Abstract 1799: Hypoxia-induced alterations of renal cell carcinoma cells and their modulation by tyrosine kinase inhibitors

Abstract

Abstract Renal cell carcinoma (RCC) is the most common neoplasm in the adult kidney and its incidence is increasing over the last 20 years. Unfortunately, approximately 30 % of patients are diagnosed at a metastatic stage, which is associated with a poor prognosis and a 5-year survival rate of < 10 %. The clear cell RCC, representing approximately 75 % of RCC lesions, is characterized by a frequent inactivation of the Von-Hippel-Lindau protein (pVHL) resulting in the upregulation of the hypoxia-inducible factor 1α (HIF-1α), which consequently induces the transcription of hypoxia-responsive genes, such as the vascular endothelial growth factor receptor (VEGF) thereby inducing angiogenesis. Thus, the inhibition of angiogenesis is a suitable tool for the therapy of advanced clear cell RCC. During the last decade agents targeting tumor angiogenesis include inhibitors of the VEGF receptor pathway and the mammalian target of rapamycin (mTOR) have been successfully applied for the treatment of this disease. Using proteome-based studies and microRNA arrays hypoxia-regulated miRs and proteins in VHL- versus VHL+ RCC have been identified in the absence or presence of the angiogenesis inhibitors sunitinib and axitinib. (i) A differential miR and protein expression profile exhibiting an inverse correlation was found upon hypoxia, which further differed in VHL- versus wild-type VHL RCC cells. (ii) The hypoxia-regulated miRs and proteins in these cell systems were altered by the tyrosine kinase inhibitors (TKI) sunitinib and axitinib treatment. (iii) Functional analysis of the hypoxia-regulated candidate biomarkers and their modulation by both TKI are currently performed. (iv) The differential expression pattern of miRs and proteins under hypoxia as well as in the absence and presence of both TKIs were confirmed by RT-PCR and Western blot analysis. These data were shown for the first time an effect of sunitinib and axitinib on hypoxia-induced alterations in RCC, which not only leads to a better understanding of the mechanisms of action of both TKIs, but also to the define of novel strategies for the targeted treatment of RCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1799. doi:1538-7445.AM2012-1799