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（由申请人提供）：对治疗的耐药性是当今癌症医学的一项重大临床挑战，为了改善患者的治疗结果，迫切需要识别和克服引起耐药性机制的新方法。在过去的几年里，癌症中的表观遗传失调引起了越来越多的关注。染色质调节因子在多种肿瘤中异常表达，癌症基因组测序研究已经发现许多染色质调节酶频繁发生体细胞改变。此外，表观遗传变化也与耐药性的发展有关。急性 T 细胞淋巴细胞白血病 (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 经常含有 NOTCH1 的激活突变，这赋予了对 NOTCH 抑制剂（例如 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。我最近表明，T-ALL 对 NOTCH 抑制的抵抗是由表观遗传机制介导的，该机制赋予 BET 家族溴结构域蛋白独特的依赖性（Nature Genetics，2014）。然而，目前缺乏对表观遗传状态转变背后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、机械表征并治疗性验证耐药 T-ALL 中的表观遗传和代偿性致癌信号传导依赖性。体外研究结果将利用原发性人类T-ALL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。我是一名拥有博士学位的儿科肿瘤学家。以及之前在 T 细胞免疫学方面的丰富研究经验，正在寻求 K08 支持，以在 MGH / Broad 研究所的 Bradley Bernstein 博士实验室进行指导研究，并由 BWH / DFCI 的 Jon Aster 博士担任联合导师。我的长期职业目标是在学术癌症中心的儿科血液学/肿瘤学部门获得终身医师职位。 K08 奖将为我提供癌症和染色质生物学高级培训所需的受保护时间，特别是大规模表观基因组数据集的分析、实验治疗和转化研究。我将至少投入 80% 的时间用于 T 细胞急性淋巴细胞白血病表观遗传耐药机制和转化研究的重点研究项目，并将用 20% 的时间致力于血液恶性肿瘤儿童的临床护理来补充这一项目。达纳法伯癌症研究所/波士顿儿童医院、马萨诸塞州总医院以及麻省理工学院和哈佛大学的博德研究所是国际公认的研究项目，拥有干细胞生物学、造血和癌细胞生物学领域的众多专家研究人员。此外，达纳法伯癌症研究所/波士顿儿童医院的儿科血液学/肿瘤学部门在培养成功的医师科学家方面拥有杰出的记录。我组建了一个优秀的指导和咨询委员会，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历。我的咨询委员会的专业知识将得到一组其他合作者的补充，他们都是各自领域的专家（James Bradner 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疗法；Lewis Silverman 博士，儿科肿瘤学的转化和临床研究）。该研究计划是科学、技术、临床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之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，重点关注癌症表观遗传学和临床儿科肿瘤学。