Integrin αvβ3‐targeted cancer therapy

Anti‐angiogenesis is a promising strategy for the treatment of cancer. Integrins, consisting of two noncovalently bound transmembrane α and β subunits, are an important molecular family involved in tumor angiogenesis. The blockade of integrin signaling has been demonstrated to be efficient to inhibit tumor growth, angiogenesis, and metastasis. Among all the integrins, αvβ3 seems to be the most important one during tumor angiogenesis. The inhibition of integrin αvβ3 signaling with antibodies, peptides, peptidomimetics, and other antagonists has great potential in the treatment of cancer. In addition, integrin αvβ3 is highly expressed on activated endothelial cells, new‐born vessels as well as some tumor cells, but is not present in resting endothelial cells and most normal organ systems, making it a suitable target for anti‐angiogenic therapy. In this article we will review the role of integrin αvβ3 in angiogenesis, present recent progress in the use of integrin αvβ3 antagonists and integrin‐targeted delivery systems as potential cancer therapeutics, and discuss future perspectives. Drug Dev Res 69:329–339, 2008. © 2008 Wiley‐Liss, Inc.

[1]  J. Posey,et al.  A pilot trial of Vitaxin, a humanized anti-vitronectin receptor (anti alpha v beta 3) antibody in patients with metastatic cancer. , 2001, Cancer biotherapy & radiopharmaceuticals.

[2]  T. Mikkelsen,et al.  Phase I and correlative biology study of cilengitide in patients with recurrent malignant glioma. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[3]  Robert A. Beckman,et al.  Phase I Evaluation of a Fully Human Anti–αv Integrin Monoclonal Antibody (CNTO 95) in Patients with Advanced Solid Tumors , 2007, Clinical Cancer Research.

[4]  G. Alghisi,et al.  Vascular integrins in tumor angiogenesis: mediators and therapeutic targets. , 2006, Endothelium : journal of endothelial cell research.

[5]  S. Niewiarowski,et al.  Trigramin. A low molecular weight peptide inhibiting fibrinogen interaction with platelet receptors expressed on glycoprotein IIb-IIIa complex. , 1987, The Journal of biological chemistry.

[6]  David A. Cheresh,et al.  Role of integrins in cell invasion and migration , 2002, Nature Reviews Cancer.

[7]  J. Tímár,et al.  Multiple Roles for Platelet GPIIb/IIIa and αvβ3 Integrins in Tumor Growth, Angiogenesis, and Metastasis , 2002 .

[8]  D. Cheresh.  Human endothelial cells synthesize and express an Arg-Gly-Asp-directed adhesion receptor involved in attachment to fibrinogen and von Willebrand factor. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[9]  J. Folkman.  Angiogenesis in cancer, vascular, rheumatoid and other disease , 1995, Nature Medicine.

[10]  J. Debus,et al.  Inhibition of αvβ3 Integrin Survival Signaling Enhances Antiangiogenic and Antitumor Effects of Radiotherapy , 2005, Clinical Cancer Research.

[11]  D. Shaw,et al.  Pharmacology of the Novel Antiangiogenic Peptide ATN-161 (Ac-PHSCN-NH2): Observation of a U-Shaped Dose-Response Curve in Several Preclinical Models of Angiogenesis and Tumor Growth , 2008, Clinical Cancer Research.

[12]  Fan Wang,et al.  Integrin αvβ3-Targeted Radioimmunotherapy of Glioblastoma Multiforme , 2008, Clinical Cancer Research.

[13]  T. Huang,et al.  What have snakes taught us about integrins? , 1998, Cellular and Molecular Life Sciences CMLS.

[14]  Michael S. Pepper,et al.  αvβ3 and αvβ5 integrin antagonists inhibit angiogenesis in vitro , 2004, Angiogenesis.

[15]  A. Corti,et al.  Tumor Vascular Targeting with Tumor Necrosis Factor α and Chemotherapeutic Drugs , 2004 .

[16]  Juan J Calvete,et al.  Snake venom disintegrins: novel dimeric disintegrins and structural diversification by disulphide bond engineering. , 2003, The Biochemical journal.

