Beyond VEGF: Inhibition of the Fibroblast Growth Factor ... · Fibroblast Growth Factors and...

Review

Beyond VEGF: Inhibition of the Fibroblast Growth FactorPathway and Antiangiogenesis

Christopher Lieu1, John Heymach2, Michael Overman1, Hai Tran2, and Scott Kopetz1

AbstractFibroblast growth factor (FGF) signaling regulates cell proliferation, differentiation, survival, angiogen-

esis, and wound healing. Compelling evidence for deregulated FGF signaling in tumorigenesis continues to

emerge, and a growing body of research suggests that FGF may also play an integral role in the resistance

to anti-VEGF therapy. Although agents targeting FGF signaling are early in development, the potential to

target both the VEGF and FGF pathways may translate into improvements in the clinical care of cancer

patients. Clin Cancer Res; 17(19); 6130–9. �2011 AACR.

Introduction

Fibroblast growth factors (FGF) belong to a structurallyrelated family of 22 molecules that interact with high-affinity tyrosine kinase FGF receptors (FGFR) to regulatemultiple fundamental pathways and cellular behaviors (1).FGF signaling regulates events in embryonal development,including mesenchymal–epithelial signaling and the de-velopment of multiple organ systems (2, 3). FGF signalingalso regulates cell proliferation, differentiation, and surviv-al, as well as angiogenesis and wound healing (4). In somesituations, FGFs can act as a negative regulator of prolifer-ation and positive regulator of differentiation (5). Giventhe role of FGF in multiple cellular processes, compellingevidence for deregulated FGF signaling in tumorigenesiscontinues to emerge (6). Studies with animal models havesuggested that aberrant FGF signaling can promote tumordevelopment through increased cell proliferation and sur-vival, as well as increased tumor angiogenesis (7, 8). Thisbody of research indicates that FGF signaling is an impor-tant pathway in tumorigenesis and tumor angiogenesis andthat appropriate targeting of the FGFR tyrosine kinases maybe an effective therapeutic intervention for cancer.

This review describes the FGF family of growth factorsand their associated receptors, as well as their associationwith tumor development, growth, and metastasis. We alsodescribe the effect of FGFs on tumor angiogenesis, includ-ing key preclinical and clinical evidence about the role of

FGFs in the development of resistance to anti-VEGF ther-apy. Finally, FGF as a potential therapeutic target isreviewed, including the current state of drug developmentin this field.

Fibroblast Growth Factor Family

FGFs were first isolated as mitogens from pituitaryextracts and bovine brain tissue in the 1970s (9, 10). Sinceinitial discovery, 22 members of the FGF family have beenidentified, all of which are structurally related signalingmolecules ranging from 17 to 34 kDa in size (11). SomeFGFs seem to be expressed exclusively during embryonicdevelopment (FGF-3, 4, 8, 15, 17, and 19), and others areexpressed in both embryonic and adult tissues (FGF-1, 2,5–7, 9–14, 16, 18, and 20–23; ref. 11).

FGFs are structurally similar to one another, with 28highly conserved and 6 identical amino acid residues (12).Most FGFs are secreted glycoproteins (FGF-3–8, 10, 15, 17–19, and 21–23), but FGF-1 and FGF-2 are exported fromcells by mechanisms that remain unclear. FGF-1 and FGF-2may be released from damaged cells or by exocytosis that isindependent of the endoplasmic reticulum–Golgi pathway(13). FGFs have strong affinities for the glycosaminoglycanside chains of cell surface proteoglycans, which help tosequester FGFs on the surface of the secreting cell or onnearby cells, and in the binding of FGF to the FGFR.

