Comprehensive dissection of the CLL genome & phenome to improve patient outcomes

CLL 基因组的全面剖析

• 批准号: 10270036
• 负责人: Catherine Ju-Ying Wu
• 金额: $ 166.79万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10270036
• 关键词: Address; Algorithms; Apoptosis; Area; B-Lymphocytes; Biological; Biological Assay; Biology; Biometry; Cell Death; Cell Therapy; Cell physiology; Cells; Chronic Care; Chronic Lymphocytic Leukemia; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Combined Modality Therapy; Complication; Computer Analysis; DNA; Data; Data Set; Detection; Diagnosis; Diagnostic; Disease; Disease remission; Dissection; Epigenetic Process; Evaluation; Exposure to; Funding; Gene Expression Profile; Genetic; Genome; Genomics; Goals; Heterogeneity; Immuno-Chemotherapy; Immunotherapeutic agent; Individual; Institutes; International; Kinetics; Lead; Link; Lymphoma; Malignant Neoplasms; Maps; Modernization; Molecular; Monitor; Mus; Non-Invasive Cancer Detection; Outcome; Pathology; Pathway interactions; Patient-Focused Outcomes; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Physical shape; Prediction of Response to Therapy; Predisposition; Proteins; Proteomics; RNA; Refractory; Research; Resistance; Resources; Richter' s Syndrome; Sampling; Specimen; System; Therapeutic; Vision; accurate diagnosis; anti-PD1 therapy; base; behavioral phenotyping; cancer cell; cell behavior; cell free DNA; chemotherapy; clinical care; clinical investigation; combinatorial; curative treatments; design; disease classification; disorder subtype; effective therapy; epigenomics; genome editing; human disease; immunoregulation; improved; in vivo; individual patient; individualized medicine; interdisciplinary approach; methylome; molecular phenotype; molecular subtypes; mouse model; multidisciplinary; next generation; novel; novel therapeutics; personalized approach; phase I trial; phenome; programs; response; sample collection; small molecule; small molecule libraries; targeted agent; therapy resistant; transcriptomics; treatment response; tumor

OVERALL ABSTRACT Although we have made great strides in our understanding of the biology and treatment of chronic lymphocytic leukemia (CLL) over the past decade, Richter's syndrome (RS) or the transformation of CLL to aggressive lymphoma remains an area of unmet need in the clinical care of CLL patients. The challenges presented by RS mandate large-scale interdisciplinary approaches to more completely link genomic and protein-level features with cellular behavior so that more precise and sensitive molecular-based diagnostic schema and more effective treatments for this devastating disease can be devised. Our hypothesis is that genomic and epigenomic alterations define the trajectory from CLL to RS and that distinct subtypes of RS exist, leading to distinct phenotypic behaviors. Our approach to address the challenge of understanding RS builds from the strengths of our highly interactive and multi-disciplinary program in CLL research. Over the last funding period, we have succeeded in generating the largest CLL `map' to date, integrating genetic, transcriptomic and methylome data with clinical annotation from over 1000 CLL samples to discover clinically meaningful subtypes of disease and novel driver alterations. From this information, we have also generated genetically-faithful CLL mouse models reflective of human disease, defined patterns of disease kinetics and therapeutic resistance, and identified new therapeutic vulnerabilities. Over the next 5 years, we will leverage the new resources generated by our Program, ranging from computational to functional, genetic and phenotypic readouts, to confront the challenge of understanding and addressing RS. Thus, our vision is that we will enact a precision approach for understanding the distinct biology of disease transformation and the subtypes of disease, and perform functional analyses of responses to small molecules and immunotherapy agents, that could be integrated and lead to a paradigm shift in the detection and treatment for this disease. These highly translational initiatives are strongly supported by the expertise of the Core Leaders. Our overarching goal is thus to revolutionize the clinical outcomes of patients with this devastating disease and to utilize the information discovered from this Program to motivate the rational design of the next generation of personalized and even curative therapies for RS.

总体摘要 尽管我们在了解慢性淋巴细胞性疾病的生物学和治疗方面取得了长足的进步， 在过去的十年中，白血病（CLL），里希特综合征（RS）或CLL向侵袭性白血病的转化 淋巴瘤仍然是CLL患者临床护理中未满足需求的领域。RS带来的挑战 要求采用大规模跨学科的方法，将基因组和蛋白质水平的特征更完整地联系起来 与细胞的行为，使更精确和敏感的分子为基础的诊断模式，更有效的 可以设计出治疗这种毁灭性疾病的方法。我们的假设是基因组和表观基因组 改变定义了从CLL到RS的轨迹，并且存在不同的RS亚型，导致不同的 表型行为我们应对理解RS挑战的方法建立在 我们在CLL研究中高度互动和多学科的计划。在上一个融资期，我们 成功地生成了迄今为止最大的CLL“图谱”，整合了遗传、转录组和甲基化组数据 从超过1000个CLL样本中进行临床注释，以发现有临床意义的疾病亚型， 新的驱动程序更改。根据这些信息，我们还生成了遗传上忠实的CLL小鼠模型 反映了人类疾病，确定了疾病动力学和治疗耐药性的模式，并确定了新的 治疗脆弱性在接下来的5年里，我们将利用我们的计划产生的新资源， 从计算到功能，遗传和表型读数，以应对挑战， 理解和处理RS。因此，我们的愿景是，我们将制定一个精确的方法， 了解疾病转化的独特生物学和疾病的亚型，并执行功能 分析对小分子和免疫治疗剂的反应，可以整合并导致 这种疾病的检测和治疗模式的转变。这些高度转化的举措， 由核心领导人的专业知识支持。因此，我们的首要目标是彻底改变临床 这种毁灭性疾病的患者的结果，并利用从该计划中发现的信息， 激励下一代RS个性化甚至治愈性疗法的合理设计。