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ANTICANCER RESEARCH 30: 4477-4484 (2010)

Review Brivanib, A Novel Dual VEGF-R2/bFGF-R Inhibitor

WOLFRAM C.M. DEMPKE and ROLAND ZIPPEL

Elbland Clinic Riesa, Medical Oncology, D-01589 Riesa, Germany

Abstract. The process of neo-vascularisation from pre- angiogenic factors (4), is thought to push cells out of a state of existing blood vessels () plays a critical role in relative dormancy and into one characterised by the invasive both tumour growth and dissemination in multiple cancer phenotype, a hallmark of cancer pathogenesis. Among the many types. Tumour angiogenesis is an attractive target for cancer contributors to this process is the vascular endothelial growth treatment, and the VEGF/VEGF-R and FGF/FGF-R systems factor (VEGF) family of ligands and receptors (Tables I and II). have been identified as key factors for neo-angiogenesis. Since tumour angiogenesis is an attractive target for Several active compounds have been developed so far and cancer treatment, several active compounds have been some of them are already widely used in clinical protocols. developed so far and some of them are already widely used However, currently, only very few drugs have been shown to in clinical protocols. Amongst them brivanib (a novel VEGF- act synergistically with VEGF. Brivanib (BMS-582664) is a R2 and FGF-R1 and -2 inhibitor) is currently under clinical novel, orally available and selective receptor evaluation and therefore it was the objective of this paper to inhibitor that targets the key angiogenesis receptors VEGF-R2 review and discuss the potential of this new compound in and FGF-R1 and -2. The drug is currently under clinical treatment strategies for cancer. evaluation and published data as well as data on biomarker studies with brivanib are reviewed and discussed. VEGF System

Angiogenesis is a fundamental mechanism in biology that VEGF is the prototype of a large family of angiogenic and describes the multistep process of new blood vessel formation lymphangiogenic growth factors, which includes six from existing vasculature (1). The role of angiogenesis in structurally homologous, secreted glycoproteins called normal biology and pathology is now firmly established. VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E and Angiogenesis occurs during normal tissue turnover and placenta (5). VEGF-A (commonly referred to organogenesis, including vertebrate embryonic development, as VEGF) was the first such molecule to be identified by menstruation and wound repair (2, 3). Conversely, aberrant virtue of its ability to induce vascular permeability (6). The angiogenesis may contribute to the pathogenesis of a variety of VEGF ligands trigger biological effects on their interaction both non-neoplastic (e.g. diabetic retinopathy) and neoplastic with specific cell-surface receptors. The diversity of these disorders. In cancer, early angiogenesis facilitates tumour cell receptors also adds to the biological complexity of growth through the delivery of nutrients and the removal of angiogenesis and lymphangiogenesis. Two receptors were metabolic waste products from the tumour environment. originally identified on vascular endothelial cells: VEGF-R- Initially, in the course of tumour growth and expansion, tumour 1, which is a 180-kDa transmembrane , also called cells surround the microvasculature, and the resulting capillary fibromyalgia-syndrome-like tyrosine kinase-1 (Flt-1), and ‘cuff’ facilitates their growth. Subsequently, an ‘angiogenic VEGF-R2, which is a 200-kDa transmembrane protein, also switch’, characterized by the expression of multiple pro- called kinase domain receptor (KDR). A third structurally related tyrosine kinase receptor is the 180-kDa VEGF-R3 (also called Flt-4), which is expressed broadly on endothelial cells during early embryogenesis (7) (Figure 1). VEGF-R2 Correspondence to: Wolfram C.M. Dempke, MD, Ph.D., Elbland is expressed in most, if not all, adult vascular endothelial Clinic Riesa, Medical Oncology, Weinbergstrasse 8, D-01589 Riesa, cells as well as on circulating endothelial progenitor cells. Germany. Tel: +49 3525753552, Fax: +49 3525753578, e-mail: Interestingly, both epithelial and mesenchymal tumour cells [email protected] express VEGF-R1 more often than VEGF-R2 (8). However, Key Words: Angiogenesis, VEGF-R, bFGF-R, clinical studies, in several experimental tumour models, tumour cell-specific biomarker, brivanib, review. VEGF-R2 expression has been shown to be the critical driver

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Table I. Pro-angiogenetic molecules.

