Abstract 344: Targeting fibroblast growth factor signaling in prostate cancer
Authors: Wan Xinhai , Yang Jun , Starbuck Michael W. , Ravoori Murali K. , Lu Jing-Fang , Kundra Vikas , Maity Sankar , Wang Fen , Navone Nora M. 
Published: February 2011

Currently no therapy effectively controls the progression of advanced human prostate cancer. We previously reported that fibroblast growth factor 9 (FGF9) contributes to the osteoblastic progression of human prostate cancer in bone (J Clin Invest 2008;118:2697). We examined the effect of TKI258 (a receptor tyrosine kinase inhibitor [TKI] with strong activity against FGF receptor 1-3 [FGFR1-3; IC50 &lt; 40 nM]; [Novartis Pharma Corp.]) on primary mouse osteoblasts treated with and without FGF9 and TKI258. TKI258 blocked FGF9's induction of p-FRS2α (a gatekeeper that mediates FGFR downstream signals) an indication that TKI258 specifically blocks FGF signaling in osteoblasts. These observations provide strong evidence implicating FGF signaling in the osteoblastic progression of prostate cancer in bone. We hypothesized that pharmacologic blockade of the FGFR signaling has an antitumor effect in prostate cancer. To test our hypothesis, we studied the antitumor efficacy of TKI258 in the osteoblastic growth of MDA PCa 118b, a prostate cancer tumor graft that depends on FGF9 for growth. We assessed the effect of TKI258 on the growth of MDA PCa 118b prostate cancer cells in the femurs of male SCID mice. Ten mice were treated with TKI258 (20 and 60 mg/kg body weight daily by oral gavage), and another 10 mice were treated with vehicle only. Treatment started the day after we identified tumor on MRI scanning at the site of tumor cell injection and continued for 3 weeks, when we used MRI to assess tumor volumes in the femurs and microCT to assess bone mass. Femurs bearing MDA PCa 118b in mice treated with TKI258 had significantly smaller tumors (P = 0.019) and less prostate cancer-induced cortical bone (P = 0.034) than did control mice. Histopathologic analysis indicated that tumors in the treated mice were smaller than in the controls. Initial analysis of tumor-associated osteoclasts (assessed by their expression of tartrate-resistant acidic phosphatase) shows no difference between the treated and control mice. The femurs bearing MDA PCa 118b tumors were then analyzed by Western blotting to measure signaling; we found that TKI258 specifically inhibited p-ERK1/2 (an FGF signaling target gene) but not p-AKT. Taken together, these results suggest that TKI258 inhibits the growth of prostate cancer cells in bone by targeting both those cells and osteoblasts (but not osteoclasts), possibly by blocking FGF signaling. Subsequent molecular analysis of FGF downstream target genes will help elucidate the mechanism underlying TKI258's inhibition of prostate cancer growth in bone. Results from these studies will also help identify markers of response to TKI258 that will be used to interpret an ongoing clinical study with TKI258 in selected men with castrate-resistant prostate cancer with bone marrow infiltration. The results will serve as the foundation for the development of candidate predictive markers and further therapies based on targeting the FGF pathway.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 344.