targeting fibroblast growth factor pathways in prostate cancerprostate cancer is the most commonly...

Review

Targeting Fibroblast Growth Factor Pathways in ProstateCancer

Paul G. Corn1, Fen Wang2, Wallace L. McKeehan2, and Nora Navone1

AbstractAdvanced 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

Cg . The involvement of FGF pathways in multiple mechanisms relevant to prostate tumorigenesis provides

a rationale for the therapeutic blockade of this pathway, and two small-molecule tyrosine kinase inhibi-

tors—dovitinib and nintedanib—are currently in phase II 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. Clin Cancer Res; 19(21); 5856–66. �2013 AACR.

IntroductionProstate cancer is the most commonly diagnosed malig-

nancy in males and the second most deadly, with approx-imately 241,740 new cases and 28,170 deaths reported inthe United States in 2012 (1). Althoughmost cases detectedearly using prostate-specific antigen screening are curablewith local therapies, metastatic disease remains incurable.Metastatic disease is initially treated very effectively withandrogen deprivation therapy but most patients will even-tually develop castrate resistance, defined as disease pro-gression that occurs despite serum levels of testosterone <50ng/dL. Patients with metastatic castrate-resistant prostatecancer (mCRPC) carry a poor prognosis, with a medianoverall survival of approximately 14 months (2).

Although docetaxel chemotherapy remains a standardtreatment option for mCRPC, several new agents haverecently been approved. Sipuleucel-T, a cancer vaccine, isindicated for asymptomatic or minimally symptomaticmCRPC. Abiraterone acetate and enzalutamide inhibitintracrine androgen receptor signaling associated with cas-trate resistance. Both are indicated after docetaxel therapy,and abiraterone is now available for chemotherapy-naivepatients. Cabazitaxel, a taxane analog, is approved afterdocetaxel failure. Although these agents have each positive-

ly affected survival, mCRPC remains incurable and newtherapies are needed (3).

Research efforts elucidating signaling pathways and cel-lular processes involved in prostate cancer progression haveproducedmany therapies currently in clinical development,including immunomodulators, inhibitors of intracrineandrogen receptor signaling, and small-molecule inhibitorsof oncogenic pathways (4). One such pathway is the fibro-blast growth factor (FGF) axis that is required for normalprostate and skeletal development but becomes aberrantlyactivated in prostate cancer (5, 6). This review discusses therole of FGF signaling in prostate cancer and the potential forFGF inhibition as a rational therapy strategy in advanceddisease.

FGF Signaling PathwaysFGF pathway components are ubiquitously expressed

and play important roles in diverse biologic processesincluding embryonic and organ development, wound heal-ing, and carcinogenesis. The FGF axis and its downstreampathways regulate many mechanisms including mitogen-esis, differentiation, angiogenesis, survival, and motility/invasiveness (5, 6). FGF ligands comprise a gene familyconsisting of 22 structurally related proteins that are furtherdivided into seven subfamilies based on sequence homol-ogy: FGF1-2, FGF4-6, FGF3/7/10/22, FGF8/17/18, FGF9/16/20, FGF11-14, and FGF19/21/23 (6). FGF11–14 ligandsdo not function as ligands, and FGF 19/21/23 ligands areendocrine messengers. The remaining FGFs signal throughautocrine or paracrinemechanisms by activating FGF recep-tors (FGFR) in partnership with heparan sulfate proteogly-cans (HSP; refs. 7, 8). The FGFR is a single glycosylatedpolypeptide chain that has an extracellular ligand–bindingdomain, a transmembrane domain, and an intracellular

Authors' Affiliations: 1The University of Texas MD Anderson CancerCenter; and 2Institute of Biosciences and Technology, Texas A&M HealthScience Center, Houston, Texas

Corresponding Author: Paul G. Corn, Department of Genitourinary Med-ical Oncology, The University of Texas MD Anderson Cancer Center, Box1374, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-563-7204; Fax: 713-563-0099; E-mail: [email protected]

doi: 10.1158/1078-0432.CCR-13-1550

�2013 American Association for Cancer Research.

