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

基本信息

批准号：
10005126
负责人：
Catherine Ju-Ying Wu
金额：
$ 168.74万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2021-09-16
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10005126
关键词：
1-Phosphatidylinositol 3-Kinase Achievement Address Advanced Development Area B-Lymphocytes BCL2 gene Behavior Biological Biology Biometry Cancer Patient Categories Cell Line Chronic Lymphocytic Leukemia Clinical Clinical Data Clinical Management Clinical Trials Clonal Evolution Combination Drug Therapy DNA Sequence Alteration Data Development Disease Dissection Drug resistance Epigenetic Process Evolution Future Generations Genetic Genetic Heterogeneity Genetic study Genome Genomics Goals Hand Heterogeneity Human Immunotherapy Individual Indolent Joints Kinetics Knowledge Lesion Leukemic Cell Link Malignant Neoplasms Maps Mature B-Lymphocyte Mining Modernization Molecular Oncology 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 Subgroup Technology Testing Therapeutic Therapeutic Agents Time Treatment Efficacy Vision adult leukemia base behavioral phenotyping cancer cell cancer type cell behavior chronic lymphocytic leukemia cell clinical development clinical practice clinical translation clinically relevant curative treatments data integration design disease heterogeneity disorder subtype effective therapy experience genetic manipulation genome editing improved in vitro Model individual patient individualized medicine innovation interdisciplinary approach member mouse model multidimensional data next generation non-genetic novel outcome forecast personalized medicine phenome pre-clinical precision medicine pressure prognostic programs quantum response targeted agent therapeutic target therapy resistant tool tumor tumor heterogeneity

1-Phosphatidylinositol 3-Kinase Achievement Address Advanced Development Area B-Lymphocytes BCL2 gene Behavior Biological Biology Biometry Cancer Patient Categories Cell Line Chronic Lymphocytic Leukemia Clinical Clinical Data Clinical Management Clinical Trials Clonal Evolution Combination Drug Therapy DNA Sequence Alteration Data Development Disease Dissection Drug resistance Epigenetic Process Evolution Future Generations Genetic Genetic Heterogeneity Genetic study Genome Genomics Goals Hand Heterogeneity Human Immunotherapy Individual Indolent Joints Kinetics Knowledge Lesion Leukemic Cell Link Malignant Neoplasms Maps Mature B-Lymphocyte Mining Modernization Molecular Oncology 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 Subgroup Technology Testing Therapeutic Therapeutic Agents Time Treatment Efficacy Vision adult leukemia base behavioral phenotyping cancer cell cancer type cell behavior chronic lymphocytic leukemia cell clinical development clinical practice clinical translation clinically relevant curative treatments data integration design disease heterogeneity disorder subtype effective therapy experience genetic manipulation genome editing improved in vitro Model individual patient individualized medicine innovation interdisciplinary approach member mouse model multidimensional data next generation non-genetic novel outcome forecast personalized medicine phenome pre-clinical precision medicine pressure prognostic programs quantum response targeted agent therapeutic target therapy resistant tool tumor tumor heterogeneity

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项目摘要

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.

项目摘要来自任何癌症类型的样品和在单个肿瘤中，分辨率增加了。值得注意的是，肿瘤内异质性，它燃料克隆进化并产生耐药性，已被确定为最重要的障碍持续治愈。慢性淋巴细胞性白血病（CLL）是正确的，这是成熟B的初始顽固性恶性肿瘤随着时间的流逝，细胞不可避免地变得更具侵略性，其临床过程在整个方面都有高度变化个人。尽管最近批准了高度有效的药物（即ibrutinib，idelalisib），以靶向钥匙CLL 途径，耐药性 - 有时与治疗时高度侵略性相关 - 据报道。这种疾病异质性提出的挑战授权大规模跨学科将基因组特征与细胞行为联系起来的方法，以便有效的个性化治疗可以是设计。我们的假设是CLL具有异质性但相干的基因组改变，导致不同表型行为，受到进化选择性压力的影响，这会影响个体疾病的轨迹。拟议计划的成员有一个成功的记录，以合作为由地标对我们对CLL的理解做出了贡献。尽管我们对CLL和扩大针对性治疗的有效治疗的武器库，我们对该疾病将需要在功率良好的系列中跨数据层进行网络级集成，以全面绘制CLL的电路（项目1、2）和系统的方法来评估基因组的影响预后的改变和对治疗的反应（项目2，3）。当然，传统的方法缺乏忠实的细胞系和小鼠模型，功能研究CLL的遗传病变受到限制并且由于普遍操纵原代CLL细胞的广泛认可的困难。通过少校剖析CLL的方法的创新，由每个项目负责人带头，从在原代人B细胞中计算到功能性遗传和非遗传读数，我们很良好中毒以协同作用，以解决CLL中与临床相关的问题。这些举措是强烈的在核心领导人的共同专业知识的支持下，有望告知我们有关的合理设计下一代CLL的个性化和治疗疗法。