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The Antitumor and Antiangiogenic Activity of Vascular Endothelial Cancer Therapy: Preclinical The Antitumor and Antiangiogenic Activity of Vascular Endothelial Growth Factor Receptor Inhibition Is Potentiated by ErbB1Blockade Patrizia Sini,1, 2 Lorenza Wyder,1Christian Schnell,1 Terence O’Reilly,1Amanda Littlewood,1 Ralph Brandt,3 Nancy E. Hynes,2 andJeanette Wood1 Abstract Purpose: Receptor tyrosine kinases of the ErbB family play important roles in the controlof tumor growth. Vascular endothelial growth factor (VEGF) stimulates endothelial cell proliferation, enhan- ces vascular permeability, and plays an important role in tumor vascularization.We evaluated the effects of selectiveVEGFreceptor (VEGFR; PTK787/ZK222584) and ErbB (PKI166 and ZD1839) inhibitors on tumor growth and angiogenesis and asked whether additional therapeutic benefit was conferred by combination treatment. Experimental Design: The antitumor activity of each inhibitor alone or in combination was assessed in human cancer models in immunocompromised mice. ErbB receptor expression and activation of downstream signaling pathway was evaluated in both tumor and endothelial cells. Results: Both ErbB inhibitors significantly enhanced the antitumor activity of PTK787/ ZK222584. In vitro, ErbB1inhibition blocked VEGF release by tumor cells and proliferation of both tumor and endothelial cells. In an in vitro angiogenesis assay, epidermal growth factor (EGF) stimulated the release ofVEGF by smooth muscle cells resulting in increased angiogenesis, a response blocked by administration of PTK787/ZK222584. Under basal condition, both ZD1839 and PTK787/ZK222584 blocked sprouting, likely via inhibition of an autocrine ErbB1 loop and VEGFR signaling, respectively, in endothelial cells. In conditions of limiting VEGF, EGF plays an important role in endothelial cell proliferation, survival, and sprouting. Conclusion: We have shown that activation of ErbB1triggers a plethora of effects, including direct effects on tumor and endothelial cells and indirect effects mediated via induction of VEGF release. Simultaneous blockade of ErbB1andVEGFR pathways results in a cooperative antitumor effect, indicating that this combination may represent a valid therapeutic strategy. The ErbB family of receptor tyrosine kinases has four members: therefore considered valid targets for anticancer therapy. ErbB1 (EGF receptor), ErbB2 (HER-2/neu), ErbB3 (HER3), and With respect to ErbB1, both antagonistic monoclonal anti- ErbB4 (HER4). These receptors play important roles in normal bodies and small-molecule tyrosine kinase inhibitors have development and in cancer biology. In particular, ErbB1 and shown clinical efficacy. Among these, ZD1839 (Iressa, Astra ErbB2 have been implicated in multiple types of human cancer, Zeneca Pharmaceuticals, Macclesfield, United Kingdom; ref. 3) where they control proliferation, survival, and spread of and PKI166 (Novartis Pharma AG, Basel, Switzerland; ref. 4) metastatic cancer cells (1). Alterations in ErbB receptors have are orally active ErbB1 and ErbB1/ErbB2 TK inhibitors, been correlated with more aggressive disease, lower rates of respectively. ZD1839 induced durable responses in patients survival, and poor response to therapy (2). ErbB receptors are with various tumor types (5). Both compounds, in addition to inhibiting tumor growth (6), have also been documented to have antiangiogenic effects (4, 7–9). Angiogenesis, the formation of new vessels from an existing Authors’ Affiliations: 1Novartis Institute for Biomedical Research, Oncology Research, 2Friederich Miescher Institute for Biomedical Research, Basel, vascular network, is required to sustain tumor growth and Switzerland, and 3Vivo Pharm Pty, Ltd.,Therbaton, Australia invasion (10, 11). A link between angiogenesis and ErbB Received 9/24/04; revised 3/22/05; accepted 3/31/05. receptor signaling has been established. Dividing endothelial Grant support: Novartis Research Foundation (N.E. Hynes). cells express functional ErbB1 (12, 13) and undergo apoptosis The costs of publication of this article were defrayed in part by the payment of page upon blockade of its activity (4). ErbB receptor inhibitors are charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. effective in preventing the release of proangiogenic factors, such Note: Supplementary data for this article are available at Clinical Cancer Research as vascular endothelial growth factor (VEGF), from tumor cells Online (http://clincancerres.aacrjournals.org/). (14–16). VEGF exerts potent mitogenic and prosurvival effects N.E. Hynes and J. Wood contributed equally to the article. on endothelial cells and has been shown to be a key factor in Requests for reprints: Patrizia Sini, Novartis Pharma