ClinicalCancer

Research

Clin Cancer Res; 19(21) November 1, 20135856

tyrosine kinase domain. There are four recognized FGFRs(FGFR1, -2, -3, and -4) that function as receptor tyrosinekinases. Four highly conserved genes encode an extensiverepertoire of alternatively spliced variants of FGFR that varyin both the extracellular ligand-binding and the intracellu-lar kinase domains (8, 9). The extracellular domain com-prises three immunoglobulin-likemotifs, the third ofwhichhas differing specificities for various FGF ligands (10).FGFR1, FGFR2, and FGFR3 encode two versions (IIIb andIIIc) of immunoglobulin-like domains in mutually exclu-sive exons. The IIIb and IIIc isoforms are mainly expressedin epithelial and mesenchymal tissues, respectively, andhave different ligand selectivities (11, 12). Despite thediversity of ligands, FGFR variants and oligosaccharidemotifs that make up the FGFR signaling complex, cell-specific expression of isoforms, and the combination of thethree individual components confer specificity on inter-compartmental signaling. Furthermore, the partitioning ofFGF ligand and FGFR isotypes, combined with the cell-typespecificity of HSP, creates directionally specific paracrinecommunication from one cell type or compartment toanother.A schematic of FGF/FGFR signaling is shown in Fig. 1.

Current models suggest a symmetric dimeric complex oftwo FGFs, two FGFRs, and two HSP chains. Activationtriggers autophosphorylation of FGFR followed by FGFRsubstrate 2 (FRS2) phosphorylation and recruitment of thedocking proteins FRS2 and phospholipase-Cg (PLCg ;

refs. 13, 14). FRS2 has two isoforms (FRS2a and FRS2b)that largely mediate FGFR signaling. FRS2a has multipletyrosine and serine/threonine phosphorylation sites thatare phosphorylated upon ligand-induced FGFR activation.These phosphorylation sites constitute binding sites forrecruitment and activation of additional adaptors and sig-nalingmolecules, such as Shp2 and growth factor receptor–bound 2, which link to intracellular networks, most com-monly the mitogen-activated protein kinase/extracellularsignal—regulated kinase (MAPK/ERK) and phosphoinosi-tide 3-kinase (PI3K)/AKT pathways (15, 16). ActivatedERK1/2 stimulates transcription factors such as the ETSfamily of proteins, leading to alterations in cellular geneexpression. Several other pathways are also activated byFGFRs, depending on the cellular context, including the p38MAPK and JunN-terminal kinase pathways, STAT signaling,and ribosomal protein S6 kinase 2. It should be noted,however, that other important growth factor ligand receptorpathways [e.g., interleukin (IL)-6, EGF, TGF-b] signalthrough molecular intermediaries (e.g., SOS, RAS) sharedwith FGF/FGFRactivation, so cell fate is ultimately complex.

The FGF/FGFR signaling cascade is regulated by a numberof positive and negative modulators (Fig. 1). Secreted FGF-binding protein (SFBP) can reversibly bind FGF1 and FGF2,releasing them from the extracellular matrix to stimulatesignaling (17). The Sprouty (Spry) protein family is afeedback regulator of the FGF pathway at the posttransla-tional level (18). Tyrosine phosphorylation of Sprys creates

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Figure 1. The FGF/FGFRsignaling pathway. FGF ligandbinding triggers formation of theFGF/FGFR/HSP complex,leading to autophosphorylationof the FGFR. Docking proteinssuch as FGFR substrate 2(FRS2a) and PLCg activatedownstream pathways,including RAS/RAF/MEK, PI3K/AKT/mTOR, and STAT. Thepathway can be positively(HSP, SFBP) or negatively (SEF,Sprouty, MKP3) regulated atmany different nodes.Intermediaries of FGF signalingare also activated by additionalcytokines and growth factors(e.g., IL-6, EGF, and TGFb).