FGFRs are transmembrane tyrosine kinases that contain2 or 3 extracellular immunoglobulin-like domains and anextracellular heparin-binding sequence (14–16). The 2proximal immunoglobulin-like extracellular domains bindthe FGF ligand, whereas the heparin-binding sequencebinds a glycosaminoglycan moiety, resulting in the forma-tion of a complex containing 2 FGFs, 2 FGFRs, and theglycosaminoglycan moiety (17). Only 4 FGFRs are knownto exist, designated FGFR-1 through FGFR-4 (Table 1).Their specificity for various ligands is altered by processesthat create multiple isoforms. Alternative mRNA splicing of

Authors' Affiliations: Departments of 1Gastrointestinal Medical Oncologyand 2Thoracic/Head and Neck Medical Oncology, The University of TexasMD Anderson Cancer Center, Houston, Texas

Corresponding Author: Scott Kopetz, Department of GastrointestinalMedical Oncology, The University of Texas MD Anderson Cancer Center,1515 Holcombe Boulevard, Unit 0426, Houston, TX 77030. Phone: 713-792-2828; Fax: 713-563-6764; E-mail: [email protected]

doi: 10.1158/1078-0432.CCR-11-0659

�2011 American Association for Cancer Research.

ClinicalCancer

Research

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the FGFR gene significantly alters the ligand specificity bychanging the sequence of the carboxy-terminal half ofimmunoglobulin-domain III. This sequence change resultsin 2 isoforms termed IIIb and IIIc (18, 19). In general, IIIbisoforms are expressed on epithelial cells, and IIIc isoformsare expressed on mesenchymal cells, where they mediatetissue interactions in normal development and woundhealing (20–22).FGF signaling can also be modulated by several mem-

brane proteins, including cell adhesion molecules of thecadherin and immunoglobulin superfamilies (23). Thebest characterized of these is neural cell adhesion molecule(NCAM). NCAMhas been shown to be amajor regulator ofFGF-FGFR interaction in several cell types, including non-neural tissues (24). NCAM has been shown to act as anonconventional ligand that can induce a specific FGFR1-mediated cellular migration that is different from theresponse elicited by FGF-2 (25). Furthermore, NCAM ex-pression has been shown to reduce FGF-stimulated extra-cellular signal regulated kinase (ERK)1/2 activation, cellproliferation, and cell-matrix adhesion in fibroblast celllines, suggesting that NCAM acts as a novel control mech-anism for FGFR signaling (26).

Fibroblast Growth Factor and Tumor Growth

Aberrant FGF and/or FGFR signaling has a wide range ofeffects and can involve both tumor cells and the surround-ing stroma. These effects include cellular proliferation;resistance to cell death; increasedmotility and invasiveness;increased angiogenesis; enhanced metastasis; and resis-tance to chemotherapy (27). Deregulation of FGF signalingin tumorigenesis can result from activating mutations,FGFR gene amplifications, and chromosomal transloca-tions, which lead to increased autocrine and paracrinesignaling (28–30). Because aberrant signaling can promotetumorigenesis by affecting major downstream biologicprocesses, FGFs have been implicated in multiple tumortypes, including prostate, astrocytoma, breast, lung, blad-der, hepatocellular, and colon cancers (31–41).

Alternative splicing of the FGFR gene has also beenimplicated in carcinogenesis. Carcinomas have been ob-served to switch expression of FGFR to the mesenchymalisoforms, enabling cells to receive signals usually restrictedto the connective tissue, such as ectopic expression oftypically stroma-localized FGFR1-IIIc (42, 43). The IIIcsplice variant has been detected in colon carcinoma butnot in adenoma-derived cell lines, suggesting that it isupregulated during tumor progression (44). During pros-tate cancer progression, alternative splicing of FGFR2 canoccur in epithelial cells, leading to isoform changes fromFGFR2-IIIb into the more ligand-promiscuous FGFR2-IIIc(Fig. 1; refs. 8, 43). Thus, this aberrant alternative splicingof FGFR potentially destroys the balanced interdependencebetween stroma and epithelium (8, 43, 45).

