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.
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.
|Maxson, Julia E; Luty, Samuel B; MacManiman, Jason D et al. (2016) The Colony-Stimulating Factor 3 Receptor T640N Mutation Is Oncogenic, Sensitive to JAK Inhibition, and Mimics T618I. Clin Cancer Res 22:757-64|
|Maxson, Julia E; Abel, Melissa L; Wang, Jinhua et al. (2016) Identification and Characterization of Tyrosine Kinase Nonreceptor 2 Mutations in Leukemia through Integration of Kinase Inhibitor Screening and Genomic Analysis. Cancer Res 76:127-38|
|Jacob, Thomas; Agarwal, Anupriya; Ramunno-Johnson, Damien et al. (2016) Ultrasensitive proteomic quantitation of cellular signaling by digitized nanoparticle-protein counting. Sci Rep 6:28163|
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|Agarwal, A; MacKenzie, R J; Eide, C A et al. (2015) Functional RNAi screen targeting cytokine and growth factor receptors reveals oncorequisite role for interleukin-2 gamma receptor in JAK3-mutation-positive leukemia. Oncogene 34:2991-9|
|Kang, Xunlei; Lu, Zhigang; Cui, Changhao et al. (2015) The ITIM-containing receptor LAIR1 is essential for acute myeloid leukaemia development. Nat Cell Biol 17:665-77|
|Dao, Kim-Hien T; Tyner, Jeffrey W (2015) What's different about atypical CML and chronic neutrophilic leukemia? Hematology Am Soc Hematol Educ Program 2015:264-71|
|Chang, Bill H; Johnson, Kara; LaTocha, Dorian et al. (2015) YM155 potently kills acute lymphoblastic leukemia cells through activation of the DNA damage pathway. J Hematol Oncol 8:39|
|Geng, Huimin; Hurtz, Christian; Lenz, Kyle B et al. (2015) Self-enforcing feedback activation between BCL6 and pre-B cell receptor signaling defines a distinct subtype of acute lymphoblastic leukemia. Cancer Cell 27:409-25|
|Yoda, Akinori; Adelmant, Guillaume; Tamburini, Jerome et al. (2015) Mutations in G protein Î² subunits promote transformation and kinase inhibitor resistance. Nat Med 21:71-5|
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