Molecule Function

VEGF cytokine family Angiogenesis, neo-vascularisation, vessel permeability, leukocyte adhesion VEGF-R, Neuropilin-1,2 Signal transduction (pro-angiogenetic signals) -1, Tie-2 Vessel stabilisation FGF and FGF-R Endothelial proliferation, synergism with VEGF Angiopoietin-2 Augmentation of VEGF, angiopoietin-1 antagonist PDGF and PDGF-R Smooth muscle cell recruitment TGF-β, Endoglin Stimulation of extracellular matrix Adhesion of endothelial cells to the extracellular matrix VE-Cadherin (CD144) Endothelial cell–cell adhesion Ephrines Regulation of neo-vascularisation Matrix metalloproteinases (MMPs), plasminogen activator (PA) Destabilising and remodelling of extracellular matrix

Table II. Anti-angiogenetic molecules.

Molecule Function

Soluble VEGF-R1, soluble neuropilin-1 Regulation of VEGF available Thrombospondin-1 and -2 Inhibition of endothelial migration, adhesion and survival Endostatin (collagen XIII fragment) Inhibition of endothelial migration and survival Tumstatin (collagen IV fragment) Inhibition of endothelial protein synthesis Platelet factor 4 Inhibition of bFGF and VEGF binding TIMPs Suppression of tumour angiogenesis (α, β, γ), (IL-4, -12, -18) Inhibition of endothelial migration; down-regulation of bFGF Mapsins Protease inhibitor

in the pathogenesis of tumours (5, 9). VEGF binding induces organ systems, including tumour growth and angiogenesis conformational changes within VEGF-R2 followed by (11). FGFs are heparin-binding , which interact with receptor dimerisation and autophosphorylation of tyrosine low-affinity heparan sulfate proteoglycans (HSPGs). HSPGs residues in the intracellular kinase domain. These tyrosine are ubiquitous cell surface and extracellular matrix (ECM) residues (Tyr951, Tyr996, Tyr1054, and Tyr1059) serve as high- proteins, which have been shown to protect FGFs from affinity docking for a variety of signalling proteins, including thermal denaturation and proteolysis as well as to increase phospholipase Cγ, ras-GAP, focal adhesion kinase, src FGF-receptor affinity and facilitate FGF binding to cell family of tyrosine kinases, PI3K, Akt, PK-C, Raf-1 and surface receptor. In addition, ECM-associated HSPGs MAPs. The interaction of one or more of these molecules modulate FGF bioavailability by generating a local reservoir with VEGF-R2 may lead to alterations in cell proliferation, for the growth factor and allowing a sustained stimulation of migration, differentiation, tube formation, increase in endothelial cells (12). Mobilisation of FGFs from the ECM vascular permeability and vascular integrity (9) (Figure 2). storage, and in particular of FGF-1 and FGF-2, occurs via Intrinsic and acquired resistance to anti-angiogenetic drugs HSPG digestion by heparanases or glycosaminoglycan- are clinically significant problems. Preclinical studies have degrading enzymes. FGFs act through high-affinity binding begun to elucidate the mechanisms of such resistance and, to sites that mediate biological activity via a group of tyrosine date, four mechanisms of resistance have been identified: (i) kinase membrane receptors that form the FGF-R family. up-regulation of the basic (bFGF), (ii) Within the FGF-R family, four members have been overexpression of matrix metalloproteinase 9 (MMP-9), (iii) identified: FGF-R1, FGF-R2, FGF-R3 and FGF-R4. increased levels of the stromal cell-derived factor SDF-1α and Structural features shared by the FGF-R family include three (iv) hypoxia-inducible factor (HIF)-1α-induced recruitment of glycosylated immunoglobuline-like loops of the extracellular bone marrow-derived CD45+ myeloid cells (reviewed in (10)). domain and an internal conserved tyrosine kinase domain split by a short insert (13). It has been shown that the four FGF System members of the FGF-R family bind both FGF-1 and FGF-4. FGF-2 is able to bind FGF-R1, FGF-R2, and FGF-R3, The FGF family comprises 23 distinct, structurally-related whereas FGF5, FGF6 and FGF7 act through FGF-R3, FGF- proteins that exert biologic effects on different cells and R4 and FGF-R2, respectively (12).

4478 Dempke and Zippel: Brivanib, A Novel Dual Tyrosine Kinase Inhibitor (Review)

Figure 1. Cytokines and their receptors of the VEGF family. PIGF: ; Flk: foetal liver kinase.

Figure 3. Suppression of angiogenesis by anti-VEGF agents. Overexpression of FGF restores angiogenesis and, thereby, confers resistance to VEGF/VEGF-R inhibitors.

