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The Antiangiogenic Activity in Xenograft Models of Brivanib, A Published OnlineFirst January 26, 2010; DOI: 10.1158/1535-7163.MCT-09-0472 Published Online First on January 26, 2010 as 10.1158/1535-7163.MCT-09-0472 Research Article Molecular Cancer Therapeutics The Antiangiogenic Activity in Xenograft Models of Brivanib, a Dual Inhibitor of Vascular Endothelial Growth Factor Receptor-2 and Fibroblast Growth Factor Receptor-1 Kinases Rajeev S. Bhide, Louis J. Lombardo, John T. Hunt, Zhen-wei Cai, Joel C. Barrish, Susan Galbraith, Robert Jeyaseelan, Sr., Steven Mortillo, Barri S. Wautlet, Bala Krishnan, Daniel Kukral, Harold Malone, Anne C. Lewin, Benjamin J. Henley, and Joseph Fargnoli Abstract Tumor angiogenesis is a complex and tightly regulated network mediated by various proangiogenic fac- tors. The fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) family of growth fac- tors, and associated tyrosine kinase receptors have a major influence in tumor growth and dissemination and may work synergistically to promote angiogenesis. Brivanib alaninate is the orally active prodrug of brivanib, a selective dual inhibitor of FGF and VEGF signaling. Here, we show that brivanib demonstrates antitumor activity in a broad range of xenograft models over multiple dose levels and that brivanib alaninate shows dose-dependent efficacy equivalent to brivanib in L2987 human tumor xenografts. Brivanib alaninate (107 mg/kg) reduced tumor cell proliferation as determined by a 76% reduction in Ki-67 staining and reduced tumor vascular density as determined by a 76% reduction in anti-CD34 endothelial cell staining. Furthermore, Matrigel plug assays in athymic mice showed that brivanib alaninate inhibited angiogenesis driven by VEGF or basic FGF alone, or combined. Dynamic contrast-enhanced magnetic resonance imaging, used to assess the effects of brivanib alaninate on tumor microcirculation, showed a marked decrease in gadopentetate dime- glumine contrast agent uptake at 107 mg/kg dose, with a reduction in area under the plasma concentration- time curve from time 0 to 60 minutes at 24 and 48 hours of 54% and 64%, respectively. These results show that brivanib alaninate is an effective antitumor agent in preclinical models across a range of doses, and that ef- ficacy is accompanied by changes in cellular and vascular activities. Mol Cancer Ther; 9(2); OF1–10. ©2010 AACR. Introduction of growth factors and associated tyrosine kinase recep- tors (VEGF receptor, VEGFR) has been shown to have a Angiogenesis or neovascularization, the process by major influence on tumor angiogenesis, and anti-VEGF which new blood vessels are formed from preexisting agents, including bevacizumab, have been developed vessels, is critical to the growth, survival, and dissemina- and shown to provide therapeutic advantage in some tion of tumors. Initiation of tumor angiogenesis is gener- tumor types (3, 4). VEGF-A binds preferentially to ally mediated by secretion of a variety of growth factors VEGFR-1 and VEGFR-2, the latter being recognized as in response to local environmental triggers, as yet not ful- a primary mediator of vascular permeability and a pro- ly understood but thought to include hypoxia (1). Prom- moter of tumor-related endothelial cell migration and inent among these mediators are vascular endothelial proliferation. The implications for the survival and growth growth factor ligand A (VEGF-A) and fibroblast growth of tumor cells make the therapeutic targeting of VEGFR-2 factor (FGF)-1 (acidic FGF) and FGF-2 [basic FGF especially attractive (2, 5); however, there is growing evi- (bFGF)]. dence of VEGFR-1 promoting angiogenesis (2). The identification and characterization of tumor- The FGF family is also known to be influential in the derived angiogenic factors, their corresponding endothe- stimulation of endothelial cell proliferation and migra- lial cell receptors, and complex signaling networks tion (6, 7) and therefore has potential as an additional an- provides novel opportunities for the therapeutic develop- tineoplastic target (8). FGF receptor (FGFR)-1 is the ment of new antineoplastic agents (2). The VEGF family predominant FGFR to be expressed on endothelial cells, with FGFR-2 also present to a lesser extent. FGF/FGFR signaling is thought to contribute to both the early and Authors' Affiliation: Bristol-Myers Squibb Research & Development, Princeton, New Jersey late stages of tumor angiogenesis and to affect both tu- Corresponding Author: Joseph Fargnoli, Bristol-Myers Squibb, Re- mor cell invasion and migration (6, 7). Some evidence search & Development, Route 206 and Province Line Road, Princeton, suggests that stimulation of the FGF signaling network NJ 08540. Phone: 609-252-5268. E-mail: [email protected] can induce a proangiogenic effect creating a favorable en- doi: 10.1158/1535-7163.MCT-09-0472 vironment for vasculature growth through the modula- ©2010 American Association for Cancer Research. tion of endothelial cell proliferation and migration, the www.aacrjournals.org OF1 Downloaded from mct.aacrjournals.org