Genomes and Genes
Analysis of the Novel Kinase ROR2: A New Molecular Target in Renal Cell Carcinoma
Principal Investigator: Tricia M Wright
Abstract: Renal cell carcinoma (RCC), a notoriously hard to treat solid tumor and the most common form of kidney cancer, has minimal sensitivity to traditional chemotherapy. Recently, receptor tyrosine kinase (RTK) inhibitory drugs which inhibit platelet-derived growth factor (PDGF) receptor and vascular endothelial growth factor (VEGF) receptor have come into play for treating RCC. PDGF and VEGF are two growth factors highly expressed in RCC because of inactivating mutations of the von Hippel-Lindau (VHL) tumor suppressor gene. PDGFR and VEGFR are found on tumor associating pericytes and endothelial cells respectively, but not on the tumor cells themselves, with inhibition of these receptors predominantly causing disease stabilization. In other solid tumors, treatment with RTK inhibitors target tumor cell intrinsic kinases, resulting in dramatic reductions in tumor burdens. However, no disease associated cell intrinsic kinase is known for renal cell carcinoma. My aim was to identify a cancer cell specific kinase expressed on RCC as a rational target for pharmaceutical development. Using a phospho-RTK screen in renal carcinoma cells, I identified ROR2, a phosphorylated orphan receptor tyrosine kinase that was previously unknown in RCC. Preliminary work from our lab has shown that not only is ROR2 expressed in RCC cells, it is expressed in a VHL dependent manner in RCC cells from clear cell histology tumors. I would like to establish the regulation status of ROR2 by evaluating ROR2 expression as a target of VHL loss and hypoxia inducible factor regulation using a combination of RCC cell lines, shRNA knockdown cell lines and hypoxia with immunoblot and qRT-PCR techniques. I would like to further characterize the functional role of ROR2 in RCC using immunoprecipitation and autophosphorylation assays. To delineate the role ROR2 plays in renal cell carcinoma tumorigenesis, I will use a combination of shRNA knockdown cell lines to determine the influence of native ROR2 and overexpressed cell lines to delineate its oncogenic potential. The final objective is to find potential inhibitors that may be used for RCC treatment which take advantage of or exploit the presence of this kinase. This study is of importance to the public as it represents a potentially important molecular target for RCC. The long term goal of this study is not only to analyze the importance of ROR2 in RCC but also to use the gained knowledge of ROR2 function in the hopes of finding inhibitors that can be used clinically for treating RCC.
Funding Period: ----------------2007 - ---------------2010-
more information: NIH RePORT
- Receptor tyrosine kinase-like orphan receptor 2 (Ror2) expression creates a poised state of Wnt signaling in renal cancerNeal R Rasmussen
Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
J Biol Chem 288:26301-10. 2013..These results highlight a new role for Ror2 in conveying a tonic signal to stabilize soluble β-catenin and create a poised state of enhanced responsiveness to Wnt3a exogenous signals in RCC. ..
- Ror2, a developmentally regulated kinase, promotes tumor growth potential in renal cell carcinomaT M Wright
Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 7295, USA
Oncogene 28:2513-23. 2009..These findings suggest a novel pathway of tumor-promoting activity by Ror2 within a subset of renal carcinomas, with significant implications for unraveling the tumorigenesis of RCC...
- Identification of Ror2 as a hypoxia-inducible factor target in von Hippel-Lindau-associated renal cell carcinomaTricia M Wright
Department of Genetics, Curriculum in Genetics and Molecular Biology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA
J Biol Chem 285:12916-24. 2010..This data substantiates a unique regulation pattern for Ror2 in the VHL-HIF axis that has the potential to be applied to other cancer etiologies...