Transcriptional regulation of VEGF is critically dependent on HIF-1. However, not only hypoxia, but also selected growth factors may induce HIF-1 (14). Results from several studies have provided compelling evidence that hypoxia- triggered up-regulation of other pro-angiogenic factors (e.g. FGF family and PDGF-BB), in the presence of anti-VEGF agents, may re-stimulate tumour angiogenesis in a VEGF- independent fashion, thereby contributing to resistance to VEGF-blocking agents (15-17) (Figure 3). In terms of the underlying molecular mechanisms, it has been demonstrated that hypoxia induces the expression of Figure 2. Inhibition of VEGF and its receptor. HIF-1α (a key protein for tumour angiogenesis) and the

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Table III. Members of the VEGF family.

Receptor class Function and ligands

VEGF-R1 Modulates neo-vascularisation, binds VEGF-A and VEGF-B VEGF-R2 Modulates neo-angiogenesis, specifically binds VEGF-A VEGF-R3 Modulates neo-lymphangiogenesis, binds VEGF-C and VEGF-D

Figure 4. Structure of brivanib (BMS-584662) (molecular weight: 441 Da). release of bFGF further augments these hypoxic inductions. The PI3K pathway has been shown to be required for these processes as demonstrated by application of the PI3K inhibitor LY294002 (17). In addition, under hypoxic conditions, bFGF BMS-540215 has demonstrated a high plasma protein activates the MEK1/ERK pathways, and PD98059 (a MEK1/2 binding ratio (52-97%). In several tumour xenograft models, inhibitor) suppresses the bFGF-induced HIF-1 transactivity, brivanib induced significant tumour growth inhibition when suggesting that the ras signalling cascade may also be involved administered orally once daily. However, no major tumour in the resistance to anti-VEGF agents. regression was observed and, with the termination of dosing, Furthermore, it has been shown in experimental systems tumour xenografts resumed growth (18, 19). Consequently, that adding a bFGF inhibitor (brivanib, BMS-582664) to the anticipated effects of this therapeutic approach predict tumours expressing resistance to , SU6668 and tumour stasis rather than regression and, therefore, anti- ZD6474 can significantly restart re-initiation of angiogenesis angiogenic agents are expected to be used either in and tumour progression (15, Dr. Mark Ayers, PRI Princeton, conjunction with standard therapy or in an adjuvant setting. personal communication). Currently, only few drugs are available to target the FGF receptor (CHIR258, PD173074, Phase I data. In the meantime, clinical activity of brivanib has BIBF-1120, BMS-582664) (Table IV). Amongst them, been evaluated in a series of phase I studies (20, 21). The drug brivanib (BMS-582664) is a novel, orally available and demonstrated moderate and manageable side effects (Table VI) elective tyrosine kinase inhibitor that targets the key with a maximal tolerated dose of 800 mg/day for further testing angiogenesis receptors VEGF-R2 and FGF-R2 (18). Since in phase II trials. However, it is important to note that, in some resistance to VEGF blockade involves vascular re-growth in patients, thromboembolic events and bleeding episodes a VEGF-independent, second wave of angiogenesis occurred. This effect, however, has also been reported for other (mediated in part by pro-angiogenic ligands of the FGF VEGF(-R) inhibitors (e.g. bevacizumab) (22) and is regarded family), counteracting such mechanisms by multi-targeting as a class-related toxicity of anti-angiogenetic drugs. It is alternative pro-angiogenic signalling circuits may improve probably due to the VEGF-R inhibitor-induced obliteration of efficacy of anti-angiogenic therapies. tumour microvessels. During its phase I programme, antitumour activity of brivanib has also been evaluated in Brivanib: A Dual Tyrosine Kinase Inhibitor combination with standard or monoclonal antibodies. In a recently published study, 18 patients (among Brivanib (BMS-582664; Bristol-Myers Squibb, New York, them 15 patients with colorectal cancer) were treated with USA, Figure 4) is a small molecule that has shown potent brivanib (320-800 mg/day) in combination with inhibition of VEGFR-2 as well as inhibition of FGFR-1 and (loading dose: 400 mg/m2 followed by 250 mg/m2 weekly); -2, another receptor protein tyrosine kinase underlying the medium treatment duration was eight weeks (range: 1-20 angiogenic pathway (Table V). The compound is a prodrug weeks). This combination did not enhance cetuximab toxicity of BMS-540215 and undergoes rapid intestinal resorption and the progression-free survival was longer in patients after oral administration. It is mainly metabolised to the expressing FGF than in those with no FGF expression (21). active metabolite BMS-540215 by the cytochrome P450 Due to these encouraging results a phase III study system (CYP3A4). Brivanib is no longer detectable in the (brivanib/cetuximab versus cetuximab) in metastatic plasma after approximately one hour and the peak drug colorectal carcinoma patients has been designed and is open concentration is found after 1-2 hours. Following a single for recruitment (21). Another combination study (irinotecan/ oral dose of 800 mg brivanib, the peak plasma concentration cetuximab plus placebo versus brivanib plus irinotecan/ was found to be 15 μM (20). Moreover, in animal systems, cetuximab) is ongoing (23).

