Beyond VEGF: Inhibition of the Fibroblast Growth Factor Pathway and ...

Clinical Cancer Research

Review

Beyond VEGF: Inhibition of the Fibroblast Growth Factor Pathway and Antiangiogenesis Christopher Lieu1, John Heymach2, Michael Overman1, Hai Tran2, and Scott Kopetz1

Abstract Fibroblast growth factor (FGF) signaling regulates cell proliferation, differentiation, survival, angiogenesis, 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 structurally related family of 22 molecules that interact with highaffinity tyrosine kinase FGF receptors (FGFR) to regulate multiple fundamental pathways and cellular behaviors (1). FGF signaling regulates events in embryonal development, including mesenchymal–epithelial signaling and the development of multiple organ systems (2, 3). FGF signaling also regulates cell proliferation, differentiation, and survival, as well as angiogenesis and wound healing (4). In some situations, FGFs can act as a negative regulator of proliferation and positive regulator of differentiation (5). Given the role of FGF in multiple cellular processes, compelling evidence for deregulated FGF signaling in tumorigenesis continues to emerge (6). Studies with animal models have suggested that aberrant FGF signaling can promote tumor development through increased cell proliferation and survival, as well as increased tumor angiogenesis (7, 8). This body of research indicates that FGF signaling is an important pathway in tumorigenesis and tumor angiogenesis and that appropriate targeting of the FGFR tyrosine kinases may be an effective therapeutic intervention for cancer. This review describes the FGF family of growth factors and their associated receptors, as well as their association with tumor development, growth, and metastasis. We also describe the effect of FGFs on tumor angiogenesis, including key preclinical and clinical evidence about the role of

Authors' Affiliations: Departments of 1Gastrointestinal Medical Oncology and 2Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas Corresponding Author: Scott Kopetz, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 0426, Houston, TX 77030. Phone: 713792-2828; Fax: 713-563-6764; E-mail: [email protected] doi: 10.1158/1078-0432.CCR-11-0659 2011 American Association for Cancer Research.

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FGFs in the development of resistance to anti-VEGF therapy. Finally, FGF as a potential therapeutic target is reviewed, including the current state of drug development in this field.

Fibroblast Growth Factor Family FGFs were first isolated as mitogens from pituitary extracts and bovine brain tissue in the 1970s (9, 10). Since initial discovery, 22 members of the FGF family have been identified, all of which are structurally related signaling molecules ranging from 17 to 34 kDa in size (11). Some FGFs seem to be expressed exclusively during embryonic development (FGF-3, 4, 8, 15, 17, and 19), and others are expressed 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 28 highly 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 from cells by mechanisms that remain unclear. FGF-1 and FGF-2 may be released from damaged cells or by exocytosis that is independent of the endoplasmic reticulum–Golgi pathway (13). FGFs have strong affinities for the glycosaminoglycan side chains of cell surface proteoglycans, which help to sequester FGFs on the surface of the secreting cell or on nearby cells, and in the binding of FGF to the FGFR. FGFRs are transmembrane tyrosine kinases that contain 2 or 3 extracellular immunoglobulin-like domains and an extracellular heparin-binding sequence (14–16). The 2 proximal immunoglobulin-like extracellular domains bind the FGF ligand, whereas the heparin-binding sequence binds a glycosaminoglycan moiety, resulting in the formation of a complex containing 2 FGFs, 2 FGFRs, and the glycosaminoglycan moiety (17). Only 4 FGFRs are known to exist, designated FGFR-1 through FGFR-4 (Table 1). Their specificity for various ligands is altered by processes that create multiple isoforms. Alternative mRNA splicing of

Inhibition of the FGF Pathway and Antiangiogenic Therapy

Translational Relevance

Fibroblast Growth Factor and Tumor Growth

Angiogenic inhibitors have shown promise in the treatment of multiple tumor types and have improved outcomes in patients with metastatic disease. However, many patients will not respond to antiangiogenic therapy, and for those that do, resistance develops quickly. Fibroblast growth factor (FGF) seems to play an integral role in the resistance to antiangiogenic therapy, and agents that specifically target the FGF pathway are being developed and tested in clinical trials. It is critical that investigators review the existing literature on FGF and tumor angiogenesis to understand the importance of this target in various malignancies, as well as to design rational clinical trials that can expedite a potentially meaningful therapy in patients previously treated with antiangiogenic agents.

Aberrant FGF and/or FGFR signaling has a wide range of effects and can involve both tumor cells and the surrounding stroma. These effects include cellular proliferation; resistance to cell death; increased motility and invasiveness; increased angiogenesis; enhanced metastasis; and resistance to chemotherapy (27). Deregulation of FGF signaling in tumorigenesis can result from activating mutations, FGFR gene amplifications, and chromosomal translocations, which lead to increased autocrine and paracrine signaling (28–30). Because aberrant signaling can promote tumorigenesis by affecting major downstream biologic processes, FGFs have been implicated in multiple tumor types, including prostate, astrocytoma, breast, lung, bladder, hepatocellular, and colon cancers (31–41). Alternative splicing of the FGFR gene has also been implicated in carcinogenesis. Carcinomas have been observed to switch expression of FGFR to the mesenchymal isoforms, enabling cells to receive signals usually restricted to the connective tissue, such as ectopic expression of typically stroma-localized FGFR1-IIIc (42, 43). The IIIc splice variant has been detected in colon carcinoma but not in adenoma-derived cell lines, suggesting that it is upregulated during tumor progression (44). During prostate cancer progression, alternative splicing of FGFR2 can occur in epithelial cells, leading to isoform changes from FGFR2-IIIb into the more ligand-promiscuous FGFR2-IIIc (Fig. 1; refs. 8, 43). Thus, this aberrant alternative splicing of FGFR potentially destroys the balanced interdependence between stroma and epithelium (8, 43, 45). Clinical studies of FGF have suggested a critical role of FGF signaling in clinical tumor progression. In 1 study of advanced serous ovarian adenocarcinomas, FGF-1 mRNA copy number was found to be significantly correlated with DNA copy number and protein expression levels (46). Both FGF-1 mRNA and protein levels were associated with worse overall survival, possibly secondary to an increase in tumor angiogenesis and autocrine stimulation of cancer cells. In another study of 100 resected colorectal cancer surgical specimens, high FGF-2 expression was associated with increased grade, stage, lymphovascular invasion, and intratumoral microvessel density (47). Significantly elevated levels of FGF-2 in circulation were found in a small cohort of patients with metastatic colorectal cancer, relative to median levels in control subjects (48). In other studies, although increased levels of FGF-2 were found in plasma from patients with different types of cancer, it was unclear whether the higher levels resulted from tumor invasion and degradation of the extracellular matrix (ECM), liberating FGF to function as a paracrine growth factor, or whether tumor cells induced FGF2 release from stromal inflammatory infiltrate (49, 50). Loss of expression of NCAM has also been implicated in the progression of tumor metastasis. NCAM has been shown to modulate neurite outgrowth and matrix adhesion of b cells from the Rip1-Tag2 transgenic mouse model of pancreatic neuroendocrine tumors by assembling a FGFR-4

