Fibroblast Growth Factor Signalling: From Development to Cancer

Nicholas Turner; Richard Grose

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Therapeutic Approaches

Several pharmaceutical companies have developed FGFR tyrosine kinase inhibitors (TKIs) (Table 2) that are in the early phases of clinical trials. So far, all of the TKIs are ATP-competitive VEGFR2 inhibitors. The VEGFR and FGFR kinase domains have high structural similarity, and several VEGFR TKIs also inhibit the FGFRs. Dual inhibition with VEGFRs has the obvious potential benefit of targeting two pro-angiogenic growth factors, or of simultaneously targeting angiogenesis and tumour cell proliferation. However, many of these TKIs with multiple targets are less potent against the FGFRs and it is uncertain if this will be a disadvantage in clinical development. Targeting multiple kinases may also increase the side effects of these compounds, limiting the ability to deliver drugs at doses required for FGFR inhibition. Consequently, several pharmaceutical companies are developing highly potent FGFR TKIs, which are selective over VEGFRs. Preclinical development of potent FGFR TKIs has been complicated by tissue calcification. FGF23 is involved in phosphate homeostasis,[153] and in preclinical models highly potent (but not less potent) FGFR tyrosine kinase inhibitors have caused hyperphosphataemia-mediated tissue calcification owing to blockade of FGF23 signalling. It is unknown whether this will be an issue in humans.

To minimise the side effects of targeting FGFRs, therapeutic antibodies may have substantial benefits, as they can be used to treat cancer cells that are reliant on a particular FGFR and therefore reduce the potential toxicity of pan-FGFR inhibition. Antibodies targeting FGFR3 have been shown to have an anti-proliferative effect on bladder cancer cells[154,155] and t(4;14) myeloma.[155] A single chain Fv antibody that targeted FGFR1-IIIc could not be pursued further after it was found to potentially block FGF signalling in the hypothalamus, resulting in severe anorexia in rodents and monkey models.[156] It remains to be ascertained whether this would be a class effect for all FGFR1-IIIc antibodies.

A third approach is to develop FGF ligand traps; for example, FP-1039 (Five Prime Therapeutics), a soluble fusion protein that consists of extracellular FGFR1-IIIc fused to the Fc domain of IgG1. These traps could potentially block the activity of multiple FGF ligands and receptors, and exert both anti-angiogenic and anti-proliferative effects.[157]

Finally, a different approach is the use of FGF ligands to stimulate FGFRs. A recombinant FGF7 ligand, also known as keratinocyte growth factor, has been licensed for the treatment of mucositis induced by myelotoxic therapy requiring haematopoietic stem cell support (Table 2). This compound should not be used outside the licensed indications, as safety has not been established in any tumour types known to express FGFR2-IIIb, the receptor for FGF7.

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