Epigenetic mechanisms of drug resistance in T-cell acute lymphoblastic leukemia

T细胞急性淋巴细胞白血病耐药的表观遗传机制

• 批准号: 9284421
• 负责人: Birgit Knoechel
• 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: 2015
• 资助国家: 美国
• 起止时间: 2015-07-06 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9284421
• 关键词: Acute T Cell Leukemia; Advisory Committees; Affect; Area; Attention; Award; Biology; Boston; Bromodomain; Cancer Center; Cancer Model; Cell Maintenance; Cell Survival; Cells; Cellular biology; Chemicals; Child; Child Care; Chromatin; Clinical; Clinical Research; Clinical Trials; Combined Modality Therapy; Complement; Dana-Farber Cancer Institute; Data; Data Set; Dependency; Development; Development Plans; Disease Resistance; Doctor of Philosophy; Dose; Drug resistance; EZH2 gene; Ensure; Enzymes; Epigenetic Process; Equilibrium; Exhibits; Experimental Models; FRAP1 gene; Family; Foundations; Future; General Hospitals; Genetic; Goals; Hematologic Neoplasms; Hematopoiesis; Hematopoietic Neoplasms; Human; Immunology; In Vitro; Institutes; International; Investigational Therapies; Laboratories; Malignant Neoplasms; Massachusetts; Mediating; Medicine; Mentors; Modernization; Molecular; Mutation; NOTCH1 gene; Nature; Oncogenic; Pathway interactions; Patients; Pediatric Hematology; Pediatric Hospitals; Pediatric Oncologist; Pediatric Oncology; Phenotype; Physicians; Population; Positioning Attribute; Predisposition; Proteins; Proto-Oncogene Proteins c-akt; Recurrent disease; Refractory; Refractory Disease; Relapse; Research; Research Personnel; Research Proposals; Research Training; Resistance; Resistance development; Scientist; Signal Transduction; Structure; T-Lymphocyte; Testing; Therapeutic; Therapeutic Human Experimentation; Time; Training; Translational Research; Translations; base; cancer cell; cancer genome; cancer therapy; career; career development; chemotherapy; clinical care; drug development; epigenome; experience; gamma secretase; genome sequencing; histone methyltransferase; improved outcome; in vivo; inhibitor/antagonist; knock-down; mouse model; next generation sequencing; novel; novel strategies; novel therapeutic intervention; oncology; preclinical study; prevent; programs; public health relevance; resistance mechanism; stem cell biology; success; targeted therapy trials; targeted treatment; tenure track; therapeutic target; therapy resistant; tool; young adult

 DESCRIPTION (provided by applicant): Resistance to therapy presents a major clinical challenge in cancer medicine today, and novel approaches to identify and overcome the mechanisms that cause resistance are desperately needed for improving outcome in patients. Over the past years epigenetic dysreguation in cancer has gained more and more attention. Chromatin regulators are aberrantly expressed in a wide variety of tumors, and cancer genome sequencing studies have identified frequent somatic alterations in many chromatin-regulating enzymes. Furthermore, epigenetic changes have also been implicated in the development of drug resistance. Acute T-cell lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic malignancy that frequently relapses or becomes refractory. T-ALL frequently harbors activating mutations in NOTCH1, which confer sensitivity to NOTCH inhibitors such as gamma secretase inhibitors (GSI). Yet, the rapid development of resistance has limited their clinical success. I have recently shown that resistance to NOTCH inhibition in T-ALL is mediated by epigenetic mechanisms that confer unique dependencies on BET family bromodomain proteins (Nature Genetics, 2014). However, detailed understanding of the molecular mechanisms underlying the epigenetic state transitions are currently lacking. By combining functional perturbation of chromatin regulators with modern next-generation sequencing tools for chromatin state analysis, I will identify, mechanistically characterize, and therapeutically validate the epigeneti and compensatory oncogenic signaling dependencies in drug resistant T-ALL. Results of the in vitro studies will be further investigated using murine models of primary human T-ALL, and this will lay the foundation for future preclinical studies and clinical trials of targeted therapies inT-ALL. I am a pediatric oncologist with a Ph.D. and substantial prior research experience in T cell immunology who is seeking K08 support for mentored research in Dr. Bradley Bernstein's laboratory at MGH / Broad Institute with Dr. Jon Aster, BWH / DFCI acting as a co-mentor. My long-term career objective is to obtain a tenure-track position as a physician-scientist in a pediatric hematology/oncology department at an academic cancer center. The K08 award will provide the protected time I need for advanced training in cancer and chromatin biology, in particular, analysis of large-scale epigenome datasets, experimental therapeutics and translational research. I will devote a minimum of 80% of my time to a focused research program on epigenetic resistance mechanisms in T-cell acute lymphoblastic leukemia and translational research, and will complement this with 20% of my effort dedicated to clinical care for children with hematologic malignancies. Dana-Farber Cancer Institute / Boston Children's Hospital, Massachusetts General Hospital and the Broad Institute of MIT and Harvard are internationally recognized research programs with a number of expert researchers in the areas of stem cell biology, hematopoiesis, and cancer cell biology. Furthermore, the division of Pediatric Hematology/Oncology at Dana-Farber Cancer Institute / Boston Children's Hospital has a distinguished record of training successful physician-scientists. I have assembled an excellent mentoring and advisory committee, consisting of Dr. Kimberly Stegmaier, Dr. Charles Roberts and Dr. Benjamin Ebert, who will guide my research and training experiences. The expertise of my advisory committee will be complemented by a set of additional collaborators who are experts in their respective fields (Dr. James Bradner, development of chemical compounds against chromatin regulators; Dr. Andrew Kung, mouse models of cancer and experimental therapeutics; Dr. Lewis Silverman, translational and clinical research in pediatric oncology). This research proposal is part of a structured plan with scientific, technical, clinical training and career development components. The career development plan builds upon my prior research and clinical experiences with the goal of ensuring that I acquire the expertise required to become a successful, independent investigator with a focus on cancer epigenetics and clinical pediatric oncology.