the FGFR gene significantly alters the ligand specificity by changing the sequence of the carboxy-terminal half of immunoglobulin-domain III. This sequence change results in 2 isoforms termed IIIb and IIIc (18, 19). In general, IIIb isoforms are expressed on epithelial cells, and IIIc isoforms are expressed on mesenchymal cells, where they mediate tissue interactions in normal development and wound healing (20–22). FGF signaling can also be modulated by several membrane proteins, including cell adhesion molecules of the cadherin and immunoglobulin superfamilies (23). The best characterized of these is neural cell adhesion molecule (NCAM). NCAM has been shown to be a major regulator of FGF-FGFR interaction in several cell types, including nonneural tissues (24). NCAM has been shown to act as a nonconventional ligand that can induce a specific FGFR1mediated cellular migration that is different from the response elicited by FGF-2 (25). Furthermore, NCAM expression has been shown to reduce FGF-stimulated extracellular signal regulated kinase (ERK)1/2 activation, cell proliferation, and cell-matrix adhesion in fibroblast cell lines, suggesting that NCAM acts as a novel control mechanism for FGFR signaling (26).

Table 1. Receptors for the FGFR family Receptor

Specific For

FGFR-1b FGFR-1c FGFR-2b FGFR-2c FGFR-3b FGFR-3c FGFR-4

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

Adapted from Itoh and Ornitz (1).

www.aacrjournals.org


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Normal

Stroma

ECM

Stroma

Epithelium FGFR lllb

Cancer ECM

FGFR lllc

lllc

Epithelium FGFR lllc

PDGF

FGF

FGF FGF-BP

FGF

FGF

VEGF Ang2 Blood vessel

FGFR lllc

Blood vessel

FGFR lllc

NRP1 PDGFR

© 2011 American Association for Cancer Research

Figure 1. Changes in FGF and FGFR in the microenvironment and epithelium in normal tissue and cancer. Compared with normal tissue, alternative splicing of the FGFR gene can switch expression of FGFR from the IIIb isoform to the ligand promiscuous IIIc isoforms. Furthermore, release of FGF from the tumor 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.

signaling complex that leads to the modulation of b1integrin–mediated cell-matrix adhesion (51). Ablation of the expression of NCAM in this mouse model resulted in the disruption of the tumor tissue architecture, tumorassociated lymphangiogenesis, and lymph node metastasis (51, 52). Though a full review of FGF signaling and tumor growth is beyond the scope of this article, please see the comprehensive review from Turner and Grose for additional information (41).

Fibroblast Growth Factors and Angiogenesis Angiogenesis, the formation of new blood vessels from the endothelium of the existing vasculature, plays a pivotal role in tumor growth, progression, and metastasis (53, 54). Along with embryogenesis, angiogenesis was one of the first areas where FGF signaling was shown to be important (55, 56). In particular, FGF-1 and FGF-2 were found to be important for new blood vessel growth at the site of an excision wound and have been shown to stimulate angiogenesis in various assays (57–59). FGF-2 is a very potent inducer of angiogenesis. In a preclinical model of microvascular endothelial cells grown on a 3-dimensional col-

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lagen gel, VEGF and FGF-2 were able to induce cells to invade the underlying matrix to form capillary-like tubules (60). Interestingly, FGF-2 was found to be twice as potent as VEGF in this model. The critical role of FGF in tumor angiogenesis was shown through the interference of FGF function with a recombinant adenovirus expressing soluble FGFR (AdsFGFR). AdsFGFR seemed to impair the maintenance of tumor angiogenesis, in contrast to inhibition of the VEGF pathway that predominantly affected the initiation of tumor angiogenesis (61). Injection of AdsFGFR in the Rip1-Tag2 murine model of pancreatic neuroendocrine tumor resulted in repression of tumor growth, with a significant decrease in tumor vessel density. FGFs exert their effects by modulating proliferation and migration of endothelial cells, production of proteases, and promotion of integrin and cadherin receptor expression (62). In particular, FGF-1 and FGF-2 directly affect tumor angiogenesis by promoting the cellular proliferation of endothelial cells. FGF-2 has been shown to induce revascularization in various experimental models in several species, 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 healing compared with normal control mice (58). FGFR-1 is most



commonly expressed on endothelial cells, although FGFR2 has been shown to be present under certain circumstances (50, 66). The presence of FGFR-3 and FGFR-4 has not been reported in the endothelium. FGFs can exert their angiogenic mechanism of action via paracrine signaling through their release by tumor and stromal cells, or through their mobilization from the ECM (50). FGF-1, in particular, may stimulate endothelial cell growth and the motility of endothelial cells through paracrine signaling, which results in increased proliferation, survival, and motility of endothelial cells (46). FGF-2 has been studied in xenograft models in which liposomemediated gene transfer was used to deliver episomal vectors containing antisense FGF-2 or FGFR-1 cDNAs into human melanomas grown in nude mice. In contrast to the stimulation seen during deregulated FGF signaling, tumors injected with these antisense constructs showed arrested tumor growth or reduced tumor density because of blocked intratumoral angiogenesis (67). There is also evidence that FGF-2 increases the expression of angiopoietin-2, a potent regulator of vascular branching and angiogenesis, as well as VEGF in cultured human and endothelial cells (68). FGFs may also exert their effects through autocrine signaling in endothelial cells, stimulating the proliferation of new capillary endothelial cells (66). This induces a proangiogenic state that creates an environment favorable for vascular growth. Evidence for this growth is seen in a particular subtype of Kaposi sarcoma (KS) in which FGF-2, produced by the KS cells, has been found to synergize with human immunodeficiency virus type 1 Tat protein to enhance endothelial cell growth and type IV collagenase expression (66, 69). These tumors were found to have increased aggressiveness and frequency compared with other forms of KS. Preclinical models of tumor angiogenesis have suggested that FGF–binding protein (FGF-BP) serves as an angiogenic switch molecule and can be rate limiting for tumor growth (70). FGF-2 is present in most tissues under normal physiologic conditions but is inactivated by being tightly bound to the ECM. FGF-BP binds to FGF-2 in a dose-dependent manner, which results in a marked reduction of the affinity of FGF-2 to heparin and release from the ECM (Fig. 1; refs. 71, 72). Exogenously administered FGF-BP has been shown to stimulate FGF-2–dependent growth of both adrenal carcinoma and prostate carcinoma cells. In addition, downregulation of FGF-BP expression has been shown to inhibit angiogenesis in squamous cell carcinoma xenografts (73).