Targeting FGF in Prostate Cancer

www.aacrjournals.org Clin Cancer Res; 19(21) November 1, 2013 5857

a decoy site that binds the docking molecule growth factorreceptor–bound 2 and prevents Son of Sevenless fromactivating the Ras/MAPK pathway or by directly binding toRAF and blocking subsequent MAPK signaling (19–21).Furthermore, similar expression to FGF (SEF) family mem-bers and MAPK phosphatase 3 (MKP3) are attenuators ofthe FGF-activated downstream MAPK pathway. Thus, FGF/FGFR signaling is regulated differently based on the specificFGF ligand, the FGFR splice variant expressed, and thepresence and activity of regulatory factors in a tissue- andcellular-specific context (22).

FGF Signaling in Human CancerAberrant activation of FGF/FGFR signaling is common

in many epithelial cancers including hepatocellular car-cinoma, melanoma, lung, breast, bladder, endometrial,head and neck, and prostate cancers (23). There aremultiple mechanisms for dysregulation that occur prin-cipally through alterations of FGFRs rather than FGFs(23). One mechanism is ligand-independent activationof FGFR via point mutations that promote dimerizationor enhance kinase activity. For example, a point mutationin FGFR3 has been detected in 50% to 60% of non–muscle-invasive urothelial carcinomas. A second mecha-nism is FGFR gene amplification and overexpression,which result in excessive signaling. For example, ampli-fication of chromosomal region 8p11–12, which encom-passes FGFR1, is present in approximately 10% of breastcarcinomas (23). A third mechanism involves an alter-natively spliced FGFR variant with altered ligand selec-tivity that triggers inappropriate signaling activation (24).In contrast, mutations in FGF ligands seem to be rare inhuman cancers (23). Finally, FGF/FGFR–mediated onco-genesis may also be associated with a failure to attenuatesignaling resulting from loss-of-function of negative reg-ulators such as Spry (25).

FGF Signaling in Prostate CancerDevelopment and homeostasis of the normal prostate

gland depends on androgenic stimulation and epithelial–mesenchymal interactions (26, 27). Mesenchymal tissuessecrete paracrine factors that stimulate epithelial mainte-nance andgrowth, and FGF ligands are keymessengers (26).FGF10 is expressed in the mesenchyme and is requiredfor prostate growth and development, as evidenced bydevelopmental defects in prostate precursor buds in anFGF10-knockout mouse (28). Studies have also identifiedbiologically relevant levels of FGF2, FGF7, and FGF9 innormal prostate mesenchyme (fibroblasts and/or endothe-lial cells), whereas FGFRs with specificity for these ligandsare expressed in secretory prostatic epithelium (25). FGF10and FGF7 may be partially redundant, as evidenced bythe development of a viable male reproductive system inan FGF7-knockout mouse (29). FGFR2 was shown to berequired for prostate organogenesis and the acquisition ofandrogen dependency for tissue homeostasis using a con-ditional knockoutmouse (30). Thus, FGF/FGFR signaling is

necessary for development and homeostasis of the normalprostate gland.

Aberrant FGF signaling has been implicated in prostatecancer development and progression (31–34).With respectto early prostate cancer, multiple studies have showninvolvement of dysregulated FGF/FGFR signaling in alldevelopmental stages of prostatic intraepithelial neoplasia(PIN)—carcinoma in situ of the prostate characterized byinitial cell proliferation and anaplasia—followed by inva-sive carcinoma, angiogenesis, and metastasis. For example,forced expression of constitutively active mutant of FGFR1leads to development of high-grade PIN lesions (35). Per-turbations of FGF/FGFR pathway signaling also contributeto the development of PIN and prostate cancer throughmechanisms that mimic the developmental program (36).

