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

批准号：
8126307
负责人：
Jeffrey Wallace Tyner
金额：
$ 12.79万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8126307
关键词：
Accounting Acute Lymphocytic Leukemia Adult Acute Lymphocytic Leukemia Binding Biological Blood Botany Cell Line Cell Survival Cells Childhood Acute Lymphocytic Leukemia Chromosomal translocation Chronic Lymphocytic Leukemia Chronic Myeloid Leukemia Clinical Clinical Trials Dependence Disease Elements Environment Epitopes Faculty Family Gene Targeting Genes Genetic Genomics Goals Health Sciences Hematology Immunology Individual Institutes Journals Lead Leukocytes Ligands Link MAPK8 gene Malignant Neoplasms Manuscripts Medicine Mentors Microbiology Modality Molecular and Cellular Biology NF-kappa B Nature Oncogenes Oncogenic Oral Oregon Outcome Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Postdoctoral Fellow Preparation Proteins Publishing RNA Interference ROR1 gene RORA gene Receptor Protein-Tyrosine Kinases Regulation Regulatory Element Research Research Personnel Resources Scientist Screening procedure Signal Pathway Signal Transduction Small Interfering RNA Students TCF3 gene Techniques Testing Therapeutic Therapeutic Intervention Training Treatment Efficacy United States National Academy of Sciences Universities Validation Washington Work Xenograft procedure adult leukemia anticancer research base cancer cell cancer diagnosis cancer therapy career chromatin immunoprecipitation college deletion analysis experience follow-up fusion gene graduate student improved insight instrumentation kinase inhibitor leukemia member metaplastic cell transformation neutralizing antibody new therapeutic target oncology overexpression posters promoter public health relevance research study small molecule symposium t(1 19)(q23 p13)therapeutic development therapeutic target tool transcription factor

项目摘要

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: We have found that the receptor tyrosine kinase, ROR1, is uniquely and consistently overexpressed on cells from t(1;19)-positive acute lymphoblastic leukemia (ALL) patients. Expression of ROR1 is required for viability of 1;19-positive cells making it a novel therapeutic target for these patients. Elucidation of the mechanisms underlying ROR1 expression and signaling in t(1;19)-positive ALL will lead to more comprehensive understanding of disease pathogenesis and offer insights into new strategies for therapeutic intervention.

描述（由申请人提供）：候选人：杰弗里·泰纳（Jeffrey Tyner）博士在过去的15年中一直在分子和细胞生物学研究领域接受培训，担任暑期学生（普渡大学），本科研究助理（格林内尔学院），研究生（圣路易斯大学华盛顿大学）和少年研究生（OREGON HEALTY＆SECHILAL＆SCOCHICAL和科学大学）。他研究了各种生物学领域，包括植物学，免疫学，微生物学和血液学/肿瘤学。这项研究导致了21种累积发表在高影响期刊上的手稿，例如自然医学，临床研究杂志，癌症研究，国家科学院论文集以及血液以及许多其他修订或准备中的其他手稿。 Tyner博士还在主要国家会议上介绍了他在口头演讲和海报会议上的工作。 Tyner博士的研究的主题涉及鉴定靶基因癌基因和癌基因特异性疗法，以便可以为每个患者量身定制癌症疗法。为了实现这些目标，他创建了两种筛选技术，利用siRNA或小分子激酶抑制剂来识别功能上重要的靶基因以进行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ROR1，这是所有急性淋巴细胞白血病患者的候选治疗靶标的，其1; 19染色体易位。该建议旨在表征该靶基因的过表达和信号传导的机制，并确定基因特异性的治疗干预措施。 Tyner博士的长期职业目标包括建立一个独立的研究实验室，重点是癌症研究和个性化医学。环境：俄勒冈州健康与科学大学骑士癌症研究所拥有165名主要教师研究人员，他们在各种调查领域具有专业知识。 Tyner博士的导师Brian Druker博士是骑士癌症研究所的主任。 Druker博士在癌症研究领域拥有20多年的经验，并为众多学生和研究员指导了独立研究者的身份。该建议还包括理查德·古德曼博士，菲利普·斯特雷特博士和罗伯特·塞尔斯博士的支持声明。累积地，这些支持科学家以及骑士癌症研究所的整体都具有所有的仪器，资源和专业知识，以进行本申请中提出的研究。研究：针对各种癌症诊断的患者，具有激酶抑制剂的致癌信号通路的特定靶向已大大改善了临床结果，最著名的是患有慢性髓样白血病的患者。为了将这种靶向疗法的方法扩展到所有形式的癌症，必须首先鉴定和表征引起疾病的基因。为此，我们开发了一个基于RNAi的筛查，以迅速鉴定直接从白血病患者获得的原代癌细胞中的靶基因。使用此屏幕，我们已经鉴定出一种受体酪氨酸激酶ROR1，在所有t（1; 19）阳性急性急性淋巴细胞白血病（全部）的患者中均唯一且一致地过表达，占所有儿童的大约5％的所有儿童全部和1-2％的成年病例。 ROR1的沉默导致T（1; 19）阳性所有细胞的生存力显着降低，但对其他所有细胞或正常白细胞的生存能力没有影响。此外，在大多数病例中，对慢性淋巴细胞性白血病（CLL）的先前研究（CLL）已确定了ROR1的过表达。将ROR1作为真正的治疗靶标的验证需要更好地理解ROR1有助于细胞转化的遗传调节和信号传导的机制。但是，关于控制ROR1表达的调节元件或ROR1所采用的信号通路来影响细胞生存力的情况很少，并且目前尚无可用的ROR1进行治疗靶向的可用策略。 t（1; 19）阳性所有细胞中ROR1过表达和ROR1依赖性的发现提供了研究此问题的独特工具。我们建议一种多管齐者的研究方法1）ROR1表达的调节，2）ROR1通过其促进转化的信号传导机制，以及3）抑制ROR1的治疗策略的发展将阐明ROR1依赖性恶性肿瘤的疾病发病机制，例如T（1; 19） - 精神效应和越来越多的新策略，以进行新的策略，以适应这些策略。公共卫生相关性：我们发现，受体酪氨酸激酶ROR1在T（1; 19）阳性急性急性淋巴细胞白血病（所有）患者的细胞上唯一且一致地过表达。 ROR1的表达是1; 19阳性细胞的生存力所必需的，使其成为这些患者的新型治疗靶点。阐明t（1; 19）阳性的ROR1表达和信号传导的机制，所有这些都将使人们对疾病发病机理有更全面的了解，并为治疗干预的新策略提供见解。