Renal cell carcinoma is a devastating cancer affecting 36,600 individuals per year in the US and rising steadily in incidence, but with few effective treatments. Mutations in the von Hippel-Lindau (VHL) gene have been associated with the majority of sporadic cancers of the kidney, and with the hereditary syndrome of VHL disease in which mutational carriers are at risk for development of renal cell carcinoma, as well as hemangioblastoma of the nervous system, and pheochromocytoma. Individual missense mutations predispose predictably to the penetrance of each of these tumors. VHL protein (pVHL) has been implicated in many activities, most notably the oxygen dependent regulation of the hypoxia inducible factors HIF1-alpha and HIF2-alpha which trancriptionally regulation a large cohort of hypoxia response genes. However, other activities of pVHL are also tumor-promoting, as missense mutations associated with exclusively pheochromocytoma have no effect on regulation of hypoxia response genes. VHL mutation, however, is implicated early in the pathway of tumorigenesis of the kidney, likely playing a tumor-initiating role. The mutations which augment the development of invasive renal cell carcinoma are not well-understood, and may contribute to the refractoriness of this tumor to conventional therapies. Understanding the complete spectrum of carcinogenic activities of VHL loss as well as the cellular events which supplement tumor progression in the kidney is an essential goal in a mission to improve treatments for renal cell carcinoma. This proposal outlines an integrated and balanced approach to meeting this goal by developing in vitro and in vivo models of VHL mutations associated with the complete spectrum of VHL disease, and exploiting the strong genotype:phenotype correlation of VHL disease in a mouse model system. Additionally, we propose a strategy to induce somatic loss of VHL in the kidney tubule to model VHL initiation of renal carcinogenesis, as well as somatic activation of putative renal tumor """"""""progression"""""""" pathways in a background of VHL mutation. These investigations will provide a unique model system in which many aspects of VHL-induced carcinogenesis can and will be examined in order to ultimately identify improved treatments for patients with renal cell carcinoma.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Jhappan, Chamelli
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of North Carolina Chapel Hill
Internal Medicine/Medicine
Schools of Medicine
Chapel Hill
United States
Zip Code
Sendor, Adam B; Hacker, Kathryn E; Chen, Shufen et al. (2015) Von Hippel-Lindau status influences phenotype of liver cancers arising from PTEN loss. Gastrointest Cancer 5:61-71
Arreola, Alexandra; Cowey, C Lance; Coloff, Jonathan L et al. (2014) HIF1? and HIF2? exert distinct nutrient preferences in renal cells. PLoS One 9:e98705
Simon, Jeremy M; Hacker, Kathryn E; Singh, Darshan et al. (2014) Variation in chromatin accessibility in human kidney cancer links H3K36 methyltransferase loss with widespread RNA processing defects. Genome Res 24:241-50
Desimone, Michelle C; Rathmell, W Kimryn; Threadgill, David W (2013) Pleiotropic effects of the trichloroethylene-associated P81S VHL mutation on metabolism, apoptosis, and ATM-mediated DNA damage response. J Natl Cancer Inst 105:1355-64
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
Brannon, A Rose; Haake, Scott M; Hacker, Kathryn E et al. (2012) Meta-analysis of clear cell renal cell carcinoma gene expression defines a variant subgroup and identifies gender influences on tumor biology. Eur Urol 61:258-68
Teng, Brian L; Hacker, Kathryn E; Chen, Shufen et al. (2011) Tumor suppressive activity of prolyl isomerase Pin1 in renal cell carcinoma. Mol Oncol 5:465-74
Hacker, Kathryn E; Rathmell, W Kimryn (2010) Emerging molecular classification in renal cell carcinoma: implications for drug development. Target Oncol 5:75-84
Cowey, C Lance; Amin, Chirag; Pruthi, Raj S et al. (2010) Neoadjuvant clinical trial with sorafenib for patients with stage II or higher renal cell carcinoma. J Clin Oncol 28:1502-7
Chen, Shufen; Sanford, Christie A; Sun, Junjiang et al. (2010) VHL and PTEN loss coordinate to promote mouse liver vascular lesions. Angiogenesis 13:59-69

Showing the most recent 10 out of 22 publications