Integrins as A New Target for Cancer Treatment

Author(s): Izabela Łasiñska* , Jacek Mackiewicz .

Journal Name: Anti-Cancer Agents in Medicinal Chemistry

Volume 19 , Issue 5 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Despite the great progress in the development of targeted therapies for different types of cancer utilizing monoclonal antibodies (e.g., cetuximab for colorectal cancer and head and neck cancer therapy), kinase inhibitors (e.g., sorafenib for kidney cancer and gastrointestinal stromal tumours therapy), and immunomodulatory treatments (e.g., nivolumab and pembrolizumab for melanoma therapy and lung cancer therapy), there is still a need to search for new, more effective treatments.

Integrins are responsible for intercellular adhesion and interaction with the cellular matrix. The function of integrins is related to the transduction of intracellular signals associated with adhesion, migration, cell proliferation, differentiation, and apoptosis. Molecules targeting integrins that lead to cancer cell death have been developed. The most advanced molecules studied in clinical trials are abituzumab, intetumumab and cilengitide. There are different groups of anti-integrin drugs: monoclonal antibodies (e.g., abituzumab) and other such as cilengitide, E7820 and MK-0429. These drugs have been evaluated in various cancer types. However, they have shown modest efficacy, and none of them have yet been approved for cancer treatment. Studies have shown that patient selection using biomarkers might improve the efficacy of anti-integrin cancer treatment. Many preclinical models have demonstrated promising results using integrin visualization for cancer detection and treatment efficacy monitoring; however, these strategies require further evaluation in humans.

Keywords: Integrins, targeted therapy, cancer treatment, monoclonal antibodies, transmembrane glycoproteins, signal transduction.

[1]
Brower, D.L.; Brower, S.M.; Hayward, D.C.; Ball, E.E. Molecular evolution of integrins: Genes encoding integrin beta subunits from a coral and a sponge. Int. Rev. Cytol., 1999, 191, 257-284.
[2]
Hynes, R.O. Integrins: A family of cell surface receptors. Cell, 1987, 48(4), 549-554.
[3]
Hynes, R.O. Integrins: Bidirectional, allosteric signaling machines. Cell, 2002, 110(6), 673-687.
[4]
Plow, E.F.; Haas, T.A.; Zhang, L.; Loftus, J.; Smith, J.W. Ligand binding to integrins. J. Biol. Chem., 2000, 275(29), 21785-21788.
[5]
Stanley, P.; McDowall, A.; Bates, P.A.; Brashaw, J.; Hogg, N. The second domain of intercellular adhesion molecule-1 (ICAM-1) maintains the structural integrity of the leucocyte function-associated antigen-1 (LFA-1) ligand-binding site in the first domain. Biochem. J., 2000, 351, 79-86.
[6]
Kotovuori, A.; Pessa-Morikawa, T.; Kotovuori, P.; Nortamo, P.; Gahmberg, C.G. ICAM-2 and a peptide from its binding domain are efficient activators of leukocyte adhesion and integrin affinity. J. Immunol., 1999, 162(11), 6613-6620.
[7]
Neelamegham, S.; Taylor, A.D.; Shankaran, H.; Smith, C.W.; Simon, S.I. Shear and time-dependent changes in Mac-1, LFA-1, and ICAM-3 binding regulate neutrophil homotypic. J. Immunol., 2000, 164(7), 3798-3805.
[8]
Hermand, P.; Huet, M.; Callebau, I.; Gane, P.; Ihanus, E.; Gahmberg, C.G.; Cartron, J.P.; Bailly, P. Binding sites of leukocyte beta 2 integrins (LFA-1, Mac-1) on the human ICAM-4/LW blood group protein. J. Biol. Chem., 2000, 275, 26002-26010.
[9]
Tian, L.; Kilgannon, P.; Yoshihara, Y.; Mori, K.; Gallatin, W.M.; Carpén, O.; Gahmberg, C.G. Binding of T lymphocytes to hippocampal neurons through ICAM-5 (telencephalin) and characterization of its interaction with the leukocyte integrin CD11a/CD18. J. Immunol., 2000, 30(3), 810-818.
[10]
Schwartz, M.A.; Schaller, M.D.; Ginsberg, M.H. Integrins: Emerging paradigms of signal transduction. Annu. Rev. Cell Dev. Biol., 1995, 11, 549-599.