Fibroblast Growth Factor–2 Cross-Talk with Angiogenic Factors VEGF plays an integral role in the development of new blood vessels in tumor formation, and angiogenesis inhibitors targeting the VEGF pathway have proved to be efficacious in preclinical cancer models and in clinical trials (74, 75). A significant amount of cross-talk is thought to exist between members of the VEGF family and FGF-2 during angiogenesis, with VEGF appearing earlier during angiogen-


esis than does FGF (50). In 1 study, the angiogenic response occurred more quickly when VEGF and FGF-2 were added simultaneously to microvascular endothelial cells on 3dimensional collagen gels than the response to either cytokine alone, suggesting synergy between the 2 cytokines (60). It has also been shown that induction of FGF-2–induced angiogenesis is partly dependent on the activation of VEGF and the presence of endogenous VEGF and VEGF-C (76). Evidence for synergy between VEGF and FGF-2 has also been shown in xenograft models expressing FGF-2 and VEGF in tumor cell transfectants. Simultaneous expression of FGF-2 and VEGF resulted in fast-growing lesions with high blood vessel density and permeability (77). Interestingly, inhibition of FGF-2 production caused a significant decrease in tumor burden with a concomitant decrease in blood vessel density and size. This differed from the effects of VEGF inhibition, which caused a decrease in pericyte organization, vessel patency, and permeability. This finding suggests that FGF-2 and VEGF stimulate angiogenesis synergistically but with 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 to activate hypoxia-induced VEGF release through augmentation of the phosphoinositide 3-kinase pathway, as well as hypoxia-inducible factor-1a expression (78). FGF-2 has also been shown to indirectly enhance the effect of VEGF through upregulation of neurolipin-1 (NRP-1), a coreceptor for VEGF. FGF-2 increased NRP-1 levels and enhanced the migration of human vascular smooth muscle cells in response to VEGF. There is also evidence of cross-talk between FGF-2 and platelet-derived growth factor (PDGF)–BB. FGF-2 and PDGF-BB together have been shown to synergistically promote tumor angiogenesis and pulmonary metastasis, as well as formation of high-density primitive vascular plexuses coated with pericytes and vascular smooth muscle cells (79). Pericyte recruitment to coat nascent vessels during angiogenesis is essential for the stabilization and further establishment of a tumor’s vascular network. FGF-2 seems to upregulate PDGF receptor (PDGFR) expression, which causes increased responsiveness to PDGF-BB, and PDGF-BB–treated vascular smooth muscle cells become responsive to FGF-2 signaling through upregulation of FGFR-1. Interestingly, overexpression of PDGF-BB alone in tumor cells was shown to result in decreased recruitment of pericytes and dissociation of vascular smooth muscle cells. In tumor cells subjected to prior upregulation of FGF-2 caused by VEGF receptor 2 (VEGFR2) inhibition, PDGFR-b inhibition also attenuated the expression of FGF-2 (80). In a mouse model of cervical carcinogenesis, pharmacologic blockade of PDGFR signaling with imatinib slowed progression of premalignant cervical lesions and impaired the growth of preexisting invasive carcinomas through suppression of the expression of FGF-2 and FGF-7, which resulted in decreased proliferation and angiogenesis within the lesions (81). Treatment with an FGF trap also impaired the angiogenic phenotype similar to the blockade of the PDGFR with imatinib.


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Fibroblast Growth Factor Signaling and Resistance to Anti-VEGF Therapy Emerging evidence has suggested that upregulation of FGF and FGFR may serve as a mechanism of resistance to anti-VEGF therapy. Preclinical trials of anti-VEGF therapy in a murine pancreatic neuroendocrine tumor model (PNET), Rip1-Tag2, showed that tumors with an initial response to VEGFR2 blockade expressed higher levels of FGF-2 at the time of progression compared with stable tumors (82). When the tumors were first treated with a VEGFR inhibitor alone and subsequently treated at the peak of response with an FGF trap, the combination attenuated revascularization and slowed tumor growth (Fig. 2). The dual tyrosine kinase inhibitor (TKI) of VEGFR and FGFR, brivanib, has also been studied in this murine model and has proved to be efficacious following the failure of 2 VEGFR inhibitors (83). It was even more effective when used in the frontline setting, suggesting that dual inhibition of VEGFR and FGFR was able to delay induction of evasive resistance. Further evidence for the role of alternative angiogenic factors in tumor escape from angiogenesis inhibitors has been shown in tumors in which growth was impaired by ectopic expression of the endogenous angiogenesis inhibitors thrombospondin-1, tumstatin, and endostatin (84). In that study, renal carcinoma cells transfected with thrombospondin-1 resisted angiogenesis inhibition by upregulating the proangiogenic factors FGF-2, angiopoietin 2, and PDGF-A, despite high

baseline levels of VEGF. In 1 xenograft model of renal cell carcinoma, tumors unresponsive to sunitinib treatment were sensitive to a dual inhibitor of the VEGF and FGFRs (85). This inhibitor seemed to reduce blood vessel density through inhibition of FGF-2–induced angiogenesis. Clinical evidence in colon cancer also supports the role of FGF-2 in resistance to bevacizumab-containing regimens. To determine the dynamic changes in circulating factors during the emergence of therapeutic resistance, profiles of cytokines and angiogenic factors were assessed in 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 and FOLFIRI plus bevacizumab, at the time of progression, and at the nadir of radiographic response (86, 87). The investigators showed that FGF-2 levels were elevated immediately prior to progression compared with baseline levels. Strikingly, 30% of patients had an increase in FGF-2 to 10fold the upper limit of normal, suggesting significant heterogeneity in the FGF-2 response. In 1 study of neoadjuvant bevacizumab with 5-FU and radiation in rectal cancer, the administration of a short regimen of bevacizumab in combination with chemotherapy had no significant effect on plasma FGF-2 levels, suggesting that elevations in FGF-2 are instead a later event temporally associated with the development of resistance to the bevacizumab combination regimen (88). Elevated FGF-2 levels have also been shown in glioblastoma patients treated with a VEGFR small molecule

160 140

Tumor burden (mm3)

120 *

100 80 60 40 20 0 Control

Control

t=0

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Anti-R2

10 days

Anti-R2

Figure 2. VEGFR2 blockade transiently stops tumor growth and decreases vascularity, followed by tumor progression, reinduction of angiogenesis, and reestablishment of the tumor vasculature. Quantification of overall tumor burden plotted as average and SD per animal at the time of initiation of treatment (t ¼ 0; purple bar), after treatment for 10 days (orange bars), and at 4 weeks of age (teal and green bars) for the different treatment arms. Averages from cohorts of 8 to 10 mice per group are plotted with their respective SD bars. (Adapted from Cancer Cell, with permission from Elsevier; ref. 82.)

