Abstract #1850: Combination of sorafenib and vorinostat causes synergistic growth inhibition in carcinomas of the kidney and lung.

Abstract

Metastatic tumors of the kidney and lung (RCC, NSCLC) remain largely incurable. Sorafenib inhibits VEGFR2, VEGFR3 and B-RAF, among other kinases, and is active in advanced RCC, although results in lung cancer patients have been less promising. Vorinostat is a histone deacetylase inhibitor that modulates the transcription of multiple genes including those affecting cell-cycle and apoptosis in cancer cells. We found that both sorafenib and vorinostat inhibited in vitro growth in a panel of RCC and NSCLC lines in a dose-dependent manner, although RCCs were collectively more sensitive to both agents. With increasing doses of sorafenib (8 \#956;M, which is obtainable in patients), synergistic growth inhibition was achieved with most doses of vorinostat. Sorafenib effects on phospho-ERK were mixed, failing to inhibit or even increasing phosphorylation in a number of lines. This supports the existence of relevant non-RAF targets, since nearly all lines were growth inhibited. Similar mixed results were obtained with vorinostat, alone and in combination with sorafenib. Among angiogenic factors and cell cycle regulators, sorafenib up-regulated VEGF in 21/34 tumor lines, while vorinostat caused both an inhibition of cyclin D1 (20/34) and up-regulation of p21^Waf1. While sorafenib treatment initially inhibits in vivo tumor growth, eventual escape from VEGF blockade permits subsequent angiogenesis and re-growth. We examined a set of 13 angiogenic factors by realtime RT-PCR to determine which might contribute to escape from VEGF blockade. Several angiogenic genes were expressed at substantial levels prior to treatment and a number were increased by sorafenib, vorinostat or the combination, suggesting these as a component of the escape mechanism. Overall, our results support the use of higher dose sorafenib, especially in combination with vorinostat, and indicate that this agent pair warrants further examination in the treatment of patients with RCC and NSCLC.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1850.