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

全面剖析 CLL 基因组和表型组以改善患者预后

• 批准号: 9149996
• 负责人: Catherine Ju-Ying Wu
• 金额: $ 175.58万
• 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 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9149996
• 关键词: 1-Phosphatidylinositol 3-Kinase; Achievement; Address; Advanced Development; Area; B-Lymphocytes; BCL2 gene; Behavior; Biology; Cancer Patient; Categories; Cell Line; Cells; Chronic Lymphocytic Leukemia; Clinical; Clinical Data; Clinical Management; Clinical Trials; Clonal Evolution; Combination Drug Therapy; DNA Sequence Alteration; Data; Development; Disease; Dissection; Drug resistance; Drug resistance pathway; Epigenetic Process; Evolution; Future; Generations; Genetic; Genetic Heterogeneity; Genetic study; Genome; Genomics; Goals; Hand; Hereditary Disease; Heterogeneity; Human; Immunotherapy; Individual; Indolent; Joints; Kinetics; Knowledge; Lead; Lesion; Link; Malignant Neoplasms; Maps; Mature B-Lymphocyte; Mining; Molecular; Outcome; Pathway interactions; Patient Care; Patient Rights; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Predisposition; Receptor Signaling; Receptors, Antigen, B-Cell; Relapse; Reporting; Resistance; Resolution; Role; Sampling; Series; Side; Signal Pathway; Signal Transduction; Staging; Subgroup; Technology; Testing; Therapeutic; Therapeutic Agents; Time; Translations; Vision; adult leukemia; base; cancer cell; cancer type; clinical practice; clinically relevant; curative treatments; data integration; design; disease heterogeneity; disorder subtype; effective therapy; experience; functional genomics; genome editing; improved; in vitro Model; individual patient; innovation; interdisciplinary approach; leukemia; member; mouse model; next generation; non-genetic; novel; oncology; outcome forecast; personalized medicine; phenome; pre-clinical; precision medicine; pressure; programs; quantum; response; targeted agent; therapeutic target; therapy resistant; tool; tumor; tumor heterogeneity

Project Summary The vast heterogeneity of genetic and epigenetic features both among samples from any cancer type and within individual tumors has been documented with increasing resolution. Of note, intratumoral heterogeneity, which fuels clonal evolution and generates treatment resistance, has been identified as the foremost obstacle to lasting cure. This is true of chronic lymphocytic leukemia (CLL), an initially indolent malignancy of mature B cells which inevitably becomes more aggressive over time, and whose clinical course is highly variable across individuals. Despite the recent approval of highly potent drugs (i.e. ibrutinib, idelalisib) that target key CLL pathways, drug resistance—sometimes associated with highly aggressive relapse while on treatment—has been reported. The challenges presented by this disease heterogeneity mandate large-scale interdisciplinary approaches to link genomic features with cellular behavior so that effective personalized treatments can be devised. Our hypothesis is that CLL has heterogeneous yet coherent genomic alterations leading to distinct phenotypic behaviors, subject to evolutionary selective pressures, which impact individual disease trajectories. The members of the proposed Program have a successful track record of collaborating together to make landmark contributions to our understanding of CLL. Despite our growing knowledge about CLL and the expanding armamentarium of effective therapeutics targeting it, the next quantum leap in our understanding of this disease will require network-level integration across data layers in well-powered series to comprehensively map the circuitry of CLL (Projects 1, 2), and systematic approaches to evaluate the impact of genomic alterations on prognosis and response to therapy (Projects 2, 3). Certainly, conventional approaches to functionally study genetic lesions of CLL have been limited by the lack of faithful cell lines and mouse models and by the widely acknowledged difficulties in genetically manipulating primary CLL cells. Through major innovations in approaches to dissect CLL, spearheaded by each Project Leader and ranging from computational to functional genetic and non-genetic based readouts in primary human B cells, we are well- poised to synergize together to address clinically relevant questions in CLL. These initiatives are strongly supported by the joint expertise of the Core Leaders and are expected to inform us on the rational design of the next generation of personalized and curative therapies for CLL.

项目概要 任何癌症类型的样本之间遗传和表观遗传特征的巨大异质性 单个肿瘤内部的情况已得到越来越多的分辨率的记录。值得注意的是，瘤内异质性， 它促进克隆进化并产生治疗耐药性，已被确定为最重要的障碍 达到持久治愈的目的。慢性淋巴细胞白血病 (CLL) 就是如此，它是一种成熟 B 细胞最初惰性的恶性肿瘤。 随着时间的推移，细胞不可避免地变得更具攻击性，并且其临床过程在不同国家之间差异很大 个人。尽管最近批准了针对关键 CLL 的高效药物（即 ibrutinib、idelalisib） 途径、耐药性（有时与治疗期间的高度侵袭性复发相关）已 被举报。这种疾病异质性带来的挑战要求大规模的跨学科研究 将基因组特征与细胞行为联系起来的方法，以便可以进行有效的个性化治疗 设计的。我们的假设是，CLL 具有异质但一致的基因组改变，导致不同的 表型行为受到进化选择压力的影响，从而影响个体的疾病轨迹。 拟议计划的成员拥有共同合作的成功记录，以实现 对我们对 CLL 的理解做出了里程碑式的贡献。尽管我们对 CLL 和 扩大针对它的有效疗法的军备库，这是我们理解的下一个巨大飞跃 这种疾病需要在强大的系列中跨数据层进行网络级集成，以全面 绘制 CLL 的电路图（项目 1、2），以及评估基因组影响的系统方法 预后和治疗反应的改变（项目 2、3）。当然，传统的方法 由于缺乏可靠的细胞系和小鼠模型，CLL 基因损伤的功能研究受到限制 以及众所周知的对原代 CLL 细胞进行基因操作的困难。通过专业 剖析 CLL 方法的创新，由每个项目负责人带头，范围包括 计算到原代人类 B 细胞中基于功能遗传和非遗传的读数，我们很好地- 准备共同协作解决 CLL 的临床相关问题。这些举措有力 得到核心领导者联合专业知识的支持，预计将向我们提供有关合理设计的信息 下一代 CLL 个性化和治愈性疗法。