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

• 批准号: 8544411
• 负责人: Jeffrey Wallace Tyner
• 金额: $ 23.36万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-12 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8544411
• 关键词: Accounting; Acute Lymphocytic Leukemia; Address; Adult Acute Lymphocytic Leukemia; Award; Binding; Biological; Blood; Botany; Cell Line; Cell Survival; Cells; ChIP-seq; 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; NIH Program Announcements; 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; Signal Pathway; Signal Transduction; Small Interfering RNA; Students; TCF3 gene; Techniques; Testing; Therapeutic; Therapeutic Intervention; Training; Treatment Efficacy; United States National Academy of Sciences; United States National Institutes of Health; 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; research study; screening; small molecule; symposium; t(1; 19)(q23; p13); therapeutic development; therapeutic target; tool; transcription factor; undergraduate research

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.

项目摘要/摘要 此申请地址计划公告编号：PA-09-036，NIH独立途径 奖项（K99/R00）。 候选人：杰弗里·泰纳（Jeffrey Tyner）博士一直在分子和细胞生物学研究领域进行培训 过去15年作为夏季学生（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个累积发表的高影响力的手稿 诸如自然医学等期刊，临床研究杂志，癌症研究，论文集 国家科学院，血液以及修订或准备中的许多其他手稿。博士 泰纳（Tyner）还在主要国家会议上的口头演讲和海报会议上介绍了他的作品。 泰纳博士的研究主题涉及鉴定目标致癌基因和特定于癌基因的癌基因 治疗剂，使癌症疗法可以针对每个患者量身定制。为了实现这些目标， 他创建了两种筛选技术，可利用siRNA或小分子激酶抑制剂来识别 功能上重要的靶基因，用​​于随访特征和基因组研究。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中的候选治疗靶标 患有1; 19个染色体易位的患者。该建议旨在表征 该靶基因的过表达和信号传导，并确定治疗基因特异性的方式 干涉。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学。 环境：俄勒冈州健康与科学大学骑士癌症研究所有165个小学教师 在各种各样的探究领域中都有专业知识的调查人员。泰纳博士的导师布莱恩博士 Druker是骑士癌症研究所的主任。 Druker博士在该领域拥有20多年的经验 癌症研究并指导了众多学生和研究员到独立的研究者身份。这 提案还包括理查德·古德曼博士，菲利普·斯特雷特博士和罗伯特博士的支持声明 塞尔斯。累积地，这些支持科学家以及骑士癌症研究所的整体都有所有 在本应用程序中提出的研究的仪器，资源和专业知识。 研究：用激酶抑制剂对致癌信号通路的特定靶向已大大改善 患有多种癌症诊断的患者的临床结局，最著名的是患有慢性髓样的患者 白血病。为了将这种靶向疗法扩展到所有形式的癌症，引起疾病的基因必须首先 被识别和表征。为此，我们开发了一个基于RNAi的屏幕来快速 鉴定直接从白血病患者获得的原发性癌细胞中的靶基因。使用此屏幕，我们 已经鉴定出一种受体酪氨酸激酶ROR1，在所有人中都唯一而始终如一地过表达 T（1; 19） - 阳性急性淋巴细胞白血病（ALL）患者，约占所有的5％ 小儿全部和1-2％的成年病例。 ROR1的沉默导致显着降低 t（1; 19）阳性所有细胞，但对其他儿科所有细胞或正常白细胞的生存能力没有影响。 此外，先前对慢性淋巴细胞白血病（CLL）的研究约占30％ 成年白血病病例在大多数病例中都发现了ROR1过表达。验证ROR1作为一个 真正的治疗靶标需要更好地理解遗传调节的机制和 ROR1有助于细胞转化的信号传导。但是，关于 控制ROR1表达的调节元件或ROR1使用的信号传导途径影响 细胞活力，目前尚无可用的ROR1进行治疗靶向的策略。 在t（1; 19）阳性的所有单元中的ROR1过表达和ROR1依赖性的发现提供了独特的工具 研究这个问题。我们建议一种多管齐下的研究方法1）ROR1的调节 表达，2）ROR1有助于转化的信号传导机制，3） 制定抑制ROR1的治疗策略将阐明 依赖ROR1的恶性肿瘤，例如t（1; 19） - 阳性全部或CLL，并为 这些患者的治疗干预。