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有助于改善主要研究者（PI）的教育和职业目标，并将在癌症表观遗传学领域取得重要发现，旨在提高治疗潜力在T细胞白血病中。高达 25% 的急性淋巴细胞白血病 (ALL) 儿童一线治疗失败，其预后很差，治愈率仅为 20%。尽管晚期复发的患者预后较好，但大多数最终还是死于该病（总体治愈率 40% 至 50%）。通常，中枢神经系统（CNS）受累、较低的缓解率和再诱导率以及进入缓解期的患者早期二次复发是治疗的重要障碍，而更积极的治疗类型（包括骨髓移植）已达到耐受极限中毒死亡率一般 范围为 3-19%。此外，直接抑制 T 细胞 ALL (T-ALL) 中的 Notch 通路也受到胃肠道毒性的困扰。该提案的假设是表观遗传药物可用作急性淋巴细胞白血病的靶向治疗，特别是当经典化疗和/或放疗失败时。利用小鼠模型和原始人类样本，我们最近发现了 T-ALL 中多梳抑制复合物 2 (PRC2) 成员的失活遗传改变，并揭示了组蛋白 3 赖氨酸 27 (H3K27me3) 抑制标记三甲基化水平在 T-ALL 中的重要性。白血病发生。我们还就两种 H3K27me3 去甲基酶 JUMONJI D3（JMJD3 或 KDM6B）和 UTX（或 KDM6A）在同一疾病中的显着但对比的作用生成了强有力的数据。 JMJD3 是致癌过程的促进剂，而 UTX 是肿瘤抑制因子，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， 粒细胞白血病和生理细胞。此外，我们还发现代谢基因琥珀酸脱氢酶（SDH）家族是UTX的转录靶标。由于这些基因已被证明在内分泌来源的肿瘤中发挥肿瘤抑制作用，因此基于强有力的初步结果，我们假设 UTX 作用的一部分是通过 SDH 家族过滤的。在该提案的 K99 阶段，我们的目标是：1) 识别和表征白血病中包含 NOTCH1 和 JMJD3 的致癌拓扑结构域 (TD)，2) 将特定 TD 与疾病进展（预后模型）相关联，3) 识别 UTX 的相互作用伙伴，4) 了解 SDH 在 T 细胞白血病中的分子和生理作用，以及 5) 生成并执行两种动物（小鼠）模型的基本表型分析UTX 突变在人类疾病中的作用。在该项目K99阶段的执行过程中，PI将获得染色体构象捕获技术、荧光原位杂交（FISH）和基础代谢分析方面的技术技能，并将提高基础生物信息学（高通量数据）方面的知识。分析。在 R00 阶段，候选人将使用 K99 阶段产生的技能和工具，使用 GSKJ4 抑制剂对抗诊断/复发疾病样本中的去甲基酶，并将变化与样本中的表达和表型变化相关联，作为原理验证用于模型交互。此外，PI还将通过对所生成的小鼠模型进行遗传、代谢、生化和表观遗传学研究，全面分析UTX的抑癌作用。总之，我们将建立染色质模型来测试现有药物，并探索代谢途径，以了解癌症代谢与表观遗传学之间的联系，并在未来发现新的治疗靶点。我们相信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 召集了一个由经验丰富的合作者和他的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定期举行会议、生物信息学、网络、资助写作和负责任的研究行为课程以及上述学科（肿瘤代谢、癌症遗传模型）的会议，以便他传达他的想法并设定合作。总的来说，K99奖连同导师和合作者的经验以及纽约大学朗格医学中心的先进环境将为PI提供创新工具，以继续他在白血病表观遗传学和代谢之间的串扰方面的独立职业生涯。