Clear recent evidence that paracrine activation of FGFR inprostate epithelial cells leads to PIN or prostate cancer wasprovided using a tissue recombination prostate regenera-tion system (ref. 37; Fig. 2). In thismodel, adult-dissociatednormal mouse prostate epithelial cells (mNPE) are com-bined with embryonic urogenital sinus mesenchyme(UGSM) and grafted under the kidney capsule of a severecombined immunodeficient (SCID)mouse, resulting in theformation of prostate gland–like structures. This modelallows for genetic manipulation of the epithelial andmesynchymal compartments independently to study effectsof paracrine factors on adult prostate epithelial cells. In thissystem, mesenchymal expression of FGF10 leads to FGFR1-dependent PIN or prostate cancer development andenhanced androgen receptor expression in the neoplasticepithelium (Fig. 2). Inhibitionof epithelial FGFR1 signalingusing a dominant-negative FGFR1 led to reversal of thecancer phenotype.

In addition, altered expression of FGFR1, but not ofFGFR2, has been shown to induce PIN in the juxtapositionof chemical inducers of dimerization (CID) and kinase(JOCK)-1 and -2 transgenic mouse models, respectively(ref. 38; Fig. 3A). JOCK-1 mice subsequently develop inva-sive prostate carcinoma and metastasis. Furthermore, con-ditional deletion of FRS2a in the mouse prostate inhibitedthe initiation and progression of prostate cancer induced byoncogenic viral proteins (ref. 39; Fig. 3B). Conditionalinactivation of FGFR1 also impairs development of PIN,prostate cancer progression, and metastasis in the TRAMPmodel (40). Together, these reports suggest that activationof FGFR1 signaling is sufficient to induce prostate cancerdevelopment and progression in mouse models of prostatecancer.

It has also been shown that increased production of FGFligands by prostatic secretory epithelial cells induces auto-crine signaling and independence from stromal regulation,stimulating aberrant epithelial growth, and cellular dyspla-sia (26, 27). For example, FGF8 and its cognate receptorsFGFR1IIIc and FGFR2IIIc are overexpressed in human sam-ples of PIN and prostate cancer compared with controls(41). Also, the FGF9/FGFR3 axis has been reported to signalfrom neoplastic epithelium to mesenchyme in DunningR3327 rat prostate cancer models (42).

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Clin Cancer Res; 19(21) November 1, 2013 Clinical Cancer Research5858

With respect to later stages of prostate cancer progres-sion, multiple studies have shown involvement ofaberrant FGF/FGFR signaling in driving epithelial–mes-enchymal transition (EMT). EMT is a process wherebypolarized epithelial cells lose epithelial characteristicsand acquire mesenchymal features, including enhancedmigratory capacity, invasiveness and elevated resistanceto apoptosis (43). EMTs normally occur during embry-onic development and wound healing/tissue regenera-tion, but the mechanism is co-opted during the acqui-sition of malignancy. In JOCK-1 mice, inducible ectopicFGFR1 induced the formation of tumors that possessedmesenchymal-like cells with residual epithelial hallmarksthat were presumed to be remnants of EMT (38). Also ofnote, shifts in alternative splicing of FGFR1 and FGFR2from IIIb (epithelial) to IIIc (mesenchymal) isoforms are

associated with EMT in prostate and other types of cancer(24).

In support of the aforementioned data, upregulation ofFGF family members in primary prostate cancer is positivelyassociatedwith higher grades of cancer and clinical stage (44,45). FGFs have been shown to be overexpressed predomi-nantly in epithelial cells (FGF1, FGF6, FGF8, FGF17), stromalfibroblasts (FGF2), or both (FGF7), supporting the existenceof autocrine/paracrine growth-promoting effects (25). Fur-thermore, FGF8 is expressed at low levels in normal prostate,but its overexpression in prostate cancer (46–48) is associ-atedwithdecreasedpatient survival (45).Mechanistic studieshave established links between some ligands and prostatecancer. For example, attenuating FGF2 activity inhibits cellproliferation,migration, and invasion in cell culture (49, 50),whereas FGF2 knockout in a transgenic mouse model of

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Figure 2. Mesenchymalexpression of FGF10 leadsto the formation of FGFR1-dependent PIN or prostatecancer in a tissuerecombination prostateregeneration system. WhenmNPEs are mixed withembryonic UGSM and graftedunder the kidney capsule ofmice, epithelial glandsresembling the mouse prostateare formed. When mNPEsare mixed with UGSM-overexpressing FGF10, well-differentiated prostatecarcinoma develops and thesecancer cells express higherandrogen receptor levels thanthat observed in normalprostate-like glands. Inhibitionof epithelial FGFR1 signalingusing dominant-negativeFGFR1 leads to reversal of thecancer phenotype.



prostate adenocarcinoma inhibited tumor progression (51).In addition, exogenous FGF1 induces expression of matrixmetalloproteinases, which are suggested to play a role intumor metastasis, in prostate cancer LNCaP cells (52).