[11]
Humphries, J.D.; Byron, A.; Humphries, M.J. Integrin ligands at a glance. J. Cell Sci., 2006, 119(19), 3901-3903.
[12]
van-der-Flier, A.; Sonnenberg, A. Function and interactions of integrins. Cell Tissue Res., 2001, 305(3), 285-298.
[13]
Ruggiero, F.; Comte, J.; Cabanas, C.; Garrone, R. Structural requirements for alpha 1 beta 1 and alpha 2 beta 1 integrin mediated cell adhesion to collagen V. J. Cell Sci., 1996, 109(7), 1865-1874.
[14]
Velling, T.; Kusche-Gulberg, M.; Sejersen, T.; Gulberg, D. cDNA cloning and chromosomal localization of human α 11 integrin a collagen-binding, I domain-containing, β 1- associated integrin α-chain present in muscle tissues. J. Biol. Chem., 1999, 274, 25735-25742.
[15]
Takada, Y.; Ye, X.; Simon, S. The integrins. Genome Biol., 2007, 8(5), 215.
[16]
Hogg, N.; Bates, P.A. Genetic analysis of integrin function in man: LAD-1 and other syndromes. Matrix Biol., 2000, 19(3), 211-222.
[17]
Tronik-Le Roux, D.; Rollot, V.; Poujol, C.; Kortulewski, T.; Nurden, P.; Marguerie, G. Thrombastenic mice generated by replacement of integrin alpha (IIb) gene: Demonstration that transcriptional activation of this megakaryocytic locus precedes lineage commitment. Blood, 2000, 96(4), 1399-1408.
[18]
Eliceiri, B.; Cheresh, D.A. The role of αv integrins during angiogenesis: Insights into potential mechanisms of action and clinical development. J. Clin. Invest., 1999, 103(9), 1227-1230.
[19]
Woodley, D.T.; Burgeson, R.E.; Lunstrum, G.P.; Bruckner-Tuderman, L.; Reese, M.; Briggaman, R.A. Epidermolysis bullosa acquisita antigen is the globular carboxyl terminus of type VII collagen. J. Clin. Invest., 1988, 81(3), 683-687.
[20]
Pulkkinen, L.; Kim, D.U.; Uitto, J. Epidermolysis bullosa with pyloric atresia: Novel mutations in the beta4 integrin gene (ITGB4). Am. J. Pathol., 1998, 152(1), 157-166.
[21]
Pulkkinen, L.; Kimonis, V.E.; Xu, Y.; Spanou, E.N.; McLean, I.W.H.; Uitto, J. Homozygous α6 integrin mutation in junctional epidermolysis bullosa with congenital duodenal atresia. Hum. Mol. Genet., 1997, 6(5), 669-674.
[22]
Vogan, K. ITGA3 and epithelial integrity. Nat. Genet., 2012, 10, 229-234.
[23]
Georges-Labousse, E.; Messaddeq, N.; Yehia, G.; Cadalbert, L.; Dierich, A.; Le Meur, M. Absence of integrin alpha 6 leads to epidermolysis bullosa and neonatal death in mice. Nat. Genet., 1996, 13, 370-373.
[24]
Rognoni, E.; Ruppert, R.; Fässler, R. The kindlin family: Functions, signaling properties and implications for human disease. J. Cell Sci., 2016, 129, 17-27.
[25]
Fine, J.D.; Eady, R.A.; Bauer, E.A.; Bauer, J.W.; Bruckner-Tuderman, L.; Heagerty, A.; Hintner, H.; Hovnanian, A.; Jonkman, M.F.; Leigh, I.; McGrath, J.A.; Mellerio, J.E.; Murrell, D.F.; Shimizu, H.; Uitto, J.; Vahlquist, A.; Woodley, D.; Zambruno, G. The classification of inherited Epidermolysis Bullosa (EB): Report of the third international consensus meeting on diagnosis and classification of EB. J. Am. Acad. Dermatol., 2008, 58(6), 931-950.
[26]
Bates, R.C.; Bellovin, D.I.; Brown, C.; Maynard, E.; Wu, B.; Kawakatsu, H.; Sheppard, D.; Oettgen, P.; Mercurio, A.M. Transcriptional activation of integrin β6 during the epithelial-mesenchymal transition defines a novel prognostic indicator of aggressive colon carcinoma. J. Clin. Invest., 2005, 115(2), 339-347.