Anti-R2 FGF-trap

4 weeks



inhibitor (89). In patients who experienced tumor progression while receiving treatment, increased tumor enhancement volume was associated with significant increases in plasma levels of FGF-2 and stromal cell–derived factor-1. A statistically significant positive correlation was observed between FGF-2 levels and tumor vessel size measured by MRI. This work provided further clinical evidence that FGF2 may play a role in tumor relapse in patients treated with anti-VEGF agents (89). Unlike preclinical models, clinical studies investigating levels of FGF can only show an association of elevated FGF and/or FGFR with the resistance to anti-VEGF therapy; they cannot show causation or an actual resistance mechanism. Furthermore, because most studies are conducted in combination with cytotoxic chemotherapy, it is difficult to discern whether the patient and tumor have become resistant to the chemotherapy, the antiangiogenic therapy, or both. Therefore, high-quality preclinical models will be essential for further investigation to provide a sound preclinical rationale for future clinical studies.

Targeting Fibroblast Growth Factor Because FGFs have a clearly defined role in tumor angiogenesis, as well as a possible role in resistance to current VEGF inhibitors, several FGF pathway inhibitors are currently under development. The inhibitors entering the clinic are either TKIs or soluble antibody fragments that block ligand binding and receptor dimerization (Table 2). Most of the TKIs have dual specificity for FGFR and VEGFR, both as a matter of design and because of the structural similarities in their kinase domains. However, the inhibitors vary in their relative potency for VEGFR and FGFR, with many inhibitors having higher potency for VEGFR than FGFR (90, 91). Targeting both kinases may also increase the toxicity associated with these compounds, although biologically active doses have been shown with most of the compounds (41). The other class of compound in development, FGF ligand trap, has the potential to block the interaction of multiple FGF ligands with the soluble FGFR fragments. In 1 study, such an FGFR-1 antagonist was shown to prevent FGFR-1 ligands

from binding, and it had in vitro activity against lung and renal cell carcinoma (92). The safety of FGFR inhibitors currently under development seems acceptable. Preclinical toxicity studies with these agents have not shown a reproducible class effect, aside from hypertension, which is difficult to attribute to the VEGFR or FGFR inhibitory effects of many of the agents (93, 94). Monoclonal antibodies directed against FGFR1IIIc resulted in anorexia in mice and monkeys, which was caused 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 studies about phosphate and vitamin D metabolism have not been reflected in the reported toxicities in the early-phase studies (97). Although a separate development strategy is being pursued based on somatic mutation or amplification of FGFR (reviewed in ref. 98), antiangiogenesis strategies targeting the tumor microenvironment pose additional drug development strategies. Prior studies of anti-VEGF antibodies have shown clinical utility when the agents are used in combination with cytotoxic therapy and minimal activity as single agents with rare exceptions (75, 99). Similarly, FGF inhibition alone is unlikely to show a significant benefit in various tumor types. Combination strategies of FGF/FGFR inhibition with traditional cytotoxic therapy in tumor types in which proliferation and angiogenesis is FGF/FGFR–dependent will have the highest likelihood of achieving a clinical benefit. The timing of FGF/FGFR–directed therapy is also an area of emerging interest given the evolving evidence that the FGF axis may serve as an adaptive resistance mechanism to anti-VEGF therapy. Histopathologic evidence from a murine PNET model suggests that the switch to an FGFR inhibitor during treatment with a VEGFR inhibitor may be more effective at the time of early revascularization prior to detectable tumor growth (83). Future clinical trials will help determine whether dual inhibition of VEGFR and FGFR will be more effective in the front-line setting or whether FGFR inhibition will be better instituted at the time 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) BIBF 1120 (Vargatef; ref. 104) BMS-582664 (brivanib; ref. 105) E7080 (106) TSU-68 (SU6668; ref. 107) AZD4547 (108) FP-1039 (109) BGJ398 (110) Astex FGFR inhibitor (111)

Novartis Boehringer Ingelheim Bristol-Myers Squibb Eisai Taiho Pharmaceutical AstraZeneca Five Prime Therapeutics Novartis Janssen Oncology

FGFR, PDGFR, VEGFR FGFR, PDGFR, VEGFR FGFR and VEGFR FGFR, PDGFR, VEGFR FGFR, PDGFR, VEGFR FGFR FGF ligand trap (multiple FGFs) FGFR FGFR

Phase II Phase III Phase II and III Phase I Phase I and II Phase I Phase I Phase I Preclinical



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resistance to VEGF/VEGFR inhibitors is difficult in the clinic, as resistance to the cytotoxic component of the treatment may be sufficient to induce tumor growth in the absence of single-agent anti-VEGF activity. Determining resistance to these inhibitors is a high hurdle for development of such alternate antiangiogenic therapies, and several strategies are being considered in the early clinical development, including randomized discontinuation studies and enrichment designs. Biomarkers under consideration for FGF inhibitors include plasma levels of FGF family members and increased FGF-axis expression in the stroma; however, their use as surrogates for FGF/FGFR–dependent tumors remains unclear. Integration of imaging or biomarkers of antiangiogenesis therapy likewise has hurdles of cost reproducibility and lack of correlation with clinical efficacy, and these approaches are not routinely integrated into most clinical development strategies of these agents (100, 101). Based on the VEGF inhibitor experiences, radiographic endpoints with antiangiogenesis strategies will be difficult, and ultimately, the benefits of these agents will be measured by their ability to improve overall survival (102, 103).

Summary FGFs are a family of growth factors that are involved in many pathways that can contribute to carcinogenesis and affect cellular proliferation, migration, and survival. They

also play a large role in angiogenesis, which is a fundamental step in the transition from a dormant to a malignant state, and FGF acts synergistically with VEGF to increase tumor blood vessel growth and maturation. Evidence is also increasing that FGF may be part of the mechanism of resistance to anti-VEGF agents. Although agents targeting FGF signaling are still early in development, the potential to target both the VEGF and FGF pathways is near, and the combination or sequential inhibition of these 2 critical angiogenic pathways may translate into improvements in the clinical care of cancer patients. Successful strategies will depend on appropriate selection of tumors and patients in whom FGF inhibition is mostly likely to inhibit angiogenesis and proliferation. Disclosure of Potential Conflicts of Interest S. Kopetz: commercial research grant, AstraZeneca. The other authors disclosed 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 Investigators Award (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.