Dysregulated expression of FGFRs has also been associ-ated with prostate cancer. Overexpression of FGFR1 hasbeen found in prostate tumors (53). In addition, ectopicexpression of FGFR1 accelerated tumorigenicity of rat

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Figure 3. Activation of FGFR axis mediates prostate cancer development and progression. A, inducible FGFR1 (iFGFR1) prostate mouse model [named thejuxtaposition ofCID and kinase1 (JOCK1)]. Activation of iFGFR1withCID led toPIN, invasive prostate cancer, andmetastases. B, transgenic adenocarcinomaof the mouse prostate (TRAMP; established by expressing of SV40 T antigen in the mouse prostate) develop poorly differentiated prostate carcinomas at 24weeks of age. Conditional deletion of FRS2a in the mouse prostate inhibited the initiation and progression of prostate cancer in the TRAMP model.

Corn et al.


premalignant prostate epithelial cells (33). In contrast,FGFR2 seems to have the opposite effect, whereby its down-regulation is associated with neoplastic progression(33, 54). Furthermore, reduced levels of "similar expressionto FGF"—an FGF pathway inhibitor—is correlated withhigher grades of cancer (44), showing that oncogenicdysregulation of the FGF axis can occur via multiplemechanisms.

Rationale for FGF Inhibition in Prostate CancerFGF/FGFR signaling is intimately involved in promoting

angiogenesis, involving potential cross-talk with platelet-derived growth factor (PDGF) and VEGF pathways. In thenormal prostate, FGF2 is a known regulator of angiogenesis(55), and a correlation between FGF8 and VEGF expressionexists in prostate cancer (56). In addition, conditionalFGFR1 expression via the JOCK-1 model induced angio-genesis through upregulation of hypoxia inducible factor1a, VEGF, and angiogenin-2 and downregulation of angio-genin-1 (57). Osteoblasts can also promote angiogenesisthroughDJ-1—a soluble factor that induces angiogenesis inendothelial cells via activation of FGFR1 (58). The FGFpathway is also known to function as a resistance mecha-nism for antiangiogenic therapy in preclinical models forother tumor types (59). These data highlight FGF/FGFRsignaling as a driver of angiogenesis in prostate cancer andprovide a rationale for dual FGF/VEGFR inhibition astherapy (59).FGFs also have a role in the development of bone metas-

tases, which occur in approximately 80% of patients withadvanced prostate cancer (60). These metastases oftenabnormally express FGF8 and/or FGF9, which promoteosteoblast proliferation/differentiation in culture (61,62). It has also been shown that exogenous expression ofFGF8 forms bone lesions and spurs the growth of intratibialtumors in a model simulating bone metastasis of prostatecancer (63) and that FGF9 mediates the osteoblastic pro-gression of human prostate cancer cells in the bone of mice(61). Additional cross-talk between bone stroma and pros-tate cancer cells mediated by hedgehog and bone morpho-genic protein signaling may promote cancer survivalthrough upregulation of FGF2 (64). A model of the prin-cipal FGFs and FGRs involved inprostate cancer progressionis shown in Fig. 4A. Therefore, inhibiting the FGF pathwaycould reduce the propensity of prostate tumors to metas-tasize and/or survive in bone.Finally, the development of castrate resistance is associ-