[17]  J. Folkman.  Tumor angiogenesis: therapeutic implications. , 1971, The New England journal of medicine.

[18]  A. Berghaus,et al.  Antiangiogenic combination tumor therapy blocking αv‐integrins and VEGF‐receptor‐2 increases therapeutic effects in vivo , 2006, International journal of cancer.

[19]  Wenjun Guo,et al.  Integrin signalling during tumour progression , 2004, Nature Reviews Molecular Cell Biology.

[20]  F. Mitjans,et al.  In vivo therapy of malignant melanoma by means of antagonists of αv integrins , 2000 .

[21]  Carlos F. Barbas,et al.  Integrin αvβ3‐targeted therapy for Kaposi's sarcoma with an in vitro‐evolved antibody , 2002 .

[22]  David A. Cheresh,et al.  Definition of Two Angiogenic Pathways by Distinct αv Integrins , 1995, Science.

[23]  T. N. Campbell,et al.  Targeted antiangiogenic therapy for cancer using Vitaxin: a humanized monoclonal antibody to the integrin alphavbeta3. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[24]  F. Sarkar,et al.  Antiintegrin alpha v beta 3 blocks human breast cancer growth and angiogenesis in human skin. , 1995, The Journal of clinical investigation.

[25]  R. Colomer.  Gemcitabine and paclitaxel in metastatic breast cancer: a review. , 2004, Oncology.

[26]  M. Mascelli,et al.  Potential future clinical applications for the GPIIb/IIIa antagonist, abciximab in thrombosis, vascular and oncological indications , 2009, Pathology & Oncology Research.

[27]  R. Jordan,et al.  Inhibition of angiogenesis and tumor growth by murine 7E3, the parent antibodyof c7E3 Fab (abciximab; ReoProTM) , 2004, Angiogenesis.

[28]  A. Borkhardt,et al.  The application of siRNA technology to cancer biology discovery. , 2007, Advances in cancer research.

[29]  J. Martínez,et al.  An anti-alpha v-integrin antibody that blocks integrin function inhibits the development of a human melanoma in nude mice. , 1995, Journal of cell science.

[30]  R. Jain.  Normalization of Tumor Vasculature: An Emerging Concept in Antiangiogenic Therapy , 2005, Science.

[31]  C. Kumar.  Integrin alpha v beta 3 as a therapeutic target for blocking tumor-induced angiogenesis. , 2003, Current drug targets.

[32]  J. Folkman.  Role of angiogenesis in tumor growth and metastasis. , 2002, Seminars in oncology.

[33]  D. Santoli,et al.  New Insights on Disintegrin-Receptor Interactions: Eristostatin and Melanoma Cells , 2001, Pathophysiology of Haemostasis and Thrombosis.

[34]  M. Polokoff,et al.  Characterization and platelet inhibitory activity of bitistatin, a potent arginine-glycine-aspartic acid-containing peptide from the venom of the viper Bitis arietans. , 1989, The Journal of biological chemistry.

[35]  H. Oettle,et al.  Cilengitide (EMD 121974) arrests the growth of a heavily pretreated highly vascularised head and neck tumour. , 2004, Oral oncology.

[36]  F. McCabe,et al.  CNTO 95, a fully human anti αv integrin antibody, inhibits cell signaling, migration, invasion, and spontaneous metastasis of human breast cancer cells , 2007, Clinical & Experimental Metastasis.

[37]  E. Raymond,et al.  Phase I and pharmacokinetic study of etaracizumab (Abegrin™), a humanized monoclonal antibody against αvβ3 integrin receptor, in patients with advanced solid tumors , 2008, Investigational New Drugs.

[38]  K. O'Byrne,et al.  Angiogenesis as a biomarker and target in cancer chemoprevention. , 2001, The Lancet. Oncology.

[39]  R. Jordan,et al.  Abciximab (ReoPro, Chimeric 7E3 Fab) Demonstrates Equivalent Affinity and Functional Blockade of Glycoprotein IIb/IIIa and αvβ3 Integrins , 1998 .