Clinical studies of FGF have suggested a critical role ofFGF signaling in clinical tumor progression. In 1 study ofadvanced serous ovarian adenocarcinomas, FGF-1 mRNAcopy number was found to be significantly correlated withDNA copy number and protein expression levels (46). BothFGF-1 mRNA and protein levels were associated with worseoverall survival, possibly secondary to an increase in tumorangiogenesis and autocrine stimulation of cancer cells. Inanother study of 100 resected colorectal cancer surgicalspecimens, high FGF-2 expression was associated withincreased grade, stage, lymphovascular invasion, and intra-tumoral microvessel density (47). Significantly elevatedlevels of FGF-2 in circulation were found in a small cohortof patients with metastatic colorectal cancer, relative tomedian levels in control subjects (48). In other studies,although increased levels of FGF-2 were found in plasmafrom patients with different types of cancer, it was unclearwhether the higher levels resulted from tumor invasion anddegradation of the extracellular matrix (ECM), liberatingFGF to function as a paracrine growth factor, or whethertumor cells induced FGF2 release from stromal inflamma-tory infiltrate (49, 50).

Loss of expression of NCAM has also been implicated inthe progression of tumor metastasis. NCAM has beenshown tomodulate neurite outgrowth andmatrix adhesionof b cells from the Rip1-Tag2 transgenic mouse model ofpancreatic neuroendocrine tumors by assembling a FGFR-4

Translational Relevance

Angiogenic inhibitors have shown promise in thetreatment of multiple tumor types and have improvedoutcomes in patients with metastatic disease. However,many patients will not respond to antiangiogenic ther-apy, and for those that do, resistance develops quickly.Fibroblast growth factor (FGF) seems to play an integralrole in the resistance to antiangiogenic therapy, andagents that specifically target the FGF pathway are beingdeveloped and tested in clinical trials. It is critical thatinvestigators review the existing literature on FGF andtumor angiogenesis to understand the importance ofthis target in various malignancies, as well as to designrational clinical trials that can expedite a potentiallymeaningful therapy in patients previously treated withantiangiogenic agents.

Table 1. Receptors for the FGFR family

Receptor Specific For

FGFR-1b FGF-1, 2, 3, and 10FGFR-1c FGF-1, 2, 4, 5, and 6FGFR-2b FGF-1, 3, 7, and 10FGFR-2c FGF-1, 2, 4, 6, and 9FGFR-3b FGF-1 and 9FGFR-3c FGF-1, 2, 4, 8, and 9FGFR-4 FGF-1, 2, 4, 6, 8, and 9

Adapted from Itoh and Ornitz (1).

Inhibition of the FGF Pathway and Antiangiogenic Therapy

www.aacrjournals.org Clin Cancer Res; 17(19) October 1, 2011 6131




signaling complex that leads to the modulation of b1-integrin–mediated cell-matrix adhesion (51). Ablation ofthe expression of NCAM in this mouse model resulted inthe disruption of the tumor tissue architecture, tumor-associated lymphangiogenesis, and lymph node metastasis(51, 52).

Though a full review of FGF signaling and tumor growthis beyond the scope of this article, please see the compre-hensive review from Turner and Grose for additionalinformation (41).

Fibroblast Growth Factors and Angiogenesis

Angiogenesis, the formation of new blood vessels fromthe endothelium of the existing vasculature, plays a pivotalrole in tumor growth, progression, and metastasis (53, 54).Along with embryogenesis, angiogenesis was one of thefirst areas where FGF signaling was shown to be important(55, 56). In particular, FGF-1 and FGF-2 were found to beimportant for new blood vessel growth at the site of anexcision wound and have been shown to stimulate angio-genesis in various assays (57–59). FGF-2 is a very potentinducer of angiogenesis. In a preclinical model of micro-vascular endothelial cells grown on a 3-dimensional col-