ated with intracrine androgen receptor signaling and datafrom preclinical models, primary tumors, and metastatictumors suggest that FGF and androgen receptor signalingare tightly intertwined (26). For example, de novo expressionof androgen receptor in PC3 prostate cancer cells mayupregulate FGF signaling by increasing the use of FGF2(65). FGF7 and FGF8, which are normally induced byandrogens, are both expressed in primary castrate resistancetumors (45, 66), and the inhibition of FGF8 and FGF9signaling has an antitumor effect in castrate-resistantmouse

models (61, 67). Furthermore, the bone marrow microen-vironment supports the development of castrate-resistantgrowth (61, 68), and bone biopsies from patients withmCRPC overexpress FGF9more frequently than do primarytumors (56). FGF has also been linked to chemoresistanceto multiple classes of agents including taxanes (69, 70).Because castrate-resistant tumors are frequently treatedwithtaxane-based chemotherapy, a rationale exists to combineFGF inhibitors and chemotherapy in patients withmCRPCs. Taken together, these results suggest that targetingthe FGF pathway could have a clinical impact on CRPC inprimary prostate tumors and metastatic disease (Fig. 4B).

FGF Pathway Inhibition in Prostate CancerA number of targeted agents that inhibit FGF/FGFR

signaling now exist (Table 1). These agents include FGFRtyrosine kinase inhibitors (TKIs), monoclonal antibodies,and an FGF ligand trap. A potential advantage of TKIs with abroader spectrumof inhibition is their ability to target FGFRsimultaneously with other angiogenic receptor tyrosinekinases such as VEGFR and PDGFR. TKIs that target FGFRsalong with other kinases include dovitinib, nintedanib(BIBF 1120),masitinib, lenvatinib, brivanib, orantinib, andPD173074 (5, 71). The first six agents are in phase IIIdevelopment for non-prostate tumors including gastroin-testinal stromal tumors, multiple myeloma, melanoma,renal cell carcinoma, hepatocellular carcinoma, and pan-creatic, thyroid, and ovarian cancers (Table 1). Importantly,dovitinib and nintedanib are also being investigated inmCRPC.

Dovitinib is a small-molecule TKI that targets multiplekinases including FGFR1, FGFR3, VEGFR1-3, PDGFRb, fms-related tyrosine kinase-3, and c-KIT. Preclinical studies haveshown upregulation of the tumor suppressor proteins p21and p27 after dovitinib treatment in cell culture models ofprostate cancer (72). On the basis of findings in an andro-gen receptor–negative prostate cancer xenograft model thatsuggested a role for FGF/FGFR in osteoblastic progression ofCRPCs in bone (61), a phase II trial of dovitinib in patientswith bone mCRPCs is currently underway (ClinicalTrials.gov: NCT00831792). Of 23 patients evaluable for response(>1 cycle on therapy), 6 of 23 (26%) experienced improve-ments on bone scan [1 complete response and 3 partialresponses (PR)] or in soft tissue metastases (2 PRs) at 8weeks, with a median treatment duration of 19.9 weeks(range, 10–35 weeks). Thirteen of 23 (57%) patients expe-rienced stable disease at 8 weeks, with a median treatmentduration of 11.7 weeks (range, 6–31 weeks), and 4 of 23(17%) experienced disease progression. Toxicities weremostly grade 1 or II. Grade 3 toxicities included fatigue,rash, and generalized weakness (each found in <5% of thepatients) and there were no grade 4 toxicities (73).

Nintedanib (BIBF 1120)—a TKI that inhibits FGFR1-3,VEGFR1-3, PDGFRa and -b, Src, Lck, and Lyn—has shownpreliminary activity in a phase II study in patients withmCRPCs, yielding a PR rate of 4.3% and a stable disease rateof 30.4% (74). In a phase I trial, a combination of



nintedanib, docetaxel, and prednisone produced a �50%reduction frombaseline in prostate-specific antigen levels in68.4% of 19 evaluable patients and a PR in 1 of 6 patientswith measurable lesions (75).