4480 Dempke and Zippel: Brivanib, A Novel Dual Tyrosine Kinase Inhibitor (Review)

Table IV. VEGF-R inhibitors (small molecules) used in clinical trials.

Compound Targets Development status

Vatalanib VEGF-R1-3, PDGF-Rβ, c- Phase III Neovastat VEGF/VEGF-R binding, MMP-2,9 Phase III VEGF-R1-3, PDGF-Rβ, c-kit Phase III CEP-7055 VEGF-R1-3 Phase I/II CHIR258 VEGF-R1-3, FGF-R1-3 Phase I/II CP-547632 VEGF-R2 Phase I/II VEGF-R2, PDGF-R, c-kit Phase II/III E-7080 VEGF-R2 Phase I OSI-930 VEGF-R, c-kit Phase I/II (Sutent®) VEGF-R1-3, PDGF-Rβ, Flt-3, -c-kit, Ret Approved (Nexavar®) VEGF-R1-3, PDGF-Rβ, Flt-3, Raf Approved ZK-CDK VEGF-R1-3, PDGF-R, CDKs Phase III AG013736 VEGF-R1-3, PDGF-Rβ, c-kit Phase I/II AMG 706 VEGF-R1-2, PDGF-Rβ, c-kit Phase II KRN-951 VEGF-R1-3, PDGF-Rβ, c-kit Phase I/II Brivanib (BMS-584662) VEGF-R2, FGF-R1-2 Phase III BMS-690514 VEGF-R2, panHER, Flt-3 Phase I/II Zactima VEGF-R2, EGF-R, Ret Phase III BIBF-1120 VEGF-R1-3, FGF-R1-3, PDGF-R Phase II VEGF-R1-3, PDGF-Rβ, c-kit Phase II ABT-869 VEGF-R2,3, PDGF-R, c-kit, Flt-3 Phase I XL-999 FGF-R, VEGF-R, PDGF-R, Flt-3 Phase I/II PD173074 VEGF-R2, FGF-R2 Phase I (planned)

Table V. Inhibition of receptor tyrosine kinases by BMS-540215. The Table VI. Side-effects of brivanib. Data from four phase I studies and data are from the study of Cai et al. (19). one phase II study (modified after Park et al. (24)).

Tyrosine kinase IC50 (nM) of BMS-540215 (active metabolite) Side-effect (grade I-III) Frequency

VEGF-R1 390 Fatigue 33-45% VEGF-R2 34 Anorexia 27-39% VEGF-R3 10 Diarrhoea 14-35% Flk-1 23 Nausea 14-65% FGF-R1 148 Rash 6-24% FGF-R2 125 Hypertonia 9-28% Tie-2 445 Emesis 9-41%

Phase II data. Several phase II studies with brivanib are progression-free survival after six months (23). In parallel, a currently open for enrolment (, second cohort has been activated for HCC patients who have colorectal carcinoma and other solid tumours). For colorectal received no more than one prior anti-VEGF therapy. Both carcinoma patients, a phase I/II study with folinic acid, 5-FU studies are ongoing. Preliminary data from these studies have and oxaliplatin (FOLFOX) has been activated (N=40 been published at the 2008 meeting of the International Liver patients, FOLFOX plus brivanib versus FOLFOX plus Cancer Association in Chicago (24). The results presented placebo); however, this study was closed after recruitment of clearly demonstrated that brivanib has significant antitumour 17 patients. In addition, brivanib is being evaluated in one activity in patients with HCC and is generally well tolerated. phase II study in patients with hepatocellular carcinoma This study is continuing for patients who have failed one (HCC). In the first cohort (open since 2006, N=100 patients) anti-angiogenetic therapy. clinical efficacy of brivanib is investigated in patients with The combination of brivanib with cytostatic drugs, as locally advanced or metastatic HCC (inclusion criterion: no tested in the aforementioned studies, is critical for the future prior systemic chemotherapy). The primary endpoint is clinical development of brivanib, since, in xenograft models,

