ROR1 as a Therapeutic Target in Acute Lymphoblastic Leukemia

简介（由申请人提供）：候选人：Jeffrey Tyner博士在过去的15年里一直从事分子和细胞生物学研究领域的培训，曾作为暑期学生（普渡大学）、本科生研究助理（格林内尔学院）、研究生（圣路易斯华盛顿大学）和博士后（俄勒冈健康与科学大学）。他研究了多种生物领域，包括植物学、免疫学、微生物学和血液学/肿瘤学。本研究已累计在Nature Medicine、Journal of Clinical Investigation、Cancer research、Proceedings of the National Academy of Science、Blood等高影响力期刊发表论文21篇，并有大量论文正在修订或准备中。泰纳博士还在主要国家会议的口头报告和海报会议上介绍了他的工作。Tyner博士的研究主题涉及目标癌基因和癌基因特异性治疗的识别，这样癌症治疗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，利用siRNA或小分子激酶抑制剂来识别功能重要的靶基因，用于后续表征和基因组研究。利用这些技术，他已经确定了一个基因ROR1，它是所有急性淋巴细胞白血病患者的候选治疗靶点。19 .染色体易位。本研究旨在描述该靶基因的过表达和信号传导机制，并确定治疗干预的基因特异性模式。他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。

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.