lagen gel, VEGF and FGF-2 were able to induce cells toinvade the underlying matrix to form capillary-like tubules(60). Interestingly, FGF-2 was found to be twice as potentas VEGF in this model. The critical role of FGF in tumorangiogenesis was shown through the interference of FGFfunction with a recombinant adenovirus expressing solubleFGFR (AdsFGFR). AdsFGFR seemed to impair the mainte-nance of tumor angiogenesis, in contrast to inhibition ofthe VEGF pathway that predominantly affected the initia-tion of tumor angiogenesis (61). Injection of AdsFGFR inthe Rip1-Tag2murine model of pancreatic neuroendocrinetumor resulted in repression of tumor growth, with asignificant decrease in tumor vessel density. FGFs exerttheir effects by modulating proliferation and migrationof endothelial cells, production of proteases, and promo-tion of integrin and cadherin receptor expression (62).In particular, FGF-1 and FGF-2 directly affect tumorangiogenesis by promoting the cellular proliferation ofendothelial cells. FGF-2 has been shown to induce revas-cularization in various experimental models in severalspecies, including rabbit, chicken, and mouse (63–65).In a murine model, FGF-1 knockout mice and FGF-1/FGF-2 double-knockout mice had poor wound healingcompared with normal control mice (58). FGFR-1 is most

© 2011 American Association for Cancer Research

FGF

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Figure 1.Changes in FGF and FGFR in the microenvironment and epithelium in normal tissue and cancer. Compared with normal tissue, alternative splicing ofthe FGFR gene can switch expression of FGFR from the IIIb isoform to the ligand promiscuous IIIc isoforms. Furthermore, release of FGF from thetumor and stroma may initiate tumor angiogenesis. FGF-BP–mediated reduction of the affinity of FGF-2 to heparin can induce its release from the ECM.FGF-BP, FGF binding protein; PDGF, platelet-derived growth factor; PDGFR, platelet-derived growth factor receptor.

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commonly expressed on endothelial cells, although FGFR-2 has been shown to be present under certain circum-stances (50, 66). The presence of FGFR-3 and FGFR-4has not been reported in the endothelium.FGFs can exert their angiogenic mechanism of action via

paracrine signaling through their release by tumor andstromal cells, or through their mobilization from theECM (50). FGF-1, in particular, may stimulate endothelialcell growth and the motility of endothelial cells throughparacrine signaling, which results in increased prolifera-tion, survival, and motility of endothelial cells (46). FGF-2has been studied in xenograft models in which liposome-mediated gene transfer was used to deliver episomal vectorscontaining antisense FGF-2 or FGFR-1 cDNAs into humanmelanomas grown in nude mice. In contrast to the stim-ulation seen during deregulated FGF signaling, tumorsinjected with these antisense constructs showed arrestedtumor growth or reduced tumor density because of blockedintratumoral angiogenesis (67). There is also evidence thatFGF-2 increases the expression of angiopoietin-2, a potentregulator of vascular branching and angiogenesis, as well asVEGF in cultured human and endothelial cells (68).FGFs may also exert their effects through autocrine

signaling in endothelial cells, stimulating the proliferationof new capillary endothelial cells (66). This induces aproangiogenic state that creates an environment favorablefor vascular growth. Evidence for this growth is seen in aparticular subtype of Kaposi sarcoma (KS) in which FGF-2,produced by the KS cells, has been found to synergize withhuman immunodeficiency virus type 1 Tat protein toenhance endothelial cell growth and type IV collagenaseexpression (66, 69). These tumors were found to haveincreased aggressiveness and frequency compared withother forms of KS.Preclinical models of tumor angiogenesis have suggested

that FGF–binding protein (FGF-BP) serves as an angiogenicswitch molecule and can be rate limiting for tumor growth(70). FGF-2 is present in most tissues under normal phys-iologic conditions but is inactivated by being tightly boundto the ECM. FGF-BP binds to FGF-2 in a dose-dependentmanner, which results in a marked reduction of the affinityof FGF-2 to heparin and release from the ECM (Fig. 1; refs.71, 72). Exogenously administered FGF-BP has been shownto stimulate FGF-2–dependent growth of both adrenalcarcinoma and prostate carcinoma cells. In addition, down-regulation of FGF-BP expression has been shown to inhibitangiogenesis in squamous cell carcinoma xenografts (73).

