Stephen R Wedge
Affiliation: AstraZeneca R and D
- AZD2171: a highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancerStephen R Wedge
Cancer Bioscience, AstraZeneca, Alderley Park, Macclesfield, Cheshire, United Kingdom
Cancer Res 65:4389-400. 2005..AZD2171 is being developed clinically as a once-daily oral therapy for the treatment of cancer...
- ZD6474--a novel inhibitor of VEGFR and EGFR tyrosine kinase activityA J Ryan
Department of Cancer and Infection Research, AstraZeneca, Macclesfield, Cheshire SK10 4TG, UK
Br J Cancer 92:S6-13. 2005..RET kinase has also been identified as a third target for ZD6474. This review summarises preclinical studies with this unique agent and considers its future direction in cancer treatment...
- Use of dynamic contrast-enhanced MRI to evaluate acute treatment with ZD6474, a VEGF signalling inhibitor, in PC-3 prostate tumoursD Checkley
Department of Enabling Science and Technology, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK
Br J Cancer 89:1889-95. 2003..Dynamic contrast-enhanced magnetic resonance imaging may have a role in assessing the acute effects of VEGF signalling inhibition, in clinical dose-ranging studies...
- ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administrationStephen R Wedge
Department of Cancer and Infection Research, AstraZeneca, Cheshire SK10 4TG, United Kingdom
Cancer Res 62:4645-55. 2002..4 cm(3) volume. ZD6474 is currently in Phase I clinical development as a once-daily oral therapy in patients with advanced cancer...
- Synthesis and SAR of 1-acetanilide-4-aminopyrazole-substituted quinazolines: selective inhibitors of Aurora B kinase with potent anti-tumor activityKevin M Foote
AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom
Bioorg Med Chem Lett 18:1904-9. 2008..The combination of potent cell activity and high free-drug exposure led to pharmacodynamic changes in the tumor at low doses, indicative of Aurora B-kinase inhibition and a reduction in tumor volume...
- Acute pharmacodynamic and antivascular effects of the vascular endothelial growth factor signaling inhibitor AZD2171 in Calu-6 human lung tumor xenograftsNeil R Smith
Cancer Bioscience, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom
Mol Cancer Ther 6:2198-208. 2007..In addition, this work highlights the utility of measuring either pY1175/1173 or pY1214/1212 on VEGFR-2 as a pharmacodynamic marker of VEGFR-2 activation...
- Inhibition of vascular endothelial growth factor-a signaling induces hypertension: examining the effect of cediranib (recentin; AZD2171) treatment on blood pressure in rat and the use of concomitant antihypertensive therapyJon O Curwen
Department of Cancer Bioscience, AstraZeneca, Macclesfield, Cheshire, United Kingdom
Clin Cancer Res 14:3124-31. 2008..We examined the effect of cediranib, a highly potent VEGF signaling inhibitor, on the blood pressure of rats and the ability of standard antihypertensive agents to modulate the consequences of VEGF signaling inhibition...
- AZD1152, a selective inhibitor of Aurora B kinase, inhibits human tumor xenograft growth by inducing apoptosisRobert W Wilkinson
AstraZeneca Pharmaceuticals, Macclesfield, Cheshire, United Kingdom
Clin Cancer Res 13:3682-8. 2007..In the current study, we examined the in vivo effects of AZD1152, a novel and specific inhibitor of Aurora kinase activity (with selectivity for Aurora B)...
- Examining the acute effects of cediranib (RECENTIN, AZD2171) treatment in tumor models: a dynamic contrast-enhanced MRI study using gadopentateDaniel P Bradley
Department of Enabling Capabilities and Sciences, AstraZeneca, Mereside, Alderley Park, Cheshire, SK10 4TG, UK
Magn Reson Imaging 27:377-84. 2009..05) in both tumor models and iAUC by 23% (P>.05) and 33% (P>.005) in Lovo and C6, respectively. This is the first preclinical investigation to examine the effect of cediranib treatment on tumors by DCE-MRI with gadopentate...
- Assessing the activity of cediranib, a VEGFR-2/3 tyrosine kinase inhibitor, against VEGFR-1 and members of the structurally related PDGFR familySandra R Brave
Oncology iMED, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom
Mol Cancer Ther 10:861-73. 2011..Collectively, these data indicate that cediranib is a potent pan-VEGFR kinase inhibitor with similar activity against c-Kit but is significantly less potent than PDGFR-α and PDGFR-β...