The observation that some TKIs have dose-limiting "offtarget" toxicities has spurred the development of moreselective pan-FGFR inhibitors. AZD4547, AZD8010, andBGJ398 potently inhibit FGFR1-3, whereas AZD8010 alsoinhibits FGFR4, albeit to a lesser degree (76–78). AZD4547is undergoing investigation in a phase I trial of advanced

solid malignancies (NCT00979134). BGJ398 is being eval-uated in a phase I trial in patients with advanced solidtumors harboring amplified FGFR1 or FGFR2 genes ormutated FGFR3 (78). AZD8010 is still in preclinicaldevelopment.

FGF signaling may also be more specifically abrogatedby blocking ligand receptor binding using monoclonalantibodies or a ligand trap. Three monoclonal antibodiesthat block FGF signaling are currently in develop-ment: MFGR1877S, GP369, and 1A6. MFGR1877S is a

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Figure 4. A, a model of prostatecancer–stroma interactionsmediated by FGFR and ligands.FGFR1 is expressed byprostate cancer cells,osteoblasts, and endothelialcells. FGF2 is produced byprostate cancer cells andinduces osteogenesis, boneremodeling, and angiogenesis.Angiogenesis in turn favorsprostate cancer progression.Prostate mesenchymal cellproduction of FGF2/FGF10activates FGFR1 in prostatecancer cells leading to cancerprogression. FGF8/FGF9 isproduced by prostate cancercells during growth in bone(bone metastases) and inducesosteogenesis and boneremodeling. Activatedosteoblasts induceangiogenesis. B, inhibition ofthe FGF pathway can affecttumor progression by targetingmultiple biologic pathways.

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Table 1. FGF pathway inhibitors

Agent Company Target(s) Clinical development

Small-moleculemultikinase inhibitorsDovitinib (TKI258) Novartis FGFR1–3, VEGFR1–3,

PDGFRb, FLT-3, c-KITOngoing phase II trial in patients with

CRPC with bone metastases(NCT00831792)

Phase III investigation in metastaticrenal cell carcinoma (NCT01223027)

Nintedanib (BIBF1120) Boehringer-Ingelheim FGFR1–3, VEGFR1–3, PDGFRaand -b, Src, Lck, Lyn

Completed phase II trial inhormone-refractory prostatecancer (NCT00706628)

Phase III investigation in NSCLC(NCT00806819, NCT00805194) andovarian cancer (NCT01015118)

Masitinib AB Science FGFR3, PDGFR, c-KIT No ongoing trials specifically in CRPCPhase III investigation in GIST

(NCT00812240, NCT01694277),pancreatic cancer (NCT00789633),multiple myeloma (NCT01470131), andmetastatic melanoma (NCT01280565)

Lenvatinib (E7080) Eisai FGFR1, VEGF1–3, PDGFRaand -b, c-KIT

No investigation specifically in CRPC

Phase III investigation in thyroid cancer(NCT01321554)

Brivanib Bristol-Myers Squibb FGFR1, VEGFR2 No ongoing trials specifically in CRPCPhase III investigation in liver cancer

(NCT00825955) and HCC(NCT00908752, NCT01108705,NCT00858871)

Orantinib (TSU-68) Taiho Pharmaceuticals FGFR1, VEGFR2,PDGFRb, KDR

No ongoing trials specifically in CRPC

Phase III investigation in HCC(NCT01465464)

PD173074 None FGFR1, VEGFR2 Preclinical investigation

Small-molecule TKIsselective for FGF pathwayAZD4547 AstraZeneca FGFR1–3 No ongoing trials specifically in CRPC

Phase II investigation in breast cancer(NCT01202591) and gastric cancer(NCT01457846)

AZD8010 AstraZeneca FGFR1–4 Preclinical investigationBGJ398 Novartis FGFR1–3 Phase I trial in advanced solid

tumors with FGFR amplificationsor mutations (NCT01004224)

Monoclonal antibodiesGP369 AVEO Pharmaceuticals FGFR2-IIIb isoform Preclinical investigationMFGR1877S (R3Mab) Roche/Genentech FGFR3 Phase I trial in advanced solid

tumors (NCT01363024)1A6 Roche/Genentech FGF-19 ligand Preclinical investigation

Ligand trapHGS1036 (FP-1039) GlaxoSmithKline, Human

Genome Sciences,Five Prime Therapeutics

FGF ligands that have affinityfor the FGFR1-IIIc isoform

Phase I trials in advanced solidtumors (NCT00687505, NCT01604863)