AG, WKL.125.11.08, Klybeckstrasse, CH-4002 Basel, Switzerland. Phone: 41-61-696-1672; Fax: 41- pathologic situations that involve neovascularization and 61-696-6242; E-mail: [email protected]. changes in vascular permeability (17). The angiogenic signal F 2005 American Association for Cancer Research. is transmitted via cognate receptor tyrosine kinases (KDR and www.aacrjournals.org 4521 Clin Cancer Res 2005;11 (12) June 15, 2005 Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2005 American Association for Cancer Research. Cancer Therapy: Preclinical Flt-1), the VEGF receptors (VEGFR), located on the cell surface were cultured according to manufacturers’ instructions. The DU145 of the host vascular endothelium. Inhibition of VEGFR sig- prostate cancer cell line was obtained from American Type Culture naling prevents tumor angiogenesis thereby starving tumors of Collection (Rockville, MD). Cells were maintained in MEM EBS essential nutrients and oxygen. Various approaches have been (AMIMED, Allschwil, Switzerland) supplemented with 10% heat- inactivated FCS, 1% L-glutamine, 100 IU/mL penicillin, 100 Ag/mL adopted to interfere with the VEGF/VEGFR system including streptomycin. HC11 mouse mammary epithelial cells were grown as antagonistic antibodies (18–20), dominant-negative VEGFR described previously (35). NCI-H596 human adenosquamous lung mutants (21), recombinant soluble VEGFR proteins (22, 23), cancer cells were cultured in RPMI 1640 supplemented with 10% heat- and small-molecule tyrosine kinase inhibitors. Among these, inactivated FCS, 1% L-glutamine, 100 IU/mL penicillin, 100 Ag/mL PTK787/ZK222584 (Vatalanib, Novartis Pharma/Schering AG, streptomycin. Berlin, Germany), a potent inhibitor of both VEGFRs, inhibited Tumor models. BALB/c nu/nu mice were obtained from Iffa Cre´do growth and angiogenesis in experimental carcinoma models (L’Arbresle, France). Tumors were established by s.c. injection of (24, 25) and displayed activity in early clinical trials (26, 27). DU145 or NCI-H596 cancer cells (minimum 1-2 Â 106 cells in 100 AL Although blockade of ErbB receptor signaling would be PBS). Tumors from donor mice were passaged s.c. as fragments three expected to inhibit both tumor growth and angiogenesis, we times before use. HC11 mouse mammary epithelial cells were trans- postulated that combination with a VEGFR inhibitor may fected with oncogenic neuT and implanted as described previously (35). Three to 4 weeks after transplantation, mice showing mammary tumor provide additional therapeutic benefit. This hypothesis is growth of at least 10% during the previous 7 days were selected for supported by in vivo preclinical data we have obtained using efficacy studies. Animals were assigned to balanced groups, based on different agents to block ErbB and VEGFRs (patent no. WO02/ tumor size, so that means and SE were similar in each group (10-11 41882; refs. 28, 29). In addition, prolonged inhibition of animals/group). Tumor growth and body weights were determined tumor growth (30) and vascularization (31, 32) was observed twice per week (35). when agents targeting the VEGF axis were combined with Measurement of vascular endothelial growth factor concentration in antagonistic antibodies directed against ErbB1. plasma and tumor. Repeated plasma samples were taken from several Here we have investigated the molecular mechanisms mice at different time points (days 0, 1, and 8) and collected in underlying the effect of combining selective ErbB and VEGF separation tubes (BD Microtainer PST LH, NJ), left at room temperature j receptor inhibitors on the signaling pathways and biological for 90 seconds and spun at 4 C for 7 minutes at 7,000 rpm. Tumors were homogenized (BIO 101, Fastprep) in 500 AL PBS + 0.1% bovine functions of endothelial and tumor cells. We discuss the serum albumin and centrifuged. The concentration of human VEGF in hypothesis that in the tumor microenvironment, blockade of the supernatants and plasma was measured using a commercially ErbB1 signaling results in direct inhibition of tumor and available ELISA kit (Quantikine ELISA kit, R&D Systems, Inc., endothelial cell proliferation and survival as well as indirect Minneapolis, MN). inhibition of VEGFR signaling via a decrease in VEGF release. Immunofluorescence staining for terminal deoxynucleotidyl transferase–mediated nick-end labeling, CD31/ErbB1 and CD31/ Materials and Methods activated caspase-3. Cryosection sections (8 Am) of DU145 intra- dermal xenografts were fixed with acetone, blocked with 10% goat Antibodies and reagents. PTK787/ZK222584 was developed as a serum, and incubated with 1:100 dilution of polyclonal anti-ErbB1 and joint venture between Novartis Pharma and Schering. For in vitro assays, 1:200 dilution of monoclonal anti-CD31
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