Fibroblast Growth Factor–2 Cross-Talk withAngiogenic Factors

VEGF plays an integral role in the development of newblood vessels in tumor formation, and angiogenesis inhi-bitors targeting the VEGF pathway have proved to be effi-cacious inpreclinical cancermodels and in clinical trials (74,75). A significant amount of cross-talk is thought to existbetween members of the VEGF family and FGF-2 duringangiogenesis, with VEGF appearing earlier during angiogen-

esis than does FGF (50). In 1 study, the angiogenic responseoccurred more quickly when VEGF and FGF-2 were addedsimultaneously to microvascular endothelial cells on 3-dimensional collagen gels than the response to either cyto-kine alone, suggesting synergy between the 2 cytokines (60).It has also been shown that induction of FGF-2–inducedangiogenesis is partly dependent on the activation of VEGFand the presence of endogenous VEGF and VEGF-C (76).Evidence for synergybetweenVEGF andFGF-2has alsobeenshown in xenograft models expressing FGF-2 and VEGF intumor cell transfectants. Simultaneous expression of FGF-2and VEGF resulted in fast-growing lesions with high bloodvessel density and permeability (77). Interestingly, inhibi-tion of FGF-2 production caused a significant decrease intumor burden with a concomitant decrease in blood vesseldensity and size. This differed from the effects of VEGFinhibition,whichcausedadecrease inpericyteorganization,vessel patency, and permeability. This finding suggests thatFGF-2 and VEGF stimulate angiogenesis synergistically butwith different effects on vessel size and function.

FGF-2 may also have indirect effects on VEGF pathways.In a breast cancer cell line (T47D), FGF-2 was found toactivate hypoxia-induced VEGF release through augmenta-tion of the phosphoinositide 3-kinase pathway, as well ashypoxia-inducible factor-1a expression (78). FGF-2 hasalso been shown to indirectly enhance the effect of VEGFthrough upregulation of neurolipin-1 (NRP-1), a corecep-tor for VEGF. FGF-2 increased NRP-1 levels and enhancedthe migration of human vascular smooth muscle cells inresponse to VEGF.

There is also evidence of cross-talk between FGF-2 andplatelet-derived growth factor (PDGF)–BB. FGF-2 andPDGF-BB together have been shown to synergisticallypromote tumor angiogenesis and pulmonary metastasis,as well as formation of high-density primitive vascularplexuses coated with pericytes and vascular smooth musclecells (79). Pericyte recruitment to coat nascent vesselsduring angiogenesis is essential for the stabilization andfurther establishment of a tumor’s vascular network. FGF-2seems to upregulate PDGF receptor (PDGFR) expression,which causes increased responsiveness to PDGF-BB, andPDGF-BB–treated vascular smooth muscle cells becomeresponsive to FGF-2 signaling through upregulation ofFGFR-1. Interestingly, overexpression of PDGF-BB alonein tumor cells was shown to result in decreased recruitmentof pericytes and dissociation of vascular smooth musclecells. In tumor cells subjected to prior upregulation ofFGF-2 caused by VEGF receptor 2 (VEGFR2) inhibition,PDGFR-b inhibition also attenuated the expression ofFGF-2 (80). In a mouse model of cervical carcinogenesis,pharmacologic blockade of PDGFR signaling with imatinibslowed progression of premalignant cervical lesions andimpaired the growth of preexisting invasive carcinomasthrough suppression of the expression of FGF-2 andFGF-7, which resulted in decreased proliferation and an-giogenesis within the lesions (81). Treatment with an FGFtrap also impaired the angiogenic phenotype similar to theblockade of the PDGFR with imatinib.