4481 ANTICANCER RESEARCH 30: 4477-4484 (2010) only tumour inhibition but not tumour regression were 5 Youssoufian H, Hicklin DJ and Rowinsky EK: Review: observed during brivanib therapy. Further evidence of this Monoclonal antibodies to the vascular endothelial growth factor approach came from an earlier study. Using the matrigel receptor-2 in cancer therapy. Clin Cancer Res 18(Suppl): 5544s- 5548s, 2007. mouse model, Dupont et al. (25) showed that inhibition of 6 Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS and the FGF/FGF-R system was able to enhance - Dvorak HF: Tumor cells secrete a vascular permeability factor induced cytotoxicity, suggesting that resistance to cisplatin that promotes accumulation of ascites fluid. Science 219: 983- is mediated, at least in part, by FGF-R. 985, 1983. 7 Alitalo K and Carmeliet P: Molecular mechanisms of Biomarker for brivanib treatment. The identification of a lymphangiogenesis in health and disease. Cancer Cell 3: 219- suitable and easily measured marker of antitumour activity 227, 2002. in the clinical setting would clearly facilitate the rapid 8 Hicklin DJ and Ellis LM: Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin clinical development of brivanib and probably other anti- Oncol 23: 1011-1027, 2005. VEGF-R agents. Currently, there exists a need to identify 9 Kerbel RS: Tumor angiogenesis. N Engl J Med 358: 2039-2049, biomarkers that will be able to indicate biological activity 2008. and predict efficacy at the molecular level for anti- 10 Dempke W and Heinemann V: Resistance to EGF-R (erbB-1) and angiogenesis drugs, which are anticipated to result in tumour VEGF-R modulating agents. Eur J Cancer 45: 1117-1128, 2009. stasis rather than regression. In an attempt to identify and 11 Tassi E and Wellstein A: The angiogenetic switch molecule, validate suitable biomarkers that may be used as surrogate secreted FDF-binding protein, an inhibitor of early stages of 66 end points for the anti-angiogenetic activity of brivanib in pancreatic and colorectal adenocarcinoma. Semin Oncol : 50- 56, 2006. clinical trials, research efforts have focused on collagen IV 12 Blanckaert VD, Hebbar M, Louchez MM, Vilain MO, Schelling (4A1). Collagen IV (as part of the basal membrane in ME and Peyrat JP: Basic fibroblast growth factor receptors and tumours) has been suggested to play an important role in their prognostic value in human breast cancer. Clin Cancer Res angiogenesis and tumour progression. Furthermore, collagen 4: 2939-2947, 1998. IV is co-expressed with VEGF-R2 and may be depleted by 13 Jaye M, Schlessinger J and Dionne C: FGF receptor tyrosine VEGF-R2 inhibitors (26). Using a murine HCT116 xenograft kinases: molecular analysis and signal transduction. Biochim model, Ayers et al. (27) have provided evidence that the Biophys Acta 1135: 185-199, 1992. 14 Deudero JJ, Caramelo C, Castellanos MC, Neria F, Fernández- mRNA expression of collagen IV correlates with the tumour Sánchez R, Calabia O, Peñate S and González-Pacheco FR: response, following brivanib exposure. A similar decrease of Induction of hypoxia-inducible factor 1alpha expression by collagen IV levels has also been detected immuno- vascular endothelial growth factor. J Biol Chem 283: 11435- histochemically. These results add weight to the proposal that 11444, 2008. collagen IV may play a significant role as a surrogate marker 15 Casanovas O, Hicklin DJ, Bergers G and Hanahan D: Drug for this treatment. Collagen IV is present in the vessels and resistance by evasion of antiangiogenetic targeting of VEGF in the blood, and decreases on commencement of treatment. signaling in late-stage pancreatic islet tumors. Cancer Cell 8: 299-309, 2005. Therefore, it may be used as a surrogate marker for brivanib 16 Nissen LJ, Cao R, Hedlung EM, Wang Z, Zhao X, Wetterskog treatment and should be investigated in great detail in the D, Funa K, Bråkenhielm E and Cao Y: Angiogenetic factors ongoing brivanib trials. FGF2 and PDGF-BB synergistically promote murine tumor neovascularization and metastasis. J Clin Invest 117: 2766-2777, Acknowledgements 2007. 17 Shi YH, Bingle L, Gong LH, Wang YX, Corke KP and Fang The Authors thank Dr. Ian B. Walters (Bristol-Myers Squibb, WG: Basic FGF augments hypoxia-induced HIF-1-alpha Princeton, NJ, USA) for critical reading of the manuscript. expression and VEGF release in T47D breast cancer cells. Pathology 39: 396-400, 2007. 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4482 Dempke and Zippel: Brivanib, A Novel Dual Tyrosine Kinase Inhibitor (Review)

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