Fibroblast growth factor family as a potential target in the treatment of hepatocellular carcinoma

Figures & data

Table 1 Specificity of ligands for FGF receptor isoforms

FGF subfamily	FGF	FGFR specificity
FGF1	FGF1	All FGFRs
	FGF2	FGFR1c, FGFR3c > FGFR2c, FGFR1b, FGFR4
FGF4	FGF4
	FGF5	FGFR1c, FGFR2c > FGFR3c, FGFR4
	FGF6
FGF7	FGF3
	FGF7	FGFR2b > FGFR1b
	FGF10
	FGF22
FGF8	FGF8
	FGF17	FGFR3c > FGFR4 > FGFR2c >
	FGF18	FGFR1c >> FGFR3b
FGF9	FGF9	FGFR3c > FGFR2c > FGFR1c, FGFR3b >> FGFR4
	FGF16
	FGF20
FGF19	FGF19
	FGF21	FGFR1c, FGFR2c, FGFR3c, FGFR4
	FGF23	(weak activity)
FGF11	FGF11
	FGF12
	FGF13	No known activity
	FGF14

Notes: FGF receptors 1–3 are alternatively spliced, while FGF receptor 4 is not. This alternative splicing event is regulated in a tissue-specific manner and dramatically affects ligand binding. For example, epithelially expressed FGF receptor 2b can be activated by mesenchymal FGF7 and FGF10; however, these ligands show no activity towards mesenchymally expressed FGF receptor 2c.

Abbreviations: FGF, fibroblast growth factor; FGFR, fibroblast growth factor receptor.

Table 2 Novel targeted multikinase inhibitors currently being investigated in clinical trials for hepatocellular carcinoma

Agent	Target	Trial	Efficacy	Reference
Brivanib	FGFR 1–3 PDGFR VEGFR 1–3	Phase III, BRISK-FL. Randomized, double-blind, multi-center Phase III study of brivanib versus sorafenib as first-line treatment in patients with advanced hepatocellular carcinoma (NCT00858871)	Median OS was 9.9 months for sorafenib versus 9.5 months for brivanib	^Citation130
		Phase III, BRISK PS. A randomized, double-blind, multi-center Phase III study of brivanib plus best supportive care (BSC) versus placebo plus BSC in subjects with advanced hepatocellular carcinoma (HCC) who have failed or are intolerant to sorafenib. (NCT00825955)	Median OS was 9.4 months for brivanib versus 8.2 months for placebo	^Citation139
		Phase III, BRISK APS. A randomized, double-blind, multi-center Phase III study of brivanib plus best supportive care (BSC) versus placebo plus BSC in Asian subjects with advanced hepatocellular carcinoma (HCC) who have failed or are intolerant to sorafenib (NCT01108705)	Ongoing	^Citation133
		Phase III, BRISK-TA. A randomized, double-blind, multicenter Phase III study of brivanib versus placebo as adjuvant therapy to trans-arterial chemo-embolization (TACE) in patients with unresectable hepatocellular carcinoma (NCT00908752)	Ongoing	^Citation133
TSU-68 (orantinib)	FGFR PDGFR VEGFR	Phase III, ORIENTAL trial. A randomized, double-blind, placebo-controlled Phase III trial of TSU-68 in combination with transcatheter arterial chemoembolization in patients with unresectable hepatocellular carcinoma (NCT01465464)	Ongoing	^Citation131
Dovitinib (TKI-258)	FGFR VEGFR PDGFR	Phase II. An open-label, randomized, multi-center, Phase II study to compare the safety and efficacy of TKI258 versus sorafenib as first-line treatment in adult patients with advanced hepatocellular carcinoma (NCT01232296)	Ongoing	^Citation133
Lenvatinib (E7080)	FGFR VEGFR	Phase I/II. Phase I/II study of E7080 in patients with advanced hepatocellular carcinoma (HCC) (NCT00946153)	Ongoing	^Citation134
	PDGFR RER KIT	Phase III. A multicenter, open-label, Phase III trial to compare the efficacy and safety of lenvatinib (E7080) versus sorafenib in first-line treatment of subjects with unresectable hepatocellular carcinoma (NCT01761266)	Recruiting	^Citation133
Nintedaninb (BIBF 1120)	FGFR PDGFR VEGFR	Phase I. An open label, dose escalation Phase I study to evaluate the safety and tolerability of continuous twice-daily oral treatment of nintedanib in Japanese patients with hepatocellular carcinoma (NCT01594125)	Recruiting	^Citation133

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