[27]
Hazelbag, S.; Kenter, G.G.; Gorter, A.; Dreef, E.J.; Koopman, L.A.; Violette, S.M.; Weinreb, P.H.; Fleuren, G.J. Overexpression of the alpha v beta 6 integrin in cervical squamous cell carcinoma is a prognostic factor for decreased survival. J. Pathol., 2007, 212(3), 316-324.
[28]
Gruber, G.; Hess, J.; Stiefel, C.; Aebersold, D.M.; Zimmer, Y.; Greiner, R.H.; Studer, V.; Altermatt, H.J.; Hlushchuk, R.; Djonov, V. Correlation between the tumoral expression of β3-intergrin and outcome in cervical cancer patients who had undergone radiotherapy. Br. J. Cancer, 2005, 92, 41-46.
[29]
Friedrichs, K.; Ruiz, P.; Franke, F.; Gille, I.; Trepe, H.J.; Imhof, B.A. High expression level of α6 integrin in human breast carcinoma is correlated with reduced survival. Cancer Res., 1995, 55, 901-906.
[30]
McCabe, N.P.; De, S.; Vasanji, A.; Brainard, J.; Byzova, T.V. Prostate cancer specific integrin αv β3 modulates bone metastatic growth and tissue remodeling. Oncogene, 2007, 26, 6238-6243.
[31]
Slack-Davis, J.K.; Atkins, K.A.; Harrer, C.; Hershey, D.E.; Conaway, M. Vascular cell adhesion molecule-1 is a regulator of ovarian cancer peritonaeal metastasis. Cancer Res., 2009, 69(4), 1469-1476.
[32]
Nip, J.; Shibata, H.; Loskutoff, D.J.; Cheresh, D.A.; Brodt, P. Human melanoma cells derived from lymphatic metastases use integrin alpha v beta 3 to adhere to lymph node vitronectin. J. Clin. Invest., 1992, 90(4), 1406-1413.
[33]
Takayama, S.; Ishii, S.; Ikeda, T.; Masamura, S.; Doi, M.; Kitajima, M. The relationship between bone metatasis from human breast cancer and integrin αvβ3 expression. Anticancer Res., 2005, 25, 79-83.
[34]
Hosotani, R.; Kawaguchi, M.; Masui, T.; Koshiba, T.; Ida, J.; Fujimoto, K.; Wada, M.; Doi, R.; Imamura, M. Expression of integrin v3 in pancreatic carcinoma: Relation to MMP-2 activation and lymph node metastasis. Pancreas, 2002, 25(2), e30-e35.
[35]
Landen, C.N.; Kim, T.J.; Lin, Y.G.; Merritt, W.M.; Kamat, A.A.; Han, L.Y.; Spannuth, W.A.; Nick, A.M.; Jennnings, N.B.; Kinch, M.S.; Tice, D.; Sood, A.K. Tumor-selective response to antibody-mediated targeting of αvβ3 integrin in ovarian cancer. Neoplasia, 2008, 10(11), 1259-1267.
[36]
Inman, G.J. Switching TGFbeta from a tumor suppressor to a tumor promoter. Curr. Opin. Genet. Dev., 2011, 21, 93-99.
[37]
Yang, L.; Moses, H.L. Transforming growth factor beta: Tumor suppressor or promoter? Are host immune cells the answer? Cancer Res., 2008, 68, 9107-9111.
[38]
Connolly, E.C.; Freimuth, J.; Akhurst, R.J. Complexities of TGF-beta targeted cancer therapy. Int. J. Biol. Sci., 2012, 8, 964-978.
[39]
Bates, R.C.; Bellovin, D.I.; Brown, C.; Maynard, E.; Wu, B.; Kawakatsu, H.; Sheppard, D.; Oettgen, P.; Mercurio, A.M. Transcriptional activation of integrin beta6 during the epithelial-mesenchymal transition defines a novel prognostic indicator of aggressive colon carcinoma. J. Clin. Invest., 2005, 115, 339-347.
[40]
Elayadi, A.N.; Samli, K.N.; Prudkin, L.; Liu, Y.H.; Bian, A.; Xie, X.J.; Wistuba, I.I.; Roth, J.A.; McGuire, M.J.; Brown, K.C. A peptide selected by biopanning identifies the integrin alphavbeta6 as a prognostic biomarker for nonsmall cell lung cancer. Cancer Res., 2007, 67, 5889-5895.
