Abstract 5449: FP-1039/GSK3052230, an FGF ligand trap, enhances VEGF antagonist therapy in preclinical models of RCC and HCC

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA An increasing body of evidence has implicated FGF2 as one of the drivers of resistance to various inhibitors of VEGF-mediated angiogenesis. This resistance may play a role as a key limitation to the efficacy of therapies targeted at VEGF and its receptors. We investigated the potential for FP-1039/GSK3052230, a ligand trap that sequesters FGFs and inhibits their signaling, to enhance the activity of VEGF antagonist therapies in certain preclinical models of renal cell (RCC) and hepatocellular (HCC) carcinomas. First, we examined whether FP-1039/GSK3052230 has single agent efficacy against human RCC and HCC xenografts that express relatively high levels of FGF2, a profile that would mimic FGF2-driven resistance to VEGF therapy. We determined that this expression profile represents 34% of clear cell RCC (ccRCC) and 31% of HCC patients, based on the cancer genome atlas (TCGA) data. Human ccRCC xenografts with high FGF2 expression and low VEGFA expression demonstrated a significant inhibition in tumor growth when treated with FP-1039/GSK3052230 alone (TGI: 39-81%). In addition, we show that the high FGF2 expression profile is similarly predictive for the anti-tumor response of a human HCC model to single-agent FP-1039/GSK3052230 (TGI: 31-55%). In contrast, RCC models with low FGF2 expression, representing 66% of all ccRCC in the TCGA, are relatively insensitive to FP-1039/GSK3052230 as a single-agent. However, combination therapy of FP-1039/GSK3052230 with pazopanib in these tumors is significantly more effective than either agent alone. FP-1039/GSK3052230 not only slows tumor growth, but can induce ∼25% tumor regression when administered to mice bearing ccRCC xenografts that have become resistant to pazopanib. Together, our data demonstrate that FP-1039/GSK3052230 may be an effective therapy against RCC and HCC, both as a single agent in disease driven by FGF2 and in combination with VEGF antagonist therapies that represent the current standards of care for advanced disease. Citation Format: David I. Bellovin, Servando Palencia, Kevin Hestir, Ernestine Lee, M. Phillip DeYoung, Thomas Brennan, Gerrit Los, Kevin Baker. FP-1039/GSK3052230, an FGF ligand trap, enhances VEGF antagonist therapy in preclinical models of RCC and HCC. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5449. doi:10.1158/1538-7445.AM2014-5449