References 1. 2.

3.

4.

5.

6. 7.

8.

9. 10.

11.

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Itoh N, Ornitz DM. Evolution of the Fgf and Fgfr gene families. Trends Genet 2004;20:563–9. De Moerlooze L, Spencer-Dene B, Revest JM, Hajihosseini M, Rosewell I, Dickson C. An important role for the IIIb isoform of fibroblast growth factor receptor 2 (FGFR2) in mesenchymal-epithelial signalling during mouse organogenesis. Development 2000; 127:483–92. Yamaguchi TP, Harpal K, Henkemeyer M, Rossant J. fgfr-1 is required for embryonic growth and mesodermal patterning during mouse gastrulation. Genes Dev 1994;8:3032–44. de P, Ueno N, Ling N, Bo € hlen P, et al. Baird A, Esch F, Morme Molecular characterization of fibroblast growth factor: distribution and biological activities in various tissues. Recent Prog Horm Res 1986;42:143–205. Colvin JS, Bohne BA, Harding GW, McEwen DG, Ornitz DM. Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3. Nat Genet 1996;12:390–7. Grose R, Dickson C. Fibroblast growth factor signaling in tumorigenesis. Cytokine Growth Factor Rev 2005;16:179–86. Dickson C, Spencer-Dene B, Dillon C, Fantl V. Tyrosine kinase signalling in breast cancer: fibroblast growth factors and their receptors. Breast Cancer Res 2000;2:191–6. Feng S, Wang F, Matsubara A, Kan M, McKeehan WL. Fibroblast growth factor receptor 2 limits and receptor 1 accelerates tumorigenicity of prostate epithelial cells. Cancer Res 1997;57:5369–78. Armelin HA. Pituitary extracts and steroid hormones in the control of 3T3 cell growth. Proc Natl Acad Sci U S A 1973;70:2702–6. Gospodarowicz D. Localisation of a fibroblast growth factor and its effect alone and with hydrocortisone on 3T3 cell growth. Nature 1974;249:123–7. Ornitz DM, Itoh N. Fibroblast growth factors. Genome Biol 2001;2: reviews3005.1–3005.12.


12. 13.

14.

15. 16.

17. 18.

19.

20.

21.

Ornitz DM. FGFs, heparan sulfate and FGFRs: complex interactions essential for development. Bioessays 2000;22:108–12. Mignatti P, Morimoto T, Rifkin DB. Basic fibroblast growth factor, a protein devoid of secretory signal sequence, is released by cells via a pathway independent of the endoplasmic reticulum-Golgi complex. J Cell Physiol 1992;151:81–93. Lee PL, Johnson DE, Cousens LS, Fried VA, Williams LT. Purification and complementary DNA cloning of a receptor for basic fibroblast growth factor. Science 1989;245:57–60. Johnson DE, Williams LT. Structural and functional diversity in the FGF receptor multigene family. Adv Cancer Res 1993;60:1–41. McKeehan WL, Wang F, Kan M. The heparan sulfate-fibroblast growth factor family: diversity of structure and function. Prog Nucleic Acid Res Mol Biol 1998;59:135–76. Naski MC, Ornitz DM. FGF signaling in skeletal development. Front Biosci 1998;3:d781–94. Miki T, Bottaro DP, Fleming TP, Smith CL, Burgess WH, Chan AM, et al. Determination of ligand-binding specificity by alternative splicing: two distinct growth factor receptors encoded by a single gene. Proc Natl Acad Sci U S A 1992;89:246–50. Chellaiah AT, McEwen DG, Werner S, Xu J, Ornitz DM. Fibroblast growth factor receptor (FGFR) 3. Alternative splicing in immunoglobulin-like domain III creates a receptor highly specific for acidic FGF/ FGF-1. J Biol Chem 1994;269:11620–7. Orr-Urtreger A, Bedford MT, Burakova T, Arman E, Zimmer Y, Yayon A, et al. Developmental localization of the splicing alternatives of fibroblast growth factor receptor-2 (FGFR2). Dev Biol 1993;158: 475–86. Murgue B, Tsunekawa S, Rosenberg I, deBeaumont M, Podolsky DK. Identification of a novel variant form of fibroblast growth factor receptor 3 (FGFR3 IIIb) in human colonic epithelium. Cancer Res 1994;54:5206–11.



22.

23. 24. 25.

26.

27.

28.

29.

30.

31.

32. 33.

34.

35.

36.

37.

38.

39.

40.

41. 42.

