemogenesis; malignant state; meetings; member; mouse model; new therapeutic target; notch protein; novel therapeutic intervention; outcome forecast; predictive modeling; prognostic; programs; promoter; relapse patients; responsible research conduct; skills; small molecule inhibitor; symposium; targeted treatment; tool; transcription factor; tumor; tumor metabolism

DESCRIPTION (provided by applicant): The proposed training grant will facilitate the improvement of the education and career goals of the principal investigator (PI) as well as will lead to important findings in the field of cancer epigenetics with the aim to increase the therapeutic potential in T cell leukemia. Up to 25% of children with acute lymphoblastic leukemia (ALL) will fail frontline therapy and their prognosis is dismal with only 20% cure rate. Although prognosis is better for patients with later relapses, the majority eventually succumbs to the disease (overall cure rate 40 to 50%). Usually, central nervous system (CNS) involvement, lower remission and re-induction rates and early second relapse for those who enter remission are important obstacles in the way to treatment whereas more aggressive types of therapy, including bone marrow transplantation, reached tolerability limits with toxic death rates generally ranging from 3-19%. Also direct inhibition of Notch pathway in T cell ALL (T-ALL) has been plagued by gastrointestinal toxicity. The hypothesis of this proposal is that epigenetic drugs can be used as a targeted therapy against acute lymphoblastic leukemia, especially when classic chemotherapy and/or irradiation have failed. Using mouse models and primary human samples, we recently identified inactivating genetic alterations of members of the polycomb repressive complex 2 (PRC2) in T-ALL and revealed the importance of the levels of the repressive mark trimethylation of histone 3 lysine 27 (H3K27me3) in leukemogenesis. We have also generated strong data on the prominent but contrasting roles of two H3K27me3 demethylases JUMONJI D3 (JMJD3 or KDM6B) and UTX (or KDM6A) in the same disease. JMJD3 is a facilitator of the oncogenic process whereas UTX is a tumor suppressor although they execute the same enzymatic action. Using a specific chemical inhibitor we were able to kill T cell leukemia, sparing myeloid leukemia and physiological cells. Moreover we have identified that the family of metabolic genes succinate dehydrogenase (SDH) is transcriptional target of UTX. As these genes have been shown to play tumor suppressor roles in tumors of endocrine origin, we hypothesize, based on strong preliminary results, that a part of UTX action is filtered through SDH family. In the K99 phase of this proposal we aim to: 1) Identify and characterize the oncogenic topological domains (TD) containing NOTCH1 and JMJD3 in leukemia, 2) associate specific TD with disease progression (prognostic model), 3) identify interacting partners for UTX, 4) understand the molecular and physiological roles of SDH in T cell leukemia and 5) to generate and perform basic phenotypic analysis of two animals (mice) modeling mutations of UTX in human disease. During the execution of the K99 phase of this project, the PI will acquire technical skills on chromosome conformation capture techniques, fluorescent In situ hybridization (FISH) and basic metabolic analysis and he will also improve his knowledge on basic bioinformatics (high-throughput data) analysis. In the R00 phase, the candidate will use the skills and tools produced during the K99 phase, use the GSKJ4 inhibitor against demethylases in samples from diagnosis/relapse disease and associate changes with expression and phenotypic changes in the sample as a proof-of-principle for the model interactions. Moreover the PI will fully analyze the tumor suppressor role of UTX through genetic, metabolic, biochemical and epigenetic studies of the generated mouse models. In summary we will set up chromatin models for testing of current drugs and explore metabolic pathways with the perspective to understand the connection between metabolism and epigenetics in cancer and discover new therapeutic targets in the future. We believe that these findings can be applied to other types of cancer, as the mechanisms we explore are universal. The PI has brought together an extensive panel of experienced collaborators and his mentor. This plan includes also regular meetings with members of his advisory board, courses on bioinformatics, networking, grant writing and responsible conduct of research as well as conferences on the aforementioned disciplines (tumor metabolism, genetic models of cancer) so he conveys his ideas and set up collaborations. Overall, the K99 award together with the mentor's and collaborator's experience and the advanced environment of Langone Medical Center at New York University will provide the PI with innovative tools to continue his independent career on the crosstalk between epigenetics and metabolism in leukemia.

