ROR1 as a Therapeutic Target in Acute Lymphoblastic Leukemia

ROR1 作为急性淋巴细胞白血病的治疗靶点

基本信息

项目摘要

PROJECT SUMMARY/ABSTRACT This application addresses Program Announcement Number: PA-09-036, NIH Pathway to Independence Award (K99/R00). Candidate: Dr. Jeffrey Tyner has been training in the field of molecular and cellular biology research for the past 15 years as a summer student (Purdue University), undergraduate research assistant (Grinnell College), graduate student (Washington University in St. Louis), and post-doctoral fellow (Oregon Health & Science University). He has studied a diverse spectrum of biological fields including botany, immunology, microbiology, and hematology/oncology. This research has led to 21 cumulative published manuscripts in high-impact journals such as Nature Medicine, Journal of Clinical Investigation, Cancer Research, Proceedings of the National Academy of Science, and Blood as well as numerous other manuscripts in revision or preparation. Dr. Tyner has also presented his work in oral presentations and poster sessions at major national conferences. The theme of Dr. Tyner's research involves the identification of target oncogenes and oncogene-specific therapeutics, such that cancer therapies can be tailored to each individual patient. To accomplish these goals, he has created two screening techniques that make use of siRNA or small-molecule kinase inhibitors to identify functionally important target genes for follow-up characterization and genomic study. Using these techniques, he has identified a gene, ROR1, that is a candidate therapeutic target in all acute lymphoblastic leukemia patients with a 1;19 chromosomal translocation. This proposal aims to characterize the mechanisms of overexpression and signaling of this target gene and to identify gene-specific modalities for therapeutic intervention. Dr. Tyner's long-term career goals include establishment of an independent research lab with a focus on cancer research and personalized medicine. Environment: The Oregon Health & Science University Knight Cancer Institute has 165 primary faculty investigators who have expertise across a diverse spectrum of fields of inquiry. Dr. Tyner's mentor, Dr. Brian Druker, is the Director of the Knight Cancer Institute. Dr. Druker has over 20 years of experience in the field of cancer research and has mentored numerous students and fellows to independent investigator status. This proposal also includes statements of support from Dr. Richard Goodman, Dr. Philip Streeter, and Dr. Robert Searles. Cumulatively, these supporting scientists as well as the Knight Cancer Institute as a whole posses all the instrumentation, resources, and expertise to carry out the research proposed in this application. Research: Specific targeting of oncogenic signaling pathways with kinase inhibitors has vastly improved clinical outcomes for patients with a variety of cancer diagnoses, most notably patients with chronic myeloid leukemia. To expand this targeted-therapy approach to all forms of cancer, disease-causing genes must first be identified and characterized. Towards that end, we have developed an RNAi-based screen to rapidly identify