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: 9105805
• 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/9105805
• 关键词: Acute T Cell Leukemia; Advisory Committees; Affect; Area; Attention; Award; Biology; Boston; Bromodomain; Cancer Center; Cell Maintenance; Cell Survival; Cells; Cellular biology; Chemicals; Child; 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; FRAP1 gene; Family; Foundations; Future; General Hospitals; Genetic; Goals; Health; Hematologic Neoplasms; Hematopoiesis; Hematopoietic Neoplasms; Human; Immunology; In Vitro; Institutes; Investigational Therapies; Laboratories; Malignant Neoplasms; Massachusetts; Mediating; Medicine; Mentors; 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; Time; Training; Translational Research; Translations; base; cancer cell; cancer genome; cancer therapy; career; career development; chemotherapy; clinical care; 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; resistance mechanism; stem cell biology; success; targeted treatment; tenure track; therapeutic target; therapy resistant; tool; tumor; 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（由适用提供）：对治疗的抗性提出了当今癌症医学的主要临床挑战，并且迫切需要识别和克服引起抗药性的机制的新方法来改善患者的预后。在过去的几年中，癌症的表观遗传失调引起了越来越多的关注。染色质调节剂在多种肿瘤中异常表达，癌症基因组测序研究已经确定了许多染色质调节酶的频率体细胞改变。此外，在耐药性的发展中也实施了表观遗传变化。急性T细胞淋巴细胞白血病（T-ALL）是一种侵略性的造血恶性肿瘤，经常继发或难治性。 T-All经常在Notch1中激活突变，而Notch1会议对Notch抑制剂（例如Gamma泌尿酶抑制剂（GSI））的敏感性。然而，阻力的快速发展限制了他们的临床成功。我最近表明，T-ALL中对缺口抑制的耐药性是由表观遗传机制介导的，表观遗传机制是对BET家族溴化域蛋白的独特依赖性（自然遗传学，2014年）。但是，目前缺乏对表观遗传状态转变背后的分子机制的详细理解。通过将染色质调节剂的功能扰动与现代的下一代测序工具进行染色质状态分析，我将确定，机械表征并在治疗中验证抗药性T-All中的耐药性和代偿性致癌信号依赖性。体外研究的结果将使用原代人T-All的鼠模型进一步研究，这将为未来的临床前研究和目标疗法的临床试验奠定基础。我是一名儿科肿瘤学家，拥有博士学位。以及在T细胞免疫学方面的实质性研究经验，他们正在与MGH / Broad Institute Bradley Bernstein博士的实验室中的K08支持与乔恩·阿斯特（Jon Aster）博士（BWH / DFCI）担任同事。我的长期职业目标是在学术癌症中心的儿科血液学/肿瘤科中获得物理科学家的统治地位。 K08奖将为我提供癌症和染色质生物学的高级培训所需的受保护时间，特别是对大型表观基因组数据集，实验疗法和转化研究的分析。我将至少将80％的时间投入到T细胞急性淋巴细胞白血病和转化研究中的针对表观遗传耐药机制的重点研究计划，并将完成我的20％的努力，致力于为患有血液性恶性肿瘤的儿童致力于临床护理。达纳 - 法伯癌症研究所 /波士顿儿童医院，马萨诸塞州综合医院和麻省理工学院和哈佛大学广泛研究所是国际认可的研究计划，在干细胞生物学，造血和癌细胞生物学领域的许多专家研究人员都有许多专家研究人员。此外，达纳 - 法伯癌症研究所 /波士顿儿童医院的小儿血液学 /肿瘤学系有培训成功的医师科学家的杰出记录。我组建了一个出色的心理和咨询委员会，由Kimberly Stegmaier博士，Charles Roberts博士和Benjamin Ebert博士组成，他们将指导我的研究和培训经验。 The expert of my advisory committee will be completed 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 therapy; Dr. Lewis Silverman, translated and clinical research in pediatric oncology).该研究建议是具有科学，技术，临床的结构化计划的一部分 培训和职业发展组成部分。职业发展计划以我先前的研究和临床经验为基础，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，专注于癌症表观遗传学和临床儿科肿瘤学。