[40]  S. Robinson,et al.  Design, synthesis, and evaluation of radiolabeled integrin αvβ3 receptor antagonists for tumor imaging and radiotherapy , 2003 .

[41]  A. Heerschap,et al.  Effects of the tumor vasculature targeting agent NGR-TNF on the tumor microenvironment in murine lymphomas , 2006, Investigational New Drugs.

[42]  Richard O Hynes,et al.  Integrins Bidirectional, Allosteric Signaling Machines , 2002, Cell.

[43]  M. Schwartz.  Integrin signaling revisited. , 2001, Trends in cell biology.

[44]  V. Fried,et al.  Barbourin. A GPIIb-IIIa-specific integrin antagonist from the venom of Sistrurus m. barbouri. , 1991, The Journal of biological chemistry.

[45]  A. Corti,et al.  Inhibition of tumor growth by intramuscular injection of cDNA encoding tumor necrosis factor alpha coupled to NGR and RGD tumor-homing peptides. , 2004, Human gene therapy.

[46]  M. Bednarski,et al.  Tumor Regression by Targeted Gene Delivery to the Neovasculature , 2002, Science.

[47]  R J Gould,et al.  Echistatin. A potent platelet aggregation inhibitor from the venom of the viper, Echis carinatus. , 1988, The Journal of biological chemistry.

[48]  Wan-yu Wang,et al.  Purification, cloning and biological characterization of a novel disintegrin from Trimeresurus jerdonii venom. , 2004, Toxicon : official journal of the International Society on Toxinology.

[49]  David C. Smith,et al.  Phase II evaluations of cilengitide in asymptomatic patients with androgen-independent prostate cancer: scientific rationale and study design. , 2006, Clinical genitourinary cancer.

[50]  Milind Rajopadhye,et al.  Tumor targeting with radiolabeled alpha(v)beta(3) integrin binding peptides in a nude mouse model. , 2002, Cancer research.

[51]  A. Corti,et al.  Crucial Role for Interferon γ in the Synergism between Tumor Vasculature-Targeted Tumor Necrosis Factor α (NGR-TNF) and Doxorubicin , 2004, Cancer Research.

[52]  Kathleen R. Lamborn,et al.  Cilengitide Targeting of αvβ3 Integrin Receptor Synergizes with Radioimmunotherapy to Increase Efficacy and Apoptosis in Breast Cancer Xenografts , 2002 .

[53]  T. MacDonald,et al.  Phase I clinical trial of cilengitide in children with refractory brain tumors: Pediatric Brain Tumor Consortium Study PBTC-012. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[54]  R. Schiffelers,et al.  Cancer siRNA therapy by tumor selective delivery with ligand-targeted sterically stabilized nanoparticle. , 2004, Nucleic acids research.

[55]  W. Cai,et al.  Integrin αvβ3 Antagonists for Anti-Angiogenic Cancer Treatment , 2007 .

[56]  Weibo Cai,et al.  Anti-Angiogenic Cancer Therapy Based on Integrin αvβ3 Antagonism , 2006 .

[57]  R. Wilder,et al.  Integrin alpha V beta 3 as a target for treatment of rheumatoid arthritis and related rheumatic diseases , 2002, Annals of the rheumatic diseases.

[58]  F. Mitjans,et al.  Inhibition of human immunodeficiency virus type 1 infection in macrophages by an alpha-v integrin blocking antibody. , 2006, Antiviral research.

[59]  A. Corti,et al.  Vasculature‐targeted tumor necrosis factor‐alpha increases the therapeutic index of doxorubicin against prostate cancer , 2008, The Prostate.

[60]  D. Cheresh,et al.  Requirement of vascular integrin alpha v beta 3 for angiogenesis. , 1994, Science.

[61]  R. Benjamin,et al.  Pilot study of vitaxin—an angiogenesis inhibitor—in patients with advanced leiomyosarcomas , 2001, Cancer.