[41]
Zhang, Z.Y.; Xu, K.S.; Wang, J.S.; Yang, G.Y.; Wang, W.; Wang, J.Y.; Niu, W.B.; Liu, E.Y.; Mi, Y.T.; Niu, J. Integrin alphanvbeta6 acts as a prognostic indicator in gastric carcinoma. Clin. Oncol., 2008, 20, 61-66.
[42]
Lian, P.L.; Liu, Z.; Yang, G.Y.; Zhao, R.; Zhang, Z.Y.; Chen, Y.G.; Zhuang, Z.N.; Xu, K.S. Integrin alphavbeta6 and matrix metalloproteinase 9 correlate with survival in gastric cancer. World J. Gastroenterol., 2016, 22, 3852-3859.
[43]
Moore, K.M.; Thomas, G.J.; Duffy, S.W.; Warwick, J.; Gabe, R.; Chou, P.; Ellis, I.O.; Green, A.R.; Haider, S.; Brouilette, K.; Saha, A.; Vallath, S.; Bowen, R.; Chelala, C.; Eccles, D.; Tapper, W.J.; Thompson, A.M.; Quinlan, P.; Jordan, L.; Gillett, C.; Brentnall, A.; Violette, S.; Weinreb, P.H.; Kendrew, J.; Barry, S.T.; Hart, I.R.; Jones, J.L.; Marshall, J.F. Therapeutic targeting of integrin alphavbeta6 in breast cancer. J. Natl. Cancer Inst., 2014, 106, 8.
[44]
Guo, W.; Giancotti, F.G. Integrin signaling during tumor progression. Mol. Cell. Biol., 2004, 5, 816-826.
[45]
Danen, E.H.J. Integrin signaling as a cancer drug target. Int. J. Cell Biol., 2013, 1-14.
[46]
Hamidi, H.; Pietila, M.; Ivaska, I. The complexity of integrins in cancer and new scopes for therapeutic targeting. Br. J. Cancer, 2016, 115, 1017-1023.
[47]
Carter, A. Integrins as target: First phase III trial lauches, but question remain. J. Natl. Cancer Inst., 2010, 102(10), 675-677.
[48]
Coleman, K.R.; Braden, G.A.; Willingham, M.C.; Sane, D.C. Vitaxin, a humanized monoclonal antibody to the vitronectin receptor (avb3), reduces neointimal hyperplasia and total vessel area after balloon injury in hypercholesterolemic rabbits. Circ. Res., 1999, 84, 1268-1276.
[49]
Wu, H.; Beuerlein, G.; Nie, Y.; Smith, H.; Lee, B.A.; Hensler, M.; Huse, W.D.; Watkins, J.D. Stepwise in vitro affinity maturation of vitaxin, an αvβ3-specific humanized mAb. Proc. Natl. Acad. Sci., 1998, 95(11), 6037-6042.
[50]
Ricart, A.D.; Tolcher, A.W.; Liu, G.; Holen, K.; Schwartz, G.; Albertini, M.; Weiss, G.; Yazji, S.; Ng, C.; Wilding, G. Volociximab, a chimeric monoclonal antibody that specifically binds α5β1 integrin: A phase I, pharmacokinetic, and biological correlative study. Clin. Cancer Res., 2008, 14(23), 7924-7929.
[51]
Alfred, A.; Kang, J.S.; Jacobs, V.N.; Ross, S.J.; Rooney, C.N.; Smith, R.; Rinkenberger, J.; Cao, A.; Churchman, A.; Marshall, J.F.; Weir, H.M.; Bedian, V.; Blakey, D.C.; Foltz, I.N.; Barry, S.T. A human monoclonal antibody 264RAD targeting αvβ6 integrin reduces tumour growth and metastasis, and modulates key biomarkers in vivo. Oncogene, 2013, 32, 4406-4416.
[52]
Funahashi, Y.; Sugi, N.H.; Semba, T.; Yamamoto, Y.; Hamaoka, S.; Tsukahara-Tamai, N.; Ozawa, Y.; Tsuruoka, A.; Nara, K.; Takahashi, K.; Okabe, T.; Kamata, J.; Owa, T.; Ueda, N.; Haneda, T.; Yonaga, M.; Yoshimatsu, K.; Wakabayashi, T. Sulfonamide Derivative, E7820, is a unique angiogenesis inhibitor suppressing an expression of integrin α2 subunit on endothelium. Cancer Res., 2002, 62(21), 6116-6123.