- Dynamic contrast-enhanced MRI of vascular changes induced by the VEGF-signalling inhibitor ZD4190 in human tumour xenograftsDavid Checkley
Enabling Science and Technology, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK
Magn Reson Imaging 21:475-82. 2003..Collectively these studies suggest that DCEMRI using gadopentetate may have potential clinically, for monitoring inhibition of VEGF signaling in solid tumors...
- Anti-tumour and anti-vascular effects of cediranib (AZD2171) alone and in combination with other anti-tumour therapiesJane Kendrew
Translational Sciences, AstraZeneca Oncology, Alderley Park, Macclesfield SK10 4TF, UK
Cancer Chemother Pharmacol 71:1021-32. 2013..The aim of this preclinical study was to examine the effect of combining cediranib with mechanistically distinct anti-tumour therapies...
- An antibody targeted to VEGFR-2 Ig domains 4-7 inhibits VEGFR-2 activation and VEGFR-2-dependent angiogenesis without affecting ligand bindingJane Kendrew
Cancer Bioscience, AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire, United Kingdom
Mol Cancer Ther 10:770-83. 2011..These data show targeting VEGFR-2 outside of the ligand binding domain results in potent inhibition of VEGFR-2 signaling and inhibition of angiogenesis in vitro and in vivo...
- Placental growth factor neutralising antibodies give limited anti-angiogenic effects in an in vitro organotypic angiogenesis modelSandra R Brave
Cancer Bioscience, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK
Angiogenesis 13:337-47. 2010..Such data questions whether neutralising PlGF would have a therapeutic benefit in vivo in the presence of pathological concentrations of VEGF-A...
- Discovery, synthesis, and in vivo activity of a new class of pyrazoloquinazolines as selective inhibitors of aurora B kinaseAndrew A Mortlock
AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom
J Med Chem 50:2213-24. 2007..The compounds display striking in vivo activity, and compound 5 (AZD1152) has been selected for clinical evaluation and is currently in phase 1 clinical trials...
- The use and refinement of rodent models in anti-cancer drug discovery: a reviewJon O Curwen
Cancer Bioscience, AstraZeneca, Alderley Park, Macclesfield, UK
Altern Lab Anim 37:173-80. 2009..The changes in the UK guidelines on the use of rodents in preclinical cancer testing are also used as an illustration of the progressive refinement in tumour models and drug testing...
- Novel 4-anilinoquinazolines with C-7 basic side chains: design and structure activity relationship of a series of potent, orally active, VEGF receptor tyrosine kinase inhibitorsLaurent F Hennequin
AstraZeneca, Centre de Recherches, Z I la Pompelle, B P 1050, Chemin de Vrilly, 51689 Reims, Cedex 2, France
J Med Chem 45:1300-12. 2002..001, Mann Whitney rank sum test), and substantial inhibition (36%, P < 0.02) was evident with 12.5 mg/kg/day...
- Discovery of novel and potent thiazoloquinazolines as selective Aurora A and B kinase inhibitorsFrederic H Jung
AstraZeneca, Centre de Recherches, Parc Industriel Pompelle, BP1050, Chemin de Vrilly, 51689 Reims Cedex 2, France
J Med Chem 49:955-70. 2006....
- Mechanisms that influence tumour response to VEGF-pathway inhibitorsNeil R Smith
Oncology Innovative Medicines, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, U K
Biochem Soc Trans 42:1601-7. 2014..The present review discusses the clinical successes of the VEGF inhibitors, the factors that may limit their utility, and the potential opportunities to maximize benefit from treatment with these agents in the future. ..
- AZD3514: a small molecule that modulates androgen receptor signaling and function in vitro and in vivoSarah A Loddick
Corresponding Author A Nigel Brooks, Oncology iMED, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, United Kingdom
Mol Cancer Ther 12:1715-27. 2013..Furthermore, this class of compound showed antitumor activity in the HID28 mouse model of CRPC in vivo. AZD3514 is currently in phase I clinical evaluation...
- Tumor stromal architecture can define the intrinsic tumor response to VEGF-targeted therapyNeil R Smith
Authors Affiliations Oncology Innovative Medicines, AstraZeneca, Alderley Park, Macclesfield, Cheshire and Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom
Clin Cancer Res 19:6943-56. 2013....
- Examining changes in [18 F]FDG and [18 F]FLT uptake in U87-MG glioma xenografts as early response biomarkers to treatment with the dual mTOR1/2 inhibitor AZD8055Heather G Keen
Personalised Healthcare and Biomarkers, AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK
Mol Imaging Biol 16:421-30. 2014....