[62]  M. Trikha,et al.  CNTO 95, a fully human monoclonal antibody that inhibits αv integrins, has antitumor and antiangiogenic activity in vivo , 2004, International journal of cancer.

[63]  Arnoud Sonnenberg,et al.  Function and interactions of integrins , 2001, Cell and Tissue Research.

[64]  Rakesh K. Jain,et al.  Normalizing tumor vasculature with anti-angiogenic therapy: A new paradigm for combination therapy , 2001, Nature Medicine.

[65]  R. Pitti,et al.  Platelet glycoprotein IIb-IIIa protein antagonists from snake venoms: evidence for a family of platelet-aggregation inhibitors. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[66]  M. Coleman,et al.  Doxorubicin-formaldehyde conjugates targeting alphavbeta3 integrin. , 2004, Molecular cancer therapeutics.

[67]  C. Carron,et al.  Peptidomimetic antagonists of alphavbeta3 inhibit bone resorption by inhibiting osteoclast bone resorptive activity, not osteoclast adhesion to bone. , 2000, The Journal of endocrinology.

[68]  R. Sherwin,et al.  Intravenous liposomal delivery of the snake venom disintegrin contortrostatin limits breast cancer progression. , 2004, Molecular cancer therapeutics.

[69]  W. Cai,et al.  Integrin-targeted imaging and therapy with RGD4C-TNF fusion protein , 2008, Molecular Cancer Therapeutics.

[70]  K. Weinberg,et al.  αv‐Integrin antagonist EMD 121974 induces apoptosis in brain tumor cells growing on vitronectin and tenascin , 2002, International journal of cancer.

[71]  Thomas C Chen,et al.  Development of a Novel Recombinant Disintegrin, Contortrostatin, as an Effective Anti-Tumor and Anti-Angiogenic Agent , 2006, Pathophysiology of Haemostasis and Thrombosis.

[72]  M. Woodle,et al.  Delivering Small Interfering RNA for Novel Therapeutics , 2008, Methods in molecular biology.

[73]  H. Jin,et al.  Integrins: roles in cancer development and as treatment targets , 2004, British Journal of Cancer.

[74]  M. Hensler,et al.  Stepwise in vitro affinity maturation of Vitaxin, an αvβ3-specific humanized mAb , 1998 .

[75]  Douglas S. Conklin,et al.  Gene expression: RNA interference in adult mice , 2002, Nature.

[76]  J. Folkman.  Clinical Applications of Research on Angiogenesis , 1995 .

[77]  William F. Westlin,et al.  A Peptidomimetic Antagonist of the Integrin αvβ3 Inhibits Leydig Cell Tumor Growth and the Development of Hypercalcemia of Malignancy , 1998 .

[78]  J. Haier,et al.  Integrins in cancer treatment. , 2006, Current cancer drug targets.

[79]  P. Carmeliet,et al.  Angiogenesis in cancer and other diseases , 2000, Nature.

[80]  Daniel L. Gustafson,et al.  Assessment of the biological and pharmacological effects of the ανβ3 and ανβ5 integrin receptor antagonist, cilengitide (EMD 121974), in patients with advanced solid tumors , 2007 .

[81]  I. Rabinovitz,et al.  Use of RNA interference to inhibit integrin (α6β4)-mediated invasion and migration of breast carcinoma cells , 2004, Clinical & Experimental Metastasis.

[82]  E. Ruoslahti,et al.  Arg-Gly-Asp: A versatile cell recognition signal , 1986, Cell.

[83]  K. Meerovitch,et al.  A novel RGD antagonist that targets both αvβ3 and α5β1 induces apoptosis of angiogenic endothelial cells on type I collagen , 2003 .

[84]  Z. Hua,et al.  Enhancement of antitumor properties of TRAIL by targeted delivery to the tumor neovasculature , 2008, Molecular Cancer Therapeutics.

[85]  D. Shaw,et al.  Phase 1 trial of the antiangiogenic peptide ATN-161 (Ac-PHSCN-NH2), a beta integrin antagonist, in patients with solid tumours , 2006, British Journal of Cancer.