Fibroblast Growth Factor Signaling andResistance to Anti-VEGF Therapy

Emerging evidence has suggested that upregulation ofFGF and FGFR may serve as a mechanism of resistance toanti-VEGF therapy. Preclinical trials of anti-VEGF therapyin a murine pancreatic neuroendocrine tumor model(PNET), Rip1-Tag2, showed that tumors with an initialresponse to VEGFR2 blockade expressed higher levels ofFGF-2 at the time of progression compared with stabletumors (82). When the tumors were first treated with aVEGFR inhibitor alone and subsequently treated at thepeak of response with an FGF trap, the combinationattenuated revascularization and slowed tumor growth(Fig. 2). The dual tyrosine kinase inhibitor (TKI) of VEGFRand FGFR, brivanib, has also been studied in this murinemodel and has proved to be efficacious following thefailure of 2 VEGFR inhibitors (83). It was even moreeffective when used in the frontline setting, suggesting thatdual inhibition of VEGFR and FGFR was able to delayinduction of evasive resistance. Further evidence for therole of alternative angiogenic factors in tumor escape fromangiogenesis inhibitors has been shown in tumors in whichgrowth was impaired by ectopic expression of the endog-enous angiogenesis inhibitors thrombospondin-1, tumsta-tin, and endostatin (84). In that study, renal carcinomacells transfected with thrombospondin-1 resisted angio-genesis inhibition by upregulating the proangiogenic fac-tors FGF-2, angiopoietin 2, and PDGF-A, despite high

baseline levels of VEGF. In 1 xenograft model of renal cellcarcinoma, tumors unresponsive to sunitinib treatmentwere sensitive to a dual inhibitor of the VEGF and FGFRs(85). This inhibitor seemed to reduce blood vessel densitythrough inhibition of FGF-2–induced angiogenesis.

Clinical evidence in colon cancer also supports the roleof FGF-2 in resistance to bevacizumab-containing regi-mens. To determine the dynamic changes in circulatingfactors during the emergence of therapeutic resistance,profiles of cytokines and angiogenic factors were assessedin 40 patients receiving a regimen of 5-fluorouracil (5-FU),leucovorin, and irinotecan (FOLFIRI) plus bevacizumab.Levels were assessed after a single dose of bevacizumab andFOLFIRI plus bevacizumab, at the time of progression, andat the nadir of radiographic response (86, 87). The inves-tigators showed that FGF-2 levels were elevated immedi-ately prior to progression compared with baseline levels.Strikingly, 30% of patients had an increase in FGF-2 to 10-fold the upper limit of normal, suggesting significantheterogeneity in the FGF-2 response. In 1 study of neoad-juvant bevacizumab with 5-FU and radiation in rectalcancer, the administration of a short regimen of bevacizu-mab in combination with chemotherapy had no significanteffect on plasma FGF-2 levels, suggesting that elevations inFGF-2 are instead a later event temporally associated withthe development of resistance to the bevacizumab combi-nation regimen (88).

Elevated FGF-2 levels have also been shown in glioblas-toma patients treated with a VEGFR small molecule

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Figure 2. VEGFR2 blockadetransiently stops tumor growthand decreases vascularity,followed by tumor progression,reinduction of angiogenesis, andreestablishment of the tumorvasculature. Quantification ofoverall tumor burden plotted asaverage and SD per animal at thetime of initiation of treatment(t ¼ 0; purple bar), after treatmentfor 10 days (orange bars), and at4 weeks of age (teal and greenbars) for the different treatmentarms. Averages from cohorts of 8to 10 mice per group are plottedwith their respective SD bars.(Adapted from Cancer Cell, withpermission from Elsevier; ref. 82.)