[53]
Dechantsreiter, M.A.; Planker, E.; Mathä, B.; Lohof, E.; Hölzemann, G.; Jonczyk, A.; Goodman, S.L.; Kessler, H. N-methylated cyclic RGD peptides as highly active and selective αVβ3 integrin antagonists. J. Med. Chem., 1999, 42, 3033-3040.
[54]
Hutchinson, J.H.; Halczenko, W.; Brashear, K.M.; Breslin, M.J.; Coleman, P.J.; Duong, T.; Fernandez-Metzler, C.; Gentile, M.A.; Fisher, J.E.; Hartman, G.D.; Huff, J.R.; Kimmel, D.B.; Leu, C.T.; Meissner, R.S. Merkle.; Nagy, K.; Pennypacker, B.; Perkins, J.J.; Prueksaritanont, T.; Rodan, G.A.; Varga, S.L.; Wesolowski, G.A.; Zartman, A.E.; Rodan, S.B.; Duggan, M.E. Nonpeptide alphavbeta3 antagonists. In vitro and in vivo evaluation of a potent alphavbeta3 antagonist for the prevention and treatment of osteoporosis. J. Med. Chem., 2003, 46, 4790-4798.
[55]
Kerbel, R.S. Tumor angiogenesis. N. Engl. J. Med., 2008, 358, 2039-2049.
[56]
Friedlander, M.; Brooks, P.C.; Shaffer, R.W.; Kincaid, C.M.; Varner, J.A.; Cheresh, D.A. Definition of two angiogenic pathways by distinct alpha v integrins. Science, 1995, 270, 1500-1502.
[57]
Brooks, P.C.; Montgomery, A.M.; Rosenfeld, M.; Reisfeld, R.A.; Hu, T.; Klier, G.; Cheresh, D.A. Integrin alphav beta 3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. Cell, 1994, 79, 1157-1164.
[58]
Vermorken, J.B.; Peyrade, F.; Krauss, J.; Mesía, R.; Remenar, E.; Gauler, T.C.; Keilholz, U.; Delord, J.P.; Schafhausen, P.; Erfán, J.; Brümmendorf, T.H.; Iglesias, L.; Bethe, U.; Hicking, C.; Clement, P.M. Cisplatin, 5-fluorouracil, and cetuximab (PFE) with or without cilenglitide in recurrent/metastatic squamous cell carcinoma of head and neck: Results of the randomized phase I/II ADVANTAGE trial (phase II part). Ann. Oncol., 2014, 25(3), 682-688.
[59]
Vansteenkiste, J.; Barlesi, F.; Walker, C.F.; Bennouna, J.; Gridelli, C.; Goekkurt, E.; Verhoeven, D.; Szczesna, A.; Feurer, M.; Milanowski, J.; Germonpre, P.; Lena, H.; Atanackovic, D.; Krzakowski, M.; Hicking, C.; Straub, J.; Picard, M.; Schuette, W.; O’Byrne, K. Cilenglitide combined with cetuximab and platinum- based chemotherapy as first-line treatment in advanced Non-Small-Cell Lung Cancer (NSCLC) patients: Results of an open-label, randomized, controlled phase II study (CERTO). Ann. Oncol., 2015, 26(8), 1734-1740.
[60]
Alva, A.; Slovin, S.; Daignault, S.; Carducci, M.; Dipaola, R.; Pienta, K.; Agus, D.; Cooney, K.; Chen, A.; Smith, D.C.; Hussain, M. Phase II study of cilenglitide (EMD 121974, NSC 707544) in patients with non-metastatic castration resistant prostate cancer, NCI-6735. A study by the DOD/PCF prostate cancer clinical trials consortium. Invest. New Drugs, 2012, 30(2), 749-757.
[61]
Mikkelsen, T.; Brodie, C.; Finniss, S.; Berens, M.E.; Rennert, J.L.; Nelson, K.; Lemke, N.; Brown, S.L.; Hahn, D.; Neuteboom, B.; Goodman, S.L. Radiation sensitization of glioblastoma by cilenglitide has unanticipated schedule-dependency. Int. J. Cancer, 2008, 124(11), 2719-2727.
