Targeting fibroblast growth factor pathways in prostate cancer

Abstract

Advanced prostate cancer carries a poor prognosis and novel therapies are needed. Research has focused on identifying mechanisms that promote angiogenesis and cellular proliferation during prostate cancer progression from the primary tumor to bone-the principal site of prostate cancer metastases. One candidate pathway is the fibroblast growth factor (FGF) axis. Aberrant expression of FGF ligands and FGF receptors leads to constitutive activation of multiple downstream pathways involved in prostate cancer progression including mitogen-activated protein kinase, phosphoinositide 3-kinase, and phospholipase Cγ. The involvement of FGF pathways in multiple mechanisms relevant to prostate tumorigenesis provides a rationale for the therapeutic blockade of this pathway, and two small-molecule tyrosine kinase inhibitors-dovitinib and nintedanib-are currently in phase II clinical development for advanced prostate cancer. Preliminary results from these trials suggest that FGF pathway inhibition represents a promising new strategy to treat castrate-resistant disease.

Figure 1

The FGF/FGFR signaling pathway. FGF ligand binding triggers formation of the FGF/FGFR/HSP complex, leading to autophosphorylation of the FGFR. Docking proteins such as FGFR substrate 2 (FRS2α) and phospholipase C gamma (PLCγ) activate downstream pathways, including RAS/RAF/MEK, phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR), and signal transducer and activator of transcription. The pathway can be positively (HSP, SFBP) or negatively (SEF, Sprouty, MKP3) regulated at many different nodes. Intermediaries of FGF signaling are also activated by additional cytokines and growth factors (e.g. IL-6, EGF, and TGFβ).

Figure 2

Mesenchymal expression of FGF10 leads to the formation of FGFR1 dependent PIN or prostate cancer in a tissue recombination prostate regeneration system. When mouse normal prostate epithelial cells (mNPE) are mixed with embryonic urogenital sinus mesenchyme (UGSM) and grafted under the kidney capsule of mice, epithelial glands resembling the mouse prostate are formed. When mNPE are mixed with UGSM overexpressing FGF10, well differentiated prostate carcinoma develops and these cancer cells express higher androgen receptor levels than that observed in normal prostate-like glands. Inhibition of epithelial FGFR1 signaling using dominant-negative FGFR1 leads to reversal of the cancer phenotype.

Figure 3

Activation of FGFR axis mediates prostate cancer development and progression. A. Inducible FGFR1 (iFGFR1) prostate mouse model (named the juxtaposition of CID and kinase1 (JOCK1)). Activation of iFGFR1 with chemical inducers of dimerization (CID) led to PIN, invasive prostate cancer, and metastases. B, Transgenic adenocarcinoma of the mouse prostate (TRAMP) (established by expressing of SV40 T antigen in the mouse prostate) develop poorly differentiated prostate carcinomas at 24 weeks of age. Conditional deletion of FRS2α in the mouse prostate inhibited the initiation and progression of prostate cancer in the TRAMP model.

Figure 4

A. A model of prostate cancer-stroma interaction mediated by FGFR and ligands. FGFR1 is expressed by prostate cancer cells, osteoblasts and endothelial cells. FGF2 is produced by prostate cancer cells and induces osteogenesis, bone remodeling, and angiogenesis. Angiogenesis in turn favors prostate cancer progression. Prostate mesenchymal cell production of FGF2/FGF10 activate FGFR1 in prostate cancer cells leading cancer progression. FGF8/FGF9 is produced by prostate cancer cells during growth in bone (bone metastases) and induces osteogenesis and bone remodeling. Activated osteoblasts induce angiogenesis. B. Inhibition of the FGF pathway can affect tumor progression by targeting multiple biological pathways.

Figure 4

A. A model of prostate cancer-stroma interaction mediated by FGFR and ligands. FGFR1 is expressed by prostate cancer cells, osteoblasts and endothelial cells. FGF2 is produced by prostate cancer cells and induces osteogenesis, bone remodeling, and angiogenesis. Angiogenesis in turn favors prostate cancer progression. Prostate mesenchymal cell production of FGF2/FGF10 activate FGFR1 in prostate cancer cells leading cancer progression. FGF8/FGF9 is produced by prostate cancer cells during growth in bone (bone metastases) and induces osteogenesis and bone remodeling. Activated osteoblasts induce angiogenesis. B. Inhibition of the FGF pathway can affect tumor progression by targeting multiple biological pathways.