 描述（由申请人提供）：对治疗的耐药性是当今癌症医学的主要临床挑战，迫切需要识别和克服导致耐药性的机制的新方法来改善患者的结局。近年来，肿瘤的表观遗传学调控受到越来越多的关注。染色质调节剂在多种肿瘤中异常表达，并且癌症基因组测序研究已经确定了许多染色质调节酶的频繁体细胞改变。此外，表观遗传变化也与耐药性的发展有关。急性T淋巴细胞白血病（T-ALL）是一种侵袭性造血系统恶性肿瘤，经常复发或变得难治。T-ALL经常在NOTCH 1中携带激活突变，这赋予对NOTCH抑制剂如γ分泌酶抑制剂（GSI）的敏感性。然而，耐药性的快速发展限制了它们的临床成功。我最近已经表明，T-ALL中对NOTCH抑制的抗性是由赋予BET家族溴结构域蛋白独特依赖性的表观遗传机制介导的（Nature Genetics，2014）。然而，目前缺乏对表观遗传状态转换的分子机制的详细了解。通过将染色质调节因子的功能扰动与用于染色质状态分析的现代下一代测序工具相结合，我将识别、机械表征和治疗验证耐药T-ALL中的表观遗传和补偿性致癌信号依赖性。体外研究的结果将使用原发性人类T-ALL的小鼠模型进行进一步研究，这将为未来T-ALL靶向治疗的临床前研究和临床试验奠定基础。我是一名儿科肿瘤学家，拥有博士学位。在T细胞免疫学方面有丰富的研究经验，正在寻求K 08支持，以指导MGH / Broad Institute的布拉德利伯恩斯坦博士实验室的研究，BWH / DFCI的Jon Aster博士担任共同导师。我的长期职业目标是在一家学术癌症中心的儿科血液学/肿瘤学部门获得一个终身教职。K 08奖将为我提供在癌症和染色质生物学方面进行高级培训所需的受保护的时间，特别是大规模表观基因组数据集分析，实验疗法和转化研究。我将把至少80%的时间投入到T细胞急性淋巴细胞白血病表观遗传耐药机制的重点研究项目和转化研究中，并将用20%的时间致力于血液恶性肿瘤儿童的临床护理。丹娜-法伯癌症研究所/波士顿儿童医院、马萨诸塞州总医院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，在干细胞生物学、造血和癌细胞生物学领域拥有许多专家研究人员。此外，丹娜-法伯癌症研究所/波士顿儿童医院的儿科血液学/肿瘤学部门在培训成功的医生科学家方面有着杰出的记录。我组建了一个优秀的指导和咨询委员会，由金伯利·斯泰格迈尔博士、查尔斯·罗伯茨博士和本杰明·埃伯特博士组成，他们将指导我的研究和培训经验。我的顾问委员会的专业知识将得到一系列其他合作者的补充，他们是各自领域的专家（James布拉德纳博士，开发针对染色质调节剂的化合物; Andrew Kung博士，癌症小鼠模型和实验治疗;刘易斯西尔弗曼博士，儿科肿瘤学的转化和临床研究）。本研究提案是一个结构化计划的一部分， 培训和职业发展部分。职业发展计划建立在我以前的研究和临床经验的基础上，目的是确保我获得成为一名成功的独立研究者所需的专业知识，重点是癌症表观遗传学和临床儿科肿瘤学。