- Expression of stromal genes associated with the angiogenic response are not differentiated between human tumour xenografts with divergent vascular morphologiesMatthew Farren
Oncology iMED, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK
Angiogenesis 15:555-68. 2012..The data indicate that although the angiogenic response to the tumour results in reproducible stromal architectures, these responses are not differentiated at the level of gene expression...
- The clinical development of molecularly targeted agents in combination with radiation therapy: a pharmaceutical perspectiveOzlem U Ataman
Global Medicines Development, AstraZeneca, Alderley Park, Macclesfield, Cheshire, United Kingdom
Int J Radiat Oncol Biol Phys 84:e447-54. 2012..Collectively, this analysis suggests that such trials are not given priority by pharmaceutical companies. The potential reasons for this and some challenges and possible solutions are discussed...
- Complete structure of an increasing capillary permeability protein (ICPP) purified from Vipera lebetina venom. ICPP is angiogenic via vascular endothelial growth factor receptor signallingAmmar Gasmi
Laboratoire des Venins et Toxines, Institut Pasteur de Tunis, B P 74, 1002 Tunis Belvedere, Tunisia
J Biol Chem 277:29992-8. 2002..Therefore, we conclude that this venom-derived ICPP exerts its biological action (permeability and angiogenesis) through activation of VEGF receptor signaling (VEGF-R2 and possibly VEGF-R1)...
- ZD6474, a potent inhibitor of vascular endothelial growth factor signaling, combined with radiotherapy: schedule-dependent enhancement of antitumor activityKaye J Williams
School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, United Kingdom
Clin Cancer Res 10:8587-93. 2004..This study was designed to determine the efficacy of combining ZD6474 and radiotherapy in vivo...
- Combination antiangiogenic and androgen deprivation therapy for prostate cancer: a promising therapeutic approachBrian Nicholson
Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia, USA
Clin Cancer Res 10:8728-34. 2004..We examined combined androgen ablation and inhibition of VEGF signaling in an androgen-sensitive human prostate cancer xenograft model (LNCaP) that is known to develop androgen-independent growth after androgen ablation...
- ZD6474, an inhibitor of vascular endothelial growth factor receptor tyrosine kinase, inhibits growth of experimental lung metastasis and production of malignant pleural effusions in a non-small cell lung cancer modelYuka Matsumori
Department of Internal Medicine and Molecular Therapeutics, University of Tokushima School of Medicine, Tokushima, 3 18 15 Kuramoto cho, Tokushima, Japan
Oncol Res 16:15-26. 2006..These results indicate that ZD6474, an inhibitor of VEGFR-2, may be useful in controlling the growth of established lung metastasis and pleural effusions by NSCLC...
- Combining radiotherapy with AZD2171, a potent inhibitor of vascular endothelial growth factor signaling: pathophysiologic effects and therapeutic benefitKaye J Williams
Department of Pharmacy, University of Manchester, Coupland Street, Manchester M13 9PL, United Kingdom
Mol Cancer Ther 6:599-606. 2007..Collectively, these data support the clinical development of AZD2171 in combination with radiotherapy...
- The tyrosine kinase inhibitor cediranib blocks ligand-induced vascular endothelial growth factor receptor-3 activity and lymphangiogenesisCaroline A Heckman
Molecular Cancer Biology Laboratory, Biomedicum Helsinki and Ludwig Institute for Cancer Research, University of Helsinki, Helsinki, Finland
Cancer Res 68:4754-62. 2008..Cediranib may, therefore, be an effective means of preventing tumor progression, not only by inhibiting VEGFR-2 activity and angiogenesis, but also by concomitantly inhibiting VEGFR-3 activity and lymphangiogenesis...
- Antiangiogenic and antitumor activity of a novel vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor ZD6474 in a metastatic human pancreatic tumor modelClaudius Conrad
Department of Surgery, University of Munich Grosshadern LMU, Munich, Germany
Anticancer Drugs 18:569-79. 2007..ZD6474 decreased primary pancreatic tumor growth and reduced lymph node and liver metastases compared with controls or gemcitabine alone. Tumor growth was inhibited further in animals receiving ZD6474 and gemcitabine in combination...
- Dual inhibition of VEGFR and EGFR signaling reduces the incidence and size of intestinal adenomas in Apc(Min/+) miceDenis Alferez
Cancer Research UK, Histopathology Unit, London Research Institute, London, UK
Mol Cancer Ther 7:590-8. 2008..Therefore, targeting both VEGFR- and EGFR-dependent signaling may be a beneficial strategy in early intestinal cancer...