on September 26, 2021. © 2010 American Association for Cancer Research. Published OnlineFirst January 26, 2010; DOI: 10.1158/1535-7163.MCT-09-0472 Bhide et al. production of proteases, and the promotion of integrin Quarantine was ensured for 7 d before tumor implanta- and cadherin receptor expression (7). tion and efficacy testing. All animal studies were done Recent research has pointed to the importance of cross- under the approval of the Bristol-Myers Squibb Animal talk between bFGF and VEGF, which may reflect temporal Care and Use Committee and in accordance with the differences in their role. Synergistic vascularization act- American Association for Accreditation of Laboratory ivity is seen when the pair is coexpressed simultaneously Animal Care. in athymic mouse xenograft models, resulting in fast- growing tumors with high vessel density patency and Xenograft Tumor Models permeability (9). In mouse models, the administration of Human tumor xenografts used included L2987 (non– VEGFR-2 antagonists has been found to block both VEGF- small-cell lung carcinoma), H3396 (breast carcinoma), and bFGF-induced angiogenesis and endothelial cell pro- and HCT116/VM46 (paclitaxel-resistant colon carcino- liferation. These findings led to the hypothesis that ma), which were established at Bristol-Myers Squibb. endogenous VEGF is required for the in vitro angiogenic Tumors were implanted s.c. as small fragments of ≤0.1 effect induced by exogenous bFGF (10, 11). The expression to 0.2 mm3 using a 13-g trocar. Tumors were allowed to of dominant-negative FGFR-1 and FGFR-2 in glioma cells grow to an approximate size of 100 mm3 before the initi- has been shown to result in decreased tumor vasculariza- ation of treatment. Treatment and control groups con- tion paralleled by VEGF downregulation (12). These sisted of 8 to 10 mice. Tumor size was measured twice findings indicate that tumors may be able to evade ini- weekly. Tumor volume was calculated by measuring per- tial VEGF inhibition by altering the regulation of other pendicular tumor diameters with Vernier scale calipers, growth factors involved in angiogenesis and tumor cell and using the formula: 1/2 [length × (width)2]. The proliferation. The complexity of the regulation of tumor health of the mice was closely monitored and the mice angiogenesis suggests that the targeting of more than were immediately euthanized if any signs of distress one pathway may be beneficial (4). were observed. Brivanib is a small-molecule VEGFR/FGFR tyrosine Antitumor efficacy was expressed as percentage tumor kinase inhibitor that is currently undergoing clinical in- growth inhibition (% TGI) and therefore represents the vestigation. Due to the low aqueous solubility of briva- maximum effect. TGI was calculated as follows: nib, a prodrug strategy was pursued that resulted in a prodrug with high aqueous solubility, brivanib alaninate % TGI ¼f1 ½ðTt À T0Þ=ðCt À C0Þg  100 (13). Brivanib, the parent compound, has previously been C 3 shown to be a selective inhibitor of FGFR-1 and FGFR-2, in which t is the median tumor volume (mm ) of vehicle C – t T and VEGFR-1, VEGFR-2, and VEGFR-3 in vitro (14, 15). control ( ) treated mice at time ; t is the median tumor 3 T t C Additionally, brivanib has also shown antitumor activity volume (mm ) of treated mice, , at time ; and 0 is the 3 in vivo against the H3396 human breast tumor xenograft median tumor volume (mm ) of vehicle control–treated model (14). Here, we report the in vivo antiangiogenic mice at time 0. and tumor growth-inhibitory effects of brivanib and its Tumor volume doubling time was measured over the prodrug, brivanib alaninate, in human xenograft mouse linear growth range of the tumor, generally between 250 models across a range of tumor types. and 1,000 mm3 tumor size. TGI of ≥50% over one tumor volume doubling time was considered an active antitu- Materials and Methods mor response. Reagents Immunohistochemistry Brivanib alaninate is the L-alanine ester prodrug of bri- L2987 tumor xenografts were excised, fixed in 10% vanib to improve the low aqueous solubility of brivanib neutral buffered formalin, processed for paraffin embed- at equilibrium (14, 15). In this series of studies, brivanib ding, and sectioned at 5 μm. Slides were allowed to dry alaninate was administered at a volume of 0.01 mL/g of and immunohistochemistry was done. Cell proliferation mouse with sodium citrate buffer, with a final pH of 3.5 was evaluated using an anti-Ki67 antibody (Santa Cruz used as vehicle for the dosing solution. Brivanib was dis- Biotechnology, Inc.). Vascular density was visualized solved in a 7:3 solution of PEG400/H2O and was admin- through an anti-CD34 antibody (BD Pharmingen). The istered at a volume of 0.01 mL/g. Both compounds were dilution of both antibodies was 1:100 in a serum-free orally dosed using disposable 20-g oral gavage needles blocking agent (DAKO Cytomation). Tissue was blocked (Popper and Sons, Inc.) on a daily schedule with a gen- for endogenous peroxidase by immersion in 3% H2O2 for eral duration of 14 d.
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