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inhibitor (89). In patients who experienced tumor progres-sion while receiving treatment, increased tumor enhance-ment volume was associated with significant increases inplasma levels of FGF-2 and stromal cell–derived factor-1. Astatistically significant positive correlation was observedbetween FGF-2 levels and tumor vessel size measured byMRI. This work provided further clinical evidence that FGF-2 may play a role in tumor relapse in patients treated withanti-VEGF agents (89).Unlike preclinical models, clinical studies investigating

levels of FGF can only show an association of elevatedFGF and/or FGFR with the resistance to anti-VEGF ther-apy; they cannot show causation or an actual resistancemechanism. Furthermore, because most studies are con-ducted in combination with cytotoxic chemotherapy, it isdifficult to discern whether the patient and tumor havebecome resistant to the chemotherapy, the antiangiogenictherapy, or both. Therefore, high-quality preclinical mod-els will be essential for further investigation to provide asound preclinical rationale for future clinical studies.

Targeting Fibroblast Growth Factor

Because FGFs have a clearly defined role in tumorangiogenesis, as well as a possible role in resistance tocurrent VEGF inhibitors, several FGF pathway inhibitorsare currently under development. The inhibitors enteringthe clinic are either TKIs or soluble antibody fragmentsthat block ligand binding and receptor dimerization(Table 2). Most of the TKIs have dual specificity for FGFRand VEGFR, both as a matter of design and because of thestructural similarities in their kinase domains. However,the inhibitors vary in their relative potency for VEGFR andFGFR, with many inhibitors having higher potency forVEGFR than FGFR (90, 91). Targeting both kinases mayalso increase the toxicity associated with these com-pounds, although biologically active doses have beenshown with most of the compounds (41). The other classof compound in development, FGF ligand trap, has thepotential to block the interaction of multiple FGF ligandswith the soluble FGFR fragments. In 1 study, such anFGFR-1 antagonist was shown to prevent FGFR-1 ligands

from binding, and it had in vitro activity against lung andrenal cell carcinoma (92).

The safety of FGFR inhibitors currently under develop-ment seems acceptable. Preclinical toxicity studies withthese agents have not shown a reproducible class effect,aside from hypertension, which is difficult to attribute tothe VEGFR or FGFR inhibitory effects of many of the agents(93, 94). Monoclonal antibodies directed against FGFR1-IIIc resulted in anorexia in mice and monkeys, which wascaused by an FGF signaling blockade in the hypothalamus,and a similar toxicity was seen in 1 phase I study (95, 96).Encouragingly, the concerns based on preclinical studiesabout phosphate and vitamin Dmetabolism have not beenreflected in the reported toxicities in the early-phase studies(97).

Although a separate development strategy is being pur-sued based on somatic mutation or amplification of FGFR(reviewed in ref. 98), antiangiogenesis strategies targetingthe tumor microenvironment pose additional drug devel-opment strategies. Prior studies of anti-VEGF antibodieshave shown clinical utility when the agents are used incombination with cytotoxic therapy and minimal activityas single agents with rare exceptions (75, 99). Similarly,FGF inhibition alone is unlikely to show a significantbenefit in various tumor types. Combination strategiesof FGF/FGFR inhibition with traditional cytotoxic therapyin tumor types in which proliferation and angiogenesis isFGF/FGFR–dependent will have the highest likelihood ofachieving a clinical benefit.

The timing of FGF/FGFR–directed therapy is also an areaof emerging interest given the evolving evidence that theFGF axis may serve as an adaptive resistance mechanism toanti-VEGF therapy. Histopathologic evidence from a mu-rine PNET model suggests that the switch to an FGFRinhibitor during treatment with a VEGFR inhibitor maybe more effective at the time of early revascularization priorto detectable tumor growth (83). Future clinical trials willhelp determine whether dual inhibition of VEGFR andFGFR will be more effective in the front-line setting orwhether FGFR inhibition will be better instituted at thetime prior to or at progression after treatment with VEGF/VEGFR inhibitors. However, determination of biologic