Scotet E, Houssaint E. The choice between alternative IIIb and IIIc exons of the FGFR-3 gene is not strictly tissue-specific. Biochim Biophys Acta 1995;1264:238–42. Cavallaro U, Christofori G. Cell adhesion and signalling by cadherins and Ig-CAMs in cancer. Nat Rev Cancer 2004;4:118–32. Hinsby AM, Berezin V, Bock E. Molecular mechanisms of NCAM function. Front Biosci 2004;9:2227–44. Francavilla C, Cattaneo P, Berezin V, Bock E, Ami D, de Marco A, et al. The binding of NCAM to FGFR1 induces a specific cellular response mediated by receptor trafficking. J Cell Biol 2009;187: 1101–16. Francavilla C, Loeffler S, Piccini D, Kren A, Christofori G, Cavallaro U. Neural cell adhesion molecule regulates the cellular response to fibroblast growth factor. J Cell Sci 2007;120:4388–94. Kwabi-Addo B, Ozen M, Ittmann M. The role of fibroblast growth factors and their receptors in prostate cancer. Endocr Relat Cancer 2004;11:709–24. Greenman C, Stephens P, Smith R, Dalgliesh GL, Hunter C, Bignell G, et al. Patterns of somatic mutation in human cancer genomes. Nature 2007;446:153–8. Kunii K, Davis L, Gorenstein J, Hatch H, Yashiro M, Di Bacco A, et al. FGFR2-amplified gastric cancer cell lines require FGFR2 and Erbb3 signaling for growth and survival. Cancer Res 2008;68:2340–8. Yagasaki F, Wakao D, Yokoyama Y, Uchida Y, Murohashi I, Kayano H, et al. Fusion of ETV6 to fibroblast growth factor receptor 3 in peripheral T-cell lymphoma with a t(4;12)(p16;p13) chromosomal translocation. Cancer Res 2001;61:8371–4. € m P, Engel G, Auer G, Aspenblad U, Strander H, et al. Linder C, Bystro Correlation between basic fibroblast growth factor immunostaining of stromal cells and stromelysin-3 mRNA expression in human breast carcinoma. Br J Cancer 1998;77:941–5. Halaban R. Growth factors and melanomas. Semin Oncol 1996; 23:673–81. Bian XW, Du LL, Shi JQ, Cheng YS, Liu FX. Correlation of bFGF, FGFR-1 and VEGF expression with vascularity and malignancy of human astrocytomas. Anal Quant Cytol Histol 2000;22:267–74. Relf M, LeJeune S, Scott PA, Fox S, Smith K, Leek R, et al. Expression of the angiogenic factors vascular endothelial cell growth factor, acidic and basic fibroblast growth factor, tumor growth factor beta-1, platelet-derived endothelial cell growth factor, placenta growth factor, and pleiotrophin in human primary breast cancer and its relation to angiogenesis. Cancer Res 1997;57:963–9. Yamanaka Y, Friess H, Buchler M, Beger HG, Uchida E, Onda M, et al. Overexpression of acidic and basic fibroblast growth factors in human pancreatic cancer correlates with advanced tumor stage. Cancer Res 1993;53:5289–96. €gge I, Vetterlein M, Dekan Berger W, Setinek U, Mohr T, Kindas-Mu G, et al. Evidence for a role of FGF-2 and FGF receptors in the proliferation of non-small cell lung cancer cells. Int J Cancer 1999;83:415–23. Gazzaniga P, Gandini O, Gradilone A, Silvestri I, Giuliani L, Magnanti M, et al. Detection of basic fibroblast growth factor mRNA in urinary bladder cancer: correlation with local relapses. Int J Oncol 1999;14: 1123–7. Dellacono FR, Spiro J, Eisma R, Kreutzer D. Expression of basic fibroblast growth factor and its receptors by head and neck squamous carcinoma tumor and vascular endothelial cells. Am J Surg 1997;174:540–4. Huang X, Yu C, Jin C, Yang C, Xie R, Cao D, et al. Forced expression of hepatocyte-specific fibroblast growth factor 21 delays initiation of chemically induced hepatocarcinogenesis. Mol Carcinog 2006; 45:934–42. Galdemard C, Brison O, Lavialle C. The proto-oncogene FGF-3 is constitutively expressed in tumorigenic, but not in non-tumorigenic, clones of a human colon carcinoma cell line. Oncogene 1995;10: 2331–42. Turner N, Grose R. Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer 2010;10:116–29. Yan G, Fukabori Y, McBride G, Nikolaropolous S, McKeehan WL. Exon switching and activation of stromal and embryonic fibroblast


43.

44.

45.

46.

47.

48.

49. 50.

51.

52.

53.

54.

55. 56.

57.

58.

59. 60.

61.

62. 63.

growth factor (FGF)-FGF receptor genes in prostate epithelial cells accompany stromal independence and malignancy. Mol Cell Biol 1993;13:4513–22. Carstens RP, Eaton JV, Krigman HR, Walther PJ, Garcia-Blanco MA. Alternative splicing of fibroblast growth factor receptor 2 (FGF-R2) in human prostate cancer. Oncogene 1997;15:3059–65. €ttner S, Karner J, Klimpfinger Sonvilla G, Allerstorfer S, Heinzle C, Sta M, et al. Fibroblast growth factor receptor 3-IIIc mediates colorectal cancer growth and migration. Br J Cancer 2010;102:1145–56. Acevedo VD, Gangula RD, Freeman KW, Li R, Zhang Y, Wang F, et al. Inducible FGFR-1 activation leads to irreversible prostate adenocarcinoma and an epithelial-to-mesenchymal transition. Cancer Cell 2007;12:559–71. Birrer MJ, Johnson ME, Hao K, Wong K-K, Park D-C, Bell A, et al. Whole genome oligonucleotide-based array comparative genomic hybridization analysis identified fibroblast growth factor 1 as a prognostic marker for advanced-stage serous ovarian adenocarcinomas. J Clin Oncol 2007;25:2281–7. Elagoz S, Egilmez R, Koyuncu A, Muslehiddinoglu A, Arici S. The intratumoral microvessel density and expression of bFGF and nm23H1 in colorectal cancer. Pathol Oncol Res 2006;12:21–7. George ML, Tutton MG, Abulafi AM, Eccles SA, Swift RI. Plasma basic fibroblast growth factor levels in colorectal cancer: a clinically useful assay? Clin Exp Metastasis 2002;19:735–8. Poon RT-P, Fan S-T, Wong J. Clinical implications of circulating angiogenic factors in cancer patients. J Clin Oncol 2001;19:1207–25. Presta M, Dell’Era P, Mitola S, Moroni E, Ronca R, Rusnati M. Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis. Cytokine Growth Factor Rev 2005;16:159–78. Cavallaro U, Niedermeyer J, Fuxa M, Christofori G. N-CAM modulates tumour-cell adhesion to matrix by inducing FGF-receptor signalling. Nat Cell Biol 2001;3:650–7. Perl AK, Dahl U, Wilgenbus P, Cremer H, Semb H, Christofori G. Reduced expression of neural cell adhesion molecule induces metastatic dissemination of pancreatic beta tumor cells. Nat Med 1999;5:286–91. Folkman J, Klagsbrun M, Sasse J, Wadzinski M, Ingber D, Vlodavsky I. A heparin-binding angiogenic protein—basic fibroblast growth factor—is stored within basement membrane. Am J Pathol 1988; 130:393–400. Ingber DE, Folkman J. Mechanochemical switching between growth and differentiation during fibroblast growth factor-stimulated angiogenesis in vitro: role of extracellular matrix. J Cell Biol 1989;109: 317–30. Werner S, Grose R. Regulation of wound healing by growth factors and cytokines. Physiol Rev 2003;83:835–70. Abraham JA, Whang JL, Tumolo A, Mergia A, Friedman J, Gospodarowicz D, et al. Human basic fibroblast growth factor: nucleotide sequence and genomic organization. EMBO J 1986;5:2523–8. Greenhalgh DG, Sprugel KH, Murray MJ, Ross R. PDGF and FGF stimulate wound healing in the genetically diabetic mouse. Am J Pathol 1990;136:1235–46. Broadley KN, Aquino AM, Woodward SC, Buckley-Sturrock A, Sato Y, Rifkin DB, et al. Monospecific antibodies implicate basic fibroblast growth factor in normal wound repair. Lab Invest 1989;61:571–5. Risau W. Angiogenic growth factors. Prog Growth Factor Res 1990;2:71–9. Pepper MS, Ferrara N, Orci L, Montesano R. Potent synergism between vascular endothelial growth factor and basic fibroblast growth factor in the induction of angiogenesis in vitro. Biochem Biophys Res Commun 1992;189:824–31. Compagni A, Wilgenbus P, Impagnatiello M-A, Cotten M, Christofori G. Fibroblast growth factors are required for efficient tumor angiogenesis. Cancer Res 2000;60:7163–9. Javerzat S, Auguste P, Bikfalvi A. The role of fibroblast growth factors in vascular development. Trends Mol Med 2002;8:483–9. Gualandris A, Urbinati C, Rusnati M, Ziche M, Presta M. Interaction of high-molecular-weight basic fibroblast growth factor with endothelium: biological activity and intracellular fate of human recombinant M(r) 24,000 bFGF. J Cell Physiol 1994;161:149–59.