[62]
Readon, D.A.; Fink, K.L.; Mikkelsen, T.; Cloughesy, T.F.; O’Neill, A.; Plotkin, S.; Glantz, M.; Ravin, P.; Raizer, J.J.; Rich, K.M.; Schiff, D.; Shapiro, W.R.; Burdette-Radoux, S.; Dropcho, E.J.; Wittemer, S.M.; Nippgen, J.; Picard, M.; Nabors, L.B. Randomised Phase II study of cilenglitide, an integrin-targetnig arginine-glycine-aspartic acid peptide, in recurrent glioblastoma multiforme. J. Clin. Oncol., 2008, 26(34), 5610-5617.
[63]
Gvozdenovic, A.; Boro, A.; Meier, D.; Bode-Lesniewska, B.; Born, W.; Muff, R.; Bruno Fuchs, B. Targeting αvβ3 and αvβ5 integrins inhibits pulmonary metastasis in an intratibial xenograft osteosarcoma mouse model. Oncotarget, 2016, 7(34), 55141-55154.
[64]
Stupp, R.; Hegi, M.E.; Gorlia, T.; Erridge, S.C.; Perry, J.; Hong, Y.K.; Aldape, K.D.; Lhermitte, B.; Pietsch, T.; Grujicic, D.; Steinbach, J.P.; Wick, W.; Tarnawski, R.; Nam, D.H.; Hau, P.; Weyerbrock, A.; Taphoorn, M.J.; Shen, C.C.; Rao, N.; Thurzo, L.; Herrlinger, U.; Gupta, T.; Kortmann, R.D.; Adamska, K.; McBain, C.; Brandes, A.A.; Tonn, J.C.; Schnell, O.; Wiegel, T.; Kim, C.Y.; Nabors, L.B.; Reardon, D.A.; van den Bent, M.J.; Hicking, C.; Markivskyy, A.; Picard, M.; Weller, M. Cienglitide combined with standard treatment for patients with newly diagnosed gliblastoma with metylated MGMT promoter (CENTRIC EORTC 26071-22072 study): A multicentre, randomized, open-label, phase 3 trial. Lancet Oncol., 2014, 15(10), 1100-1108.
[65]
Elez, E.; Kocakova, I.; Hohler, T.; Martens, U.M.; Bokemeyer, C.; Van Cutsem, E.; Melichar, B.; Smakal, M.; Csőszi, T.; Topuzov, E.; Orlova, R.; Tjulandin, S.; Rivera, F.; Straub, J.; Bruns, R.; Quaratino, S.; Tabernero, J. Abituzumab combined with cetuximab plus irinotecan versus cetuximab plus irinotecan alone for patients with KRAS wild-type metastatic colorectal cancer: the randomized phase I/II POSEIDON trial. Ann. Oncol., 2014, 26(1), 132-140.
[66]
Maha, H.; Miller, K.; Rybicka, I.; Bruns, R. Primary outcomes of the placebo- controlled phase 2 study PERSEUS (NCT 1360840) investigating two dose regimens of abituzumab (DI17E6, EMD 525797) in the treatment of chemotherapy-naïve patients (pts) with asympthomatic or mildly symptomatic metastatic castration- resistant prostate cancer (mCRPC). J. Clin. Oncol., 2014, 32(5), 5030.
[68]
Heidenreich, A.; Rawal, S.K.; Szkarlat, K.; Bogdanova, N.; Dirix, L.; Stenzl, A.; Welslau, M.; Wang, G.; Dawkins, F.; de Boer, C.J.; Schrijvers, D. A randomized, double-blind, multicenter, phase 2 study of human monoclonal antibody to human αv integrins (intetumumab) in combination with docetaxel and prednisone for first-line- treatment of patients with metastatic castration-resistant prostate cancer. Ann. Oncol., 2013, 24(2), 329-336.
[69]
O’Day, S.; Pavlick, A.; Loquai, C.; Lawson, D.; Gutzmer, R.; Richards, J.; Schadendorf, D.; Thompson, J.A.; Gonzalez, R.; Trefzer, U.; Mohr, P.; Ottensmeier, C.; Chao, D.; Zhong, B.; de-Boer, C.J.; Uhlar, C.; Marshall, D.; Gore, M.E.; Lang, Z.; Hait, W.; Ho, P. A randomised, phase II study of intetumumab, an anti-av-integrin mAb, alone and with dacarbazine in stage IV melanoma. Br. J. Cancer, 2011, 105(3), 346-352.