target genes in primary cancer cells obtained directly from leukemia patients. Using this screen, we have identified a receptor tyrosine kinase, ROR1, that is uniquely and consistently overexpressed in all patients with t(1;19)-positive acute lymphoblastic leukemia (ALL), representing approximately 5% of all pediatric ALL and 1-2% of adult ALL cases. Silencing of ROR1 results in significantly decreased viability of t(1;19)-positive ALL cells, but has no effect on viability of other pediatric ALL cells or normal white blood cells. In addition, previous studies of chronic lymphocytic leukemia (CLL), which accounts for approximately 30% of adult leukemia cases, have identified ROR1 overexpression in the majority of cases. Validation of ROR1 as a bona fide therapeutic target necessitates a better understanding of the mechanisms of genetic regulation and signaling by which ROR1 contributes to cellular transformation. However, very little is known about the regulatory elements governing ROR1 expression or the signaling pathways employed by ROR1 to influence cellular viability, and there are currently no available strategies by which ROR1 can be therapeutically targeted. The finding of ROR1 overexpression and ROR1-dependence in t(1;19)-positive ALL cells offers unique tools to study this problem. We propose that a multi-pronged approach to studying 1) regulation of ROR1 expression, 2) signaling mechanisms through which ROR1 contributes to transformation, and 3) development of therapeutic strategies for inhibiting ROR1 will elucidate the disease pathogenesis of ROR1-dependent malignancies such as t(1;19)-positive ALL or CLL and offer new strategies for therapeutic intervention in these patients.
项目总结/摘要 本申请涉及计划公告编号:PA-09-036,NIH独立之路 奖项(K99/R 00)。 候选人:杰弗里泰纳博士一直在分子和细胞生物学研究领域的培训, 过去15年的暑期学生(普渡大学),本科研究助理(格林内尔学院), 研究生(圣路易斯华盛顿大学)和博士后研究员(俄勒冈州健康与科学 大学)。他研究了多种生物学领域,包括植物学、免疫学、微生物学, 血液学/肿瘤学。这项研究导致了21个高影响力的累积发表手稿 期刊如《自然医学》、《临床研究杂志》、《癌症研究》、《 国家科学院,血液以及许多其他手稿的修订或准备。博士 泰纳还提出了他的工作在口头报告和海报会议在主要的国家会议。 泰纳博士的研究主题涉及靶癌基因的识别和癌基因特异性 因此,癌症治疗可以被定制为每个个体患者。为了实现这些目标, 他发明了两种筛选技术,利用siRNA或小分子激酶抑制剂来识别 功能上重要的靶基因,用于后续表征和基因组研究。使用这些技术, 他已经确定了一个基因ROR 1,该基因是所有急性淋巴细胞白血病的候选治疗靶点 19染色体易位的患者。本提案旨在描述 该靶基因的过表达和信号传导,并鉴定用于治疗的基因特异性方式。 干预泰纳博士的长期职业目标包括建立一个独立的研究实验室, 专注于癌症研究和个性化医疗。 环境:俄勒冈州健康与科学大学奈特癌症研究所有165名小学教师 调查人员拥有各种调查领域的专门知识。泰纳博士的导师布莱恩博士 Druker是Knight癌症研究所的主任。Druker博士在以下领域拥有20多年的经验: 癌症研究,并指导了许多学生和研究员的独立调查员的地位。这 提案还包括来自Richard Goodman博士、Philip Streeter博士和Robert博士的支持声明 Searles累积起来,这些支持的科学家以及骑士癌症研究所作为一个整体, 仪器,资源和专业知识,以进行本申请中提出的研究。 研究:激酶抑制剂对致癌信号通路的特异性靶向作用已大大改善 各种癌症诊断患者的临床结局,最明显的是慢性髓性白血病患者 白血病为了将这种靶向治疗方法扩展到所有形式的癌症,致病基因必须首先 被识别和表征。为此,我们开发了一种基于RNAi的筛选方法, 在直接从白血病患者获得的原代癌细胞中鉴定靶基因。通过这个屏幕,我们 已经鉴定了一种受体酪氨酸激酶ROR 1,它在所有的 t(1;19)阳性急性淋巴细胞白血病(ALL)患者,约占所有患者的5% 儿童ALL和1-2%的成人ALL病例。ROR 1的沉默导致细胞存活率显著降低, t(1;19)阳性ALL细胞,但对其他儿科ALL细胞或正常白色血细胞的活力无影响。 此外,以前的研究慢性淋巴细胞白血病(CLL),其中约占30%, 在成人白血病病例中,已经在大多数病例中鉴定出ROR 1过表达。确认ROR 1作为 真正的治疗靶点需要更好地理解遗传调控的机制, ROR 1通过其促进细胞转化的信号传导。然而,人们对它知之甚少。 控制ROR 1表达的调控元件或ROR 1影响 细胞活力,并且目前没有可用于治疗靶向ROR 1的策略。 在t(1;19)阳性ALL细胞中发现ROR 1过表达和ROR 1依赖性,为治疗ALL提供了独特的工具。 研究这个问题。我们提出了一个多管齐下的方法来研究1)ROR 1的调节 表达,2)ROR 1促进转化的信号传导机制,和3) 抑制ROR 1的治疗策略的发展将阐明 ROR 1依赖性恶性肿瘤,如t(1;19)阳性ALL或CLL,并提供新的策略, 对这些患者进行治疗。