6137

Lieu et al.

64.

65.

66.

67.

68.

69.

70. 71.

72.

73.

74.

75.

76.

77.

78.

79.

80.

81.

82.

6138

Ribatti D, Urbinati C, Nico B, Rusnati M, Roncali L, Presta M. Endogenous basic fibroblast growth factor is implicated in the vascularization of the chick embryo chorioallantoic membrane. Dev Biol 1995;170:39–49. Passaniti A, Taylor RM, Pili R, Guo Y, Long PV, Haney JA, et al. A simple, quantitative method for assessing angiogenesis and antiangiogenic agents using reconstituted basement membrane, heparin, and fibroblast growth factor. Lab Invest 1992;67:519–28. Ensoli B, Gendelman R, Markham P, Fiorelli V, Colombini S, Raffeld M, et al. Synergy between basic fibroblast growth factor and HIV-1 Tat protein in induction of Kaposi's sarcoma. Nature 1994;371: 674–80. Wang Y, Becker D. Antisense targeting of basic fibroblast growth factor and fibroblast growth factor receptor-1 in human melanomas blocks intratumoral angiogenesis and tumor growth. Nat Med 1997;3:887–93. Fujii T, Kuwano H. Regulation of the expression balance of angiopoietin-1 and angiopoietin-2 by Shh and FGF-2. In Vitro Cell Dev Biol Anim 2010;46:487–91. Ensoli B, Nakamura S, Salahuddin SZ, Biberfeld P, Larsson L, Beaver B, et al. AIDS-Kaposi's sarcoma-derived cells express cytokines with autocrine and paracrine growth effects. Science 1989;243: 223–6. Abuharbeid S, Czubayko F, Aigner A. The fibroblast growth factorbinding protein FGF-BP. Int J Biochem Cell Biol 2006;38:1463–8. Tassi E, Al-Attar A, Aigner A, Swift MR, McDonnell K, Karavanov A, et al. Enhancement of fibroblast growth factor (FGF) activity by an FGF-binding protein. J Biol Chem 2001;276:40247–53. Aigner A, Butscheid M, Kunkel P, Krause E, Lamszus K, Wellstein A, et al. An FGF-binding protein (FGF-BP) exerts its biological function by parallel paracrine stimulation of tumor cell and endothelial cell proliferation through FGF-2 release. Int J Cancer 2001; 92:510–7. Czubayko F, Liaudet-Coopman EDE, Aigner A, Tuveson AT, Berchem GJ, Wellstein A. A secreted FGF-binding protein can serve as the angiogenic switch in human cancer. Nat Med 1997;3: 1137–40. ez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Viñals F, Pa et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 2009;15:220–31. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004; 350:2335–42. Tille JC, Wood J, Mandriota SJ, Schnell C, Ferrari S, Mestan J, et al. Vascular endothelial growth factor (VEGF) receptor-2 antagonists inhibit VEGF- and basic fibroblast growth factor-induced angiogenesis in vivo and in vitro. J Pharmacol Exp Ther 2001;299:1073–85. Giavazzi R, Sennino B, Coltrini D, Garofalo A, Dossi R, Ronca R, et al. Distinct role of fibroblast growth factor-2 and vascular endothelial growth factor on tumor growth and angiogenesis. Am J Pathol 2003;162:1913–26. Shi YH, Bingle L, Gong LH, Wang YX, Corke KP, Fang WG. Basic FGF augments hypoxia induced HIF-1-alpha expression and VEGF release in T47D breast cancer cells. Pathology 2007;39:396–400. Nissen LJ, Cao R, Hedlund E-M, Wang Z, Zhao X, Wetterskog D, et al. Angiogenic factors FGF2 and PDGF-BB synergistically promote murine tumor neovascularization and metastasis. J Clin Invest 2007;117:2766–77. Shen J, Vil MD, Prewett M, Damoci C, Zhang H, Li H, et al. Development of a fully human anti-PDGFRbeta antibody that suppresses growth of human tumor xenografts and enhances antitumor activity of an anti-VEGFR2 antibody. Neoplasia 2009;11:594–604. Pietras K, Pahler J, Bergers G, Hanahan D. Functions of paracrine PDGF signaling in the proangiogenic tumor stroma revealed by pharmacological targeting. PLoS Med 2008;5:e19. Casanovas O, Hicklin DJ, Bergers G, Hanahan D. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell 2005;8:299–309.


83.

84.

85.

86.

87.

88.

89.

90.

91.

92.

93.

94.

95.

96.

97.

98.

