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.
|Rasmussen, Neal R; Wright, Tricia M; Brooks, Samira A et al. (2013) Receptor tyrosine kinase-like orphan receptor 2 (Ror2) expression creates a poised state of Wnt signaling in renal cancer. J Biol Chem 288:26301-10|
|Wright, Tricia M; Rathmell, W Kimryn (2010) Identification of Ror2 as a hypoxia-inducible factor target in von Hippel-Lindau-associated renal cell carcinoma. J Biol Chem 285:12916-24|
|Wright, T M; Brannon, A R; Gordan, J D et al. (2009) Ror2, a developmentally regulated kinase, promotes tumor growth potential in renal cell carcinoma. Oncogene 28:2513-23|