[70]
Gutheil, J.C.; Campbell, T.N.; Pierce, P.R.; Watkins, J.D.; Huse, W.D.; Bodkin, D.J.; Cheresh, D.A. Targeted antiangiogenic therapy for cancer using Vitaxin: A humanized monoclonal antibody to the integrin alphavbeta3. Clin. Cancer Res., 2000, 6(8), 63056-63061.
[71]
Hersey, P.; Sosman, J.; O’Day, S.; Richards, J.; Bedikian, A.; Gonzalez, R.; Sharfman, W.; Weber, R.; Logan, T.; Buzoianu, M.; Hammershaimb, L.; Kirkwood, J.M. A randomized phase 2 study of etaracizumab, a monoclonal antibody against integrin alpha(v)beta(3), + or - dacarbazine in patients with stage IV metastatic melanoma. Cancer, 2010, 16(6), 1526-1534.
[72]
Pickarski, M.; Gleason, A.; Bednar, B.; Duong, L.T. Orally active ανβ3 integrin inhibitor MK-0429 reduces melanoma metastasis. Oncol. Rep., 2015, 33, 2737-2745.
[73]
Rosenthal, M.A.; Davidson, P.; Rolland, F.; Campone, M.; Xue, L.; Mehta, A.; He, W.; Lombardi, A. Evaluation of the safety, pharmacokinetics and treatment effects of an ανβ3 integrin inhibitor on bone turnover and disease activity in men with hormone-refractory prostate cancer and bone metastases. Asia Pac. J. Clin. Oncol., 2010, 6(1), 42-48.
[74]
Mita, M.; Kelly, K.R.; Mita, A.; Ricart, A.D.; Romero, O.; Tolcher, A.; Hook, L.; Okereke, C.; Krivelevich, I.; Rossignol, D.P.; Phase, I. Study of E7820, an oral inhibitor of integrin α-2 expression with antiangiogenic properties, in patients with advanced malignancies. Clin. Cancer Res., 2011, 17(1), 193-200.
[75]
Moore, K.M.; Thomas, G.J.; Duffy, S.W.; Warwick, J.; Gabe, R.; Chou, P.; Ellis, I.O.; Green, A.R.; Haider, S.; Brouilette, K.; Saha, A.; Vallath, S.; Bowen, R.; Chelala, C.; Eccles, D.; Tapper, W.J.; Thompson, A.M.; Quinlan, P.; Jordan, L.; Gillett, C.; Brentnall, A.; Violette, S.; Weinreb, P.H.; Kendrew, J.; Barry, S.T.; Hart, I.R.; Jones, J.L.; Marshall, J.F. Therapeutic targeting of integrin αvβ6 in breast cancer. J. Natl. Cancer Inst., 2014, 106, 1-14.
[76]
Samardzija, C.; Luwor, R.B.; Quinn, M.A.; Kannourakis, G.; Findlay, J.K.; Ahmed, N. Coalition of Oct 4A and β1 integrins infaciliating metastasis in ovarian cancer. BMC Cancer, 2016, 16, 432.
[77]
Barua, A.; Yellapa, A.; Bitterman, P.; Bahr, J.M.; Sharma, S.; Hales, D.B.; Luborsky, J.L.; Abramowicz, J.S. Use of contrastenhanced ultrasound imaging with microbubbles targeted to αvβ3 integrins to enhance detection of early-stage ovarian tumors. J. Clin. Oncol., 2011, 29(Suppl) abstr 5076.
[78]
Wei, Y.; Liu, N.; Huang, Y.; Hu, X.; Yuan, S. Can 18F-alfatide micro-PET predict the radiotherapy response in Lewis lung carcinoma tumor-bearing C57BL/6 mice? J. Clin. Oncol., 2017, 35e23011
[79]
Dual Integrin αvβ3 and GRPR Targeting PET Imaging in Breast Cancer Patients. Available at: https://clinicaltrials.gov/ct2/show/NCT02749019 (Accessed May 01, 2018)
[80]
Dual SSTR2 and Integrin αvβ3 Targeting PET/CT Imaging. Available at: https://clinicaltrials.gov/ct2/show/NCT02817945 (Accessed May 01, 2018)
[81]
Integrin Alpha-v-Beta and [18F]-R01-MG-F2 PET/CT in Measuring Response in Patients with Pancreatic Cancer and Healthy Volunteers Available at: https://clinicaltrials.gov/