项目成果

期刊论文数量(13)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Functional genomics for personalized cancer therapy.
个性化癌症治疗的功能基因组学。
  • DOI:
    10.1126/scitranslmed.3009586
  • 发表时间:
    2014-07-02
  • 期刊:
  • 影响因子:
    17.1
  • 作者:
    Tyner JW
  • 通讯作者:
    Tyner JW
Unpaired Extracellular Cysteine Mutations of CSF3R Mediate Gain or Loss of Function.
CSF3R 不成对的细胞外半胱氨酸突变介导功能的获得或丧失。
  • DOI:
    10.1158/0008-5472.can-17-1052
  • 发表时间:
    2017
  • 期刊:
  • 影响因子:
    11.2
  • 作者:
    Zhang,Haijiao;Means,Sophie;Schultz,AnnaReister;Watanabe-Smith,Kevin;Medeiros,BrunoC;Bottomly,Daniel;Wilmot,Beth;McWeeney,ShannonK;Kükenshöner,Tim;Hantschel,Oliver;Tyner,JeffreyW
  • 通讯作者:
    Tyner,JeffreyW
ROR1 Flow Cytometry.
ROR1 流式细胞术。
  • DOI:
    10.21769/bioprotoc.905
  • 发表时间:
    2013
  • 期刊:
  • 影响因子:
    0.8
  • 作者:
    Bicocca,VincentT;Tyner,JeffreyW
  • 通讯作者:
    Tyner,JeffreyW
The Colony-Stimulating Factor 3 Receptor T640N Mutation Is Oncogenic, Sensitive to JAK Inhibition, and Mimics T618I.
Small molecule inhibitor screen identifies synergistic activity of the bromodomain inhibitor CPI203 and bortezomib in drug resistant myeloma.
  • DOI:
    10.18632/oncotarget.4214
  • 发表时间:
    2015-08-07
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Siegel MB;Liu SQ;Davare MA;Spurgeon SE;Loriaux MM;Druker BJ;Scott EC;Tyner JW
  • 通讯作者:
    Tyner JW
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Jeffrey Wallace Tyner其他文献

Jeffrey Wallace Tyner的其他文献

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{{ truncateString('Jeffrey Wallace Tyner', 18)}}的其他基金

Administrative Core
行政核心
  • 批准号:
    10038080
  • 财政年份:
    2017
  • 资助金额:
    $ 24.11万
  • 项目类别:
Trajectory and Architecture of Tumor Intrinsic Drug Resistance in AML
AML 肿瘤内在耐药性的轨迹和结构
  • 批准号:
    10684105
  • 财政年份:
    2017
  • 资助金额:
    $ 24.11万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    10494402
  • 财政年份:
    2017
  • 资助金额:
    $ 24.11万
  • 项目类别:
Trajectory and Architecture of Tumor Intrinsic Drug Resistance in AML
AML 肿瘤内在耐药性的轨迹和结构
  • 批准号:
    10517760
  • 财政年份:
    2017
  • 资助金额:
    $ 24.11万
  • 项目类别:
Core A: Administrative Core
核心A:行政核心
  • 批准号:
    10684102
  • 财政年份:
    2017
  • 资助金额:
    $ 24.11万
  • 项目类别:
Drug Combinations to Enhance Sensitivity and Circumvent Resistance
增强敏感性和规避耐药性的药物组合
  • 批准号:
    10249170
  • 财政年份:
    2017
  • 资助金额:
    $ 24.11万
  • 项目类别:
Drug Combinations to Enhance Sensitivity and Circumvent Resistance
增强敏感性和规避耐药性的药物组合
  • 批准号:
    9985235
  • 财政年份:
    2017
  • 资助金额:
    $ 24.11万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    9985230
  • 财政年份:
    2017
  • 资助金额:
    $ 24.11万
  • 项目类别:
Core A: Administrative Core
核心A:行政核心
  • 批准号:
    10517758
  • 财政年份:
    2017
  • 资助金额:
    $ 24.11万
  • 项目类别:
Drug Combinations to Enhance Sensitivity and Circumvent Resistance
增强敏感性和规避耐药性的药物组合
  • 批准号:
    9444902
  • 财政年份:
    2017
  • 资助金额:
    $ 24.11万
  • 项目类别:

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Understanding of the onset and recurrence pattern of intractable acute lymphocytic leukemia based on clone analysis
基于克隆分析了解难治性急性淋巴细胞白血病的发病和复发模式
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The Role of Genetic Variants in Sensitivity to Methotrexate in Acute Lymphocytic Leukemia Survivors
遗传变异在急性淋巴细胞白血病幸存者对甲氨蝶呤敏感性中的作用
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    2014
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Targeting the Bone Marrow Microenvironment In Acute Lymphocytic Leukemia
针对急性淋巴细胞白血病的骨髓微环境
  • 批准号:
    8595788
  • 财政年份:
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Targeting hypoxic microenvironment in Acute Lymphocytic Leukemia
针对急性淋巴细胞白血病的缺氧微环境
  • 批准号:
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    2011
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Targeting hypoxic microenvironment in Acute Lymphocytic Leukemia
针对急性淋巴细胞白血病的缺氧微环境
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INSULIN RESISTANCE IN CHILDREN WITH ACUTE LYMPHOCYTIC LEUKEMIA UNDERGOING INDUCT
正在接受治疗的急性淋巴细胞白血病儿童的胰岛素抵抗
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