Abstract 2436: Fibroblast growth factor receptor blockade in prostate cancer bone metastases.

Abstract

Abstract Castrate-resistant progression and bone metastases (BM) are hallmarks of advanced prostate cancer (PCa) for which there is no definitive cure. We previously reported that human PCa BM highly express fibroblast growth factor (FGF)-9 (J Clin Invest. 2008;118:2697). We now discovered that human PCa xenografts growing in the bone of mice induce bone cells to express components of the FGF/FGF receptor (FGFR) complex, Fgfr1, Fgfr2 and Fgf-2, as assessed by mouse-specific RT-PCR in bone bearing MDA PCa 118b tumors and in the contralateral bone (P<0.001). Similar results were found in 2 other human PCa xenografts. We then tested antitumor activity of dovitinib (Novartis), a receptor tyrosine kinase inhibitor (TKI) active against FGFR1-3 (IC50 <40 nM) in MDA PCa 118b bone tumors. We found that treated mice had significantly smaller tumors (P=0.016) than the controls had as assessed by magnetic resonance imaging. By human- and mouse-specific RT-PCR analyses we found that 7 days’ treatment reduces FGFR1 expression in tumor-bearing bones (P<0.01). Based on this evidence, a clinical study of dovitinib in men with castrate-resistant PCa and BM was initiated (Identifier: NCT00831792). In this study, serial bone marrow biopsy specimens are collected before and 8 weeks after treatment. To date, 29 of 40 patients have been enrolled. Preliminary results demonstrate tumor regression in BM and soft tissue metastases and progression-free survival of >20 weeks in a subset of patients (∼25%). Dovitinib inhibits vascular endothelial growth factor receptors (VEGFRs) 1-3, with IC50s (∼10 nM) similar to those of FGFR1-3. To assess the relative antitumor activity of FGFR blockade (with respect to VEGFR), we tested a TKI, AZD4547 (AstraZeneca), which inhibits FGFR1-3 (IC50s <3 nM) but not VEGFRs. We found that AZD4547 had antitumor activity against MDA PCa 118b bone tumors and reduces the volume of normal bones and of FGFR1 expression in tumor-associated bone cells (P<0.001). Accordingly, we observed a decrease in the blood levels of bone-specific alkaline phosphatase of men enrolled in the dovitinib trial, and this reduction was associated with the time men remained on treatment (P=0.035) (eg, those who benefited from treatment). No association was found between PSA blood levels or urinary N-telopeptides and response to therapy. Finally, we found that PCa cells and/or osteoblasts express FGFR1 in a fraction of human PCa BM (assessed by immunohistochemistry). We conclude that dovitinib therapy benefits a subset (∼25%) of men with PCa BM and that FGFR blockade contributes to this antitumor effect, at least partially, by blockade of FGFR-mediated PCa-bone cross talk. Ongoing studies focused on further understanding the mechanism of this antitumor activity will help identify likely responders and elucidate FGF signaling interaction with other candidate targets (eg, AR, c-Met, IGF, Src, VEGF). Citation Format: Xinhai Wan, Paul Corn, Jun Yang, Eleni Efstathiou, Elsa M. Li Ning Tapia, Fen Wang, Wallace McKeehan, Christopher Logothetis, Patricia Troncoso, Nora M. Navone. Fibroblast growth factor receptor blockade in prostate cancer bone metastases. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2436. doi:10.1158/1538-7445.AM2013-2436