Blocking the FGF/FGFR system as a ⿿two-compartment⿿ antiangiogenic/antitumor approach in cancer therapy

Abstract

a b s t r a c tFibroblast growth factors (FGFs) are a family of pleiotropic factors produced by stromal and parenchymal tumor cells. Even though FGFs have been firstly characterized as angiogenic factors, they exert autocrine and paracrine functions not only on endothelial cells but also on tumor cells and other stromal components. Thus, the FGF/FGF receptor (FGFR) pathway may represent a key player in tumor growth by regulating the complex cross-talk between stromal and tumor compartments.The ligand dependent or independent activation of the FGF/FGFR system by gene upregulation, oncogenic mutation or amplification occurs in a variety of human tumors and is implicated in various key steps of tumor growth and progression. In addition, FGF/FGFR activation has been described as a mechanism of tumor escape in response to antiangiogenic/anti-VEGF therapies.Experimental and clinical evidences provide a compelling biologic rationale for the development of anti-FGF/FGFR targeting agents in cancer therapy. However, the development of drugs specifically targeting the FGF/FGFR pathway proved to be difficult, also due to the high redundancy and pleiotropic effects of FGF and FGFR family members. On the other hand, the possibility to develop "two-compartment" targeting agents endowed with both antiangiogenic and antitumor activities remains promising.Here we will review the preclinical and clinical approaches and potential therapeutics currently available to block the FGF/FGFR system in human cancer.

Tumor angiogenesis revisited: Regulators and clinical implications

“…, Table ). These include selective and nonselective small‐molecule TKIs, anti‐FGFR antibodies, and some extracellular FGF ligand traps …”

Retinoic acid signaling in vascular development

“…For example, in the central nervous system (CNS) neural-derived signals stimulate the formation of a high density vascular plexus and development of a blood-brain barrier (BBB) (R Daneman et al, 2009; Haigh et al, 2003; Stenman et al, 2008). Many of the key factors that orchestrate embryonic vascular development such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), Wnt-β-catenin and Notch, have been identified and their elucidation has facilitated therapies for several diseases, most notably anti-tumor angiogenesis therapies (reviewed in (Adams & Alitalo, 2007; Caporarello et al, 2017; Giacomini et al, 2016; Reis & Liebner, 2013). …”

Expression of FGF‐2/FGFR‐1 in normal mucosa, salivary gland, preneoplastic, and neoplastic lesions of the oral cavity

“…Fibroblast growth factor 2 (FGF‐2), also known as basic fibroblast growth factor, is one of the prototypes of the FGF family, comprising 22 members of secreted proteins acting as paracrine, autocrine, or endocrine factors that signal through FGF receptors (FGFRs) . Fibroblast growth factor receptor (FGFR) family has four (FGFR1‐4) transmembrane tyrosine kinase receptors expressed on several cell types .…”

“…Fibroblast growth factor 2 is a multifunctional cytokine expressed in several tissues and involved in a wide variety of biologic activities, such as proliferation and differentiation in various cell types . In addition to its role in embryogenesis, it regulates homeostatic functions in the adult, participating in different processes, acting mainly in angiogenesis and tissue repair …”