Targeting Fibroblast Growth Factor Pathways in Prostate Cancer

“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 s provides a rationale for the therapeutic blockade of this pathway, and two small-molecule tyrosine kinase inhibitors-dovitinib and nintedanib-are currently in phase 2 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.”

Inhibitor-Sensitive FGFR2 and FGFR3 Mutations in Lung Squamous Cell Carcinoma

In lung squamous cell carcinoma (lung SCC), one of the most frequently altered receptor tyrosine kinase families is the fibroblast growth factor receptor (FGFR) family, with amplification or mutation observed in all four family members. Here, we describe the oncogenic nature of mutations observed in FGFR2 and FGFR3. We show that several of these mutations drive cellular transformation. Transformation can be reversed by small-molecule FGFR inhibitors currently being developed for clinical use.

FGFR1 is Essential for Prostate Cancer Progression and Metastasis

The fibroblast growth factor receptor FGFR1 is ectopically expressed in prostate carcinoma cells, but its functional contributions are undefined. In this study, we report the evalulation of a tissue-specific conditional deletion mutant generated in an ARR2PBi(Pbsn)-Cre/TRAMP/fgfr1loxP/loxP transgenic mouse model of prostate cancer…”