NOTE: Mechanism of action and clinical development stage of agents targeting the FGF pathway. Trials were identified from http://www.clinicaltrials.gov.Abbreviations: FLT-3, fms-related tyrosine kinase-3; GIST, gastrointestinal stromal tumor; KDR, kinase insert domain receptor;NSCLC, non–small cell lung cancer.



monoclonal antibody against FGFR3 (79) that is currentlyundergoing phase I testing for patients with advanced solidtumors, including those with CRPCs (NCT01363024).Both GP369 and 1A6 are currently in preclinical develop-ment (80, 81). GP369 specifically blocks the IIIb splicevariant of FGFR2, and 1A6 targets the ligand FGF19.HGS1036 (FP-1039) is a construct comprising the extracel-lular domain of FGFR1c fused with the Fc portion of IgG1and is expected to be a decoy for FGF ligands having affinityfor FGFR1c. A phase I study of HGS1036 in patients withmetastatic or locally advanced unresectable solid tumorshas been completed. A preliminary report documented apatient with prostate cancer who had tumor shrinkage (82),and final results are anticipated shortly. These agents havethe potential to clinically affect mCRPCs, and further inves-tigation is expected.

Conclusions and Future DirectionsAn enlarging body of evidence supports a role for FGF/

FGFR signaling in prostate cancer. Dysregulated signalingis associated with the development of PIN, EMT, andangiogenesis—critical biologic processes involved in can-cer progression and metastasis. FGF/FGFR signalingbetween bone stroma and prostate cancer cells also pro-motes the formation of bone metastases and the emer-gence of castrate-resistant disease. Evidence from preclin-ical and clinical studies suggest that inhibitors of FGF/FGFR signaling warrant further investigation as a rationaltherapeutic strategy for the treatment of patients withadvanced prostate cancer.

Disclosure of Potential Conflicts of InterestP.G.Cornhas served on aNovartis-sponsored advisory board for dovitnib

but did not receive any financial compensation. N. Navone has received aresearch grant fromAstraZeneca to study AZD4547. No potential conflicts ofinterest were disclosed by the other authors.

Authors' ContributionsConception and design: F. Wang, W.L. McKeehen, N. NavoneDevelopment of methodology: W.L. McKeehenAcquisitionofdata (provided animals, acquired andmanagedpatients,provided facilities, etc.): W.L. McKeehenAnalysis and interpretation of data (e.g., statistical analysis, biosta-tistics, computational analysis): W.L. McKeehenWriting, review, and/or revision of the manuscript: P.G. Corn, F. Wang,W.L. McKeehen, N. Navone

AcknowledgmentsThe authors acknowledge medical editorial assistance from Melanie

Vishnu.

Grant SupportMedical editorial assistance was funded byNovartis Pharmaceuticals. The

authors are supportedbyNIHgrantsCA096824 (to F.Wang) and theProstatecancer SPORE grant 5P50CA140388 (toN.Navone, P.G. Corn, F.Wang, andW.L. McKeehen); by the Prostate Cancer Foundation (to N. Navone and P.G.Corn); by the Cancer Prevention&Research Institute of Texas grant RP11055(to N. Navone, F. Wang, and W. McKeehen); and by the David H. KochCenter for Applied Research in Genitourinary Cancers at The University ofTexas MDAnderson Cancer Center (to N. Navone and P.G. Corn), Houston,TX.

The costs of publication of this article were defrayed in part by thepayment of page charges. This article must therefore be hereby markedadvertisement in accordance with 18 U.S.C. Section 1734 solely to indicatethis fact.

Received June 5, 2013; revised August 2, 2013; accepted August 10, 2013;published OnlineFirst September 19, 2013.

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targeting fibroblast growth factor pathways in prostate cancerprostate cancer is the most commonly...

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