描述（由申请人提供）：拟议的培训补助金将促进主要研究者（PI）的教育和职业目标的改善，并将导致癌症表观遗传学领域的重要发现，旨在提高T细胞白血病的治疗潜力。多达25％的急性淋巴细胞白血病儿童（全部）将失败一线治疗，预后仅为20％。尽管预后对以后复发的患者更好，但大多数最终屈服于该疾病（总体治愈率为40至50％）。通常，中枢神经系统（CNS）参与，较低的缓解和重新诱导率以及进入缓解者的第二次复发是进行治疗的重要障碍，而更具侵略性的治疗类型（包括骨髓移植）达到了有毒死亡率的耐受性限制 范围为3-19％。胃肠道毒性也困扰着T细胞中的Notch途径。该提议的假设是表观遗传药物可以用作针对急性淋巴细胞白血病的有针对性治疗，尤其是在经典化学疗法和/或辐照失败的情况下。使用小鼠模型和原代人样品，我们最近确定了T-ALL中Polycomb抑制复合物2（PRC2）成员的遗传改变，并揭示了在白血病中，组蛋白3赖氨酸27（H3K27ME3）的抑制性标记三甲基化水平的重要性。我们还产生了有关两个H3K27ME3脱甲基酶Jumonji D3（JMJD3或KDM6B）和UTX（或KDM6A）在同一疾病中的显着但对比的作用的强大数据。 JMJD3是致癌过程的促进者，而UTX是肿瘤抑制剂，尽管它们执行相同的酶促作用。使用特定的化学抑制剂，我们能够杀死T细胞白血病，保留 髓样白血病和生理细胞。此外，我们已经确定代谢基因琥珀酸脱氢酶（SDH）的家族是UTX的转录靶标。由于这些基因已显示出在内分泌起源肿瘤中扮演肿瘤抑制作用的作用，因此我们基于强烈的初步结果假设，UTX作用的一部分通过SDH家族过滤。在该提案的K99阶段中，我们的目的是：1）确定并表征白血病中包含Notch1和JMJD3的致癌拓扑结构域（TD），2）将特定的TD与疾病的进展（预后模型）相关联（预后模型），3），3）识别ut的相互作用零件，4）与SD的分子和物理学的分析相关性，4）了解SD的分子和生理学现象。人类疾病中UTX的两种动物（小鼠）建模突变。在该项目的K99阶段执行期间，PI将获得有关染色体构象捕获技术，荧光原位杂交（FISH）和基本代谢分析的技术技能，他还将提高他对基本生物信息学（高通量数据）分析的知识。在R00阶段，候选人将使用K99阶段中产生的技能和工具，在诊断/复发疾病中的样品中使用GSKJ4抑制剂对脱甲基酶，并将样本中的表达和表型变化的变化作为模型相互作用的原则证明。此外，PI将通过对产生的小鼠模型的遗传，代谢，生化和表观遗传学研究充分分析UTX的肿瘤抑制作用。总而言之，我们将建立染色质模型，以测试当前药物并探索代谢途径，以了解癌症中代谢和表观遗传学之间的联系，并在未来发现新的治疗靶标。我们认为，这些发现可以应用于其他类型的癌症，因为我们探索的机制是普遍的。 PI汇集了一个由经验丰富的合作者及其导师组成的广泛小组。该计划还包括与他的顾问委员会成员的定期会议，有关生物信息学的课程，网络，赠款写作和负责任的研究以及关于上述学科的会议（肿瘤代谢，癌症的遗传模型），因此他传达了他的想法并建立了合作。总体而言，K99奖以及导师和合作者的经验以及纽约大学Langone医学中心的高级环境将为PI提供创新的工具，以继续他在白血病的表观遗传学和代谢之间的串扰上的独立职业。