Allen E, Walters I, Hanahan D. Brivanib, a dual FGF/VEGF Inhibitor, is active both first and second line against mouse pancreatic neuroendocrine tumors developing adaptive/evasive resistance to VEGF inhibition. Clin Cancer Res 2011;17:5299–5310. Fernando NT, Koch M, Rothrock C, Gollogly LK, D’Amore PA, Ryeom S, et al. Tumor escape from endogenous, extracellular matrix-associated angiogenesis inhibitors by up-regulation of multiple proangiogenic factors. Clin Cancer Res 2008;14:1529–39. Bello E, Colella G, Scarlato V, Oliva P, Berndt A, Valbusa G, et al. E3810 is a potent dual inhibitor of VEGFR and FGFR that exerts antitumor activity in multiple preclinical models. Cancer Res 2011;71:1396–405. Kopetz S, Hoff M, Eng C, Overman M, Glover K, Chang Z, et al. Levels of angiogenic cytokines prior to disease progression in metastatic colorectal cancer patients treated with bevacizumab. Gastrointestinal Cancers Symposium; 2009 Jan 15–17; San Francisco, CA; 2009. Kopetz S, Hoff PM, Morris JS, Wolff RA, Eng C, Glover KY, et al. Phase II trial of infusional fluorouracil, irinotecan, and bevacizumab for metastatic colorectal cancer: efficacy and circulating angiogenic biomarkers associated with therapeutic resistance. J Clin Oncol 2009;24:8252. Willett CG, Duda DG, di Tomaso E, Boucher Y, Ancukiewicz M, Sahani DV, et al. Efficacy, safety, and biomarkers of neoadjuvant bevacizumab, radiation therapy, and fluorouracil in rectal cancer: a multidisciplinary phase II study. J Clin Oncol 2009;27:3020–6. Batchelor TT, Sorensen AG, di Tomaso E, Zhang W-T, Duda DG, Cohen KS, et al. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 2007;11:83–95. Garrett CR, Siu LL, Giaccone G, El-Khoueiry A, Marshall J, LoRusso P, et al. A phase I study of BMS-582664 (brivanib alaninate), an oral dual inhibitor of VEGFR and FGFR tyrosine kinases, in combination with full-dose cetuximab in patients with advanced gastrointestinal malignancies who failed prior therapy. J Clin Oncol 2007;25 (18S):14018. Matsui J, Yamamoto Y, Funahashi Y, Tsuruoka A, Watanabe T, Wakabayashi T, et al. E7080, a novel inhibitor that targets multiple kinases, has potent antitumor activities against stem cell factor producing human small cell lung cancer H146, based on angiogenesis inhibition. Int J Cancer 2008;122:664–71. Zhang H, Masuoka L, Baker K, Sadra A, Bosch E, Brennan T, et al. FP-1039 (FGFR1:Fc), a soluble FGFR1 receptor antagonist, inhibits tumor growth and angiogenesis. AACR-NCI-EORTC International Conference; 2007 Oct 22–26; San Francisco, CA; 2007. Jonker DJ, Rosen LS, Sawyer MB, de Braud F, Wilding G, Sweeney CJ, et al. A phase I study to determine the safety, pharmacokinetics and pharmacodynamics of a dual VEGFR and FGFR inhibitor, brivanib, in patients with advanced or metastatic solid tumors. Ann Oncol 2011;22:1413–9. Okamoto I, Kaneda H, Satoh T, Okamoto W, Miyazaki M, Morinaga R, et al. Phase I safety, pharmacokinetic, and biomarker study of bibf 1120, an oral triple tyrosine kinase inhibitor in patients with advanced solid tumors. Mol Cancer Ther 2010;9:2825–33. Sun HD, Malabunga M, Tonra JR, DiRenzo R, Carrick FE, Zheng H, et al. Monoclonal antibody antagonists of hypothalamic FGFR1 cause potent but reversible hypophagia and weight loss in rodents and monkeys. Am J Physiol Endocrinol Metab 2007; 292:E964–76. Sarker D, Molife R, Evans TR, Hardie M, Marriott C, ButzbergerZimmerli P, et al. A phase I pharmacokinetic and pharmacodynamic study of TKI258, an oral, multitargeted receptor tyrosine kinase inhibitor in patients with advanced solid tumors. Clin Cancer Res 2008;14:2075–81. Shimada T, Kakitani M, Yamazaki Y, Hasegawa H, Takeuchi Y, Fujita T, et al. Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. J Clin Invest 2004;113:561–8. Greulich H, Pollock PM. Targeting mutant fibroblast growth factor receptors in cancer. Trends Mol Med 2011;17:283–92.



99.

100.

101.

102.

103.

104.

105.

Saltz LB, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 2008;26:2013–9. Jain RK, Duda DG, Willett CG, Sahani DV, Zhu AX, Loeffler JS, et al. Biomarkers of response and resistance to antiangiogenic therapy. Nat Rev Clin Oncol 2009;6:327–38. Murukesh N, Dive C, Jayson GC. Biomarkers of angiogenesis and their role in the development of VEGF inhibitors. Br J Cancer 2010;102:8–18. Chun YS, Vauthey JN, Boonsirikamchai P, Maru DM, Kopetz S, Palavecino M, et al. Association of computed tomography morphologic criteria with pathologic response and survival in patients treated with bevacizumab for colorectal liver metastases. JAMA 2009;302:2338–44. Ocaña A, Amir E, Vera F, Eisenhauer EA, Tannock IF. Addition of bevacizumab to chemotherapy for treatment of solid tumors: similar results but different conclusions. J Clin Oncol 2011;29: 254–6. Santos ES, Gomez JE, Raez LE. Targeting angiogenesis from multiple pathways simultaneously: BIBF 1120, an investigational novel triple angiokinase inhibitor. Invest New Drugs 2011. [Epub ahead of print] 25 Feb 2011. Dempke WCM, Zippel R. Brivanib, a novel dual VEGF-R2/bFGF-R inhibitor. Anticancer Res 2010;30:4477–83.


106. Yamada K, Yamamoto N, Yamada Y, Nokihara H, Fujiwara Y, Hirata T, et al. Phase I dose-escalation study and biomarker analysis of E7080 in patients with advanced solid tumors. Clin Cancer Res 2011;17:2528–37. 107. Ueda Y, Shimoyama T, Murakami H, Yamamoto N, Yamada Y, Arioka H, et al. Phase I and pharmacokinetic study of TSU-68, a novel multiple receptor tyrosine kinase inhibitor, by twice daily oral administration between meals in patients with advanced solid tumors. Cancer Chemother Pharmacol 2011;67:1101–9. 108. Gavine P, Mooney L, Kilgour E, Thomas A, Al-Kadhimi K, Beck S, et al. Characterization of AZD4547: An orally bioavailable, potent and selective inhibitor of FGFR tyrosine kinases 1, 2, and 3. 102nd AACR Annual Meeting; 2011 Apr 2–6; Orlando, FL; 2011. 109. Harding T, Palencia S, Long L, Finer J, Keer H, Baker K, et al. Preclinical efficacy of FP-1039 (FGFR1:Fc) in endometrial carcinoma models with activating mutations in FGFR2. American AACR Annual Meeting; 2010 Apr 17–21; Washington, DC; 2010. 110. ClinicalTrials.gov. Bethesda (MD): NIH; 2011. Novartis. A dose escalation study in adult patients with advanced solid malignancies. NCT01004224. Available from: http://clinicaltrials.gov/ct2/show/ NCT01004224. 111. Saxty G, Akkari R, Angibaud P, Arts J, Benderitter P, Berdini V, et al. Fragment based drug discovery of selective inhibitors of fibroblast growth factor receptor (FGFR). 102nd AACR Annual Meeting; 2011 Apr 2–6; Orlando, FL; 2011.


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Beyond VEGF: Inhibition of the Fibroblast Growth Factor Pathway and ...

Beyond VEGF: Inhibition of the Fibroblast Growth Factor Pathway and ...

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