Table 2. Current FGF and FGFR-targeting agents

Drug Manufacturer Target(s) Clinical development stage

TKI258 (dovitinib; ref. 96) Novartis FGFR, PDGFR, VEGFR Phase IIBIBF 1120 (Vargatef; ref. 104) Boehringer Ingelheim FGFR, PDGFR, VEGFR Phase IIIBMS-582664 (brivanib; ref. 105) Bristol-Myers Squibb FGFR and VEGFR Phase II and IIIE7080 (106) Eisai FGFR, PDGFR, VEGFR Phase ITSU-68 (SU6668; ref. 107) Taiho Pharmaceutical FGFR, PDGFR, VEGFR Phase I and IIAZD4547 (108) AstraZeneca FGFR Phase IFP-1039 (109) Five Prime Therapeutics FGF ligand trap (multiple FGFs) Phase IBGJ398 (110) Novartis FGFR Phase IAstex FGFR inhibitor (111) Janssen Oncology FGFR Preclinical






resistance to VEGF/VEGFR inhibitors is difficult in theclinic, as resistance to the cytotoxic component of thetreatment may be sufficient to induce tumor growth inthe absence of single-agent anti-VEGF activity. Determiningresistance to these inhibitors is a high hurdle for develop-ment of such alternate antiangiogenic therapies, and sev-eral strategies are being considered in the early clinicaldevelopment, including randomized discontinuation stud-ies and enrichment designs.

Biomarkers under consideration for FGF inhibitors in-clude plasma levels of FGF family members and increasedFGF-axis expression in the stroma; however, their use assurrogates for FGF/FGFR–dependent tumors remains un-clear. Integration of imaging or biomarkers of antiangio-genesis therapy likewise has hurdles of cost reproducibilityand lack of correlation with clinical efficacy, and theseapproaches are not routinely integrated into most clinicaldevelopment strategies of these agents (100, 101). Basedon the VEGF inhibitor experiences, radiographic endpointswith antiangiogenesis strategies will be difficult, and ulti-mately, the benefits of these agents will be measured bytheir ability to improve overall survival (102, 103).

Summary

FGFs are a family of growth factors that are involved inmany pathways that can contribute to carcinogenesis andaffect cellular proliferation, migration, and survival. They

also play a large role in angiogenesis, which is a funda-mental step in the transition from a dormant to a malig-nant state, and FGF acts synergistically with VEGF toincrease tumor blood vessel growth and maturation. Evi-dence is also increasing that FGF may be part of themechanism of resistance to anti-VEGF agents.

Although agents targeting FGF signaling are still earlyin development, the potential to target both the VEGFand FGF pathways is near, and the combination orsequential inhibition of these 2 critical angiogenic path-ways may translate into improvements in the clinical careof cancer patients. Successful strategies will depend onappropriate selection of tumors and patients in whomFGF inhibition is mostly likely to inhibit angiogenesisand proliferation.

Disclosure of Potential Conflicts of Interest

S. Kopetz: commercial research grant, AstraZeneca. The other authorsdisclosed no potential conflicts of interest.

Grant Support

NIH T32 CA-009666 (C. Lieu); National Research Service Award (NRSA)Research Training Grant; Conquer Cancer Foundation Young InvestigatorsAward (C. Lieu); NIH CA-136980 (S. Kopetz); NIH/National Cancer Institute(NCI) Cancer Center Support Grant (CCSG) Core Grant CA-106672.

Received March 18, 2011; revised July 20, 2011; accepted July 25, 2011;published OnlineFirst September 27, 2011.

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2011;17:6130-6139. Published OnlineFirst September 27, 2011.Clin Cancer Res Christopher Lieu, John Heymach, Michael Overman, et al. and AntiangiogenesisBeyond VEGF: Inhibition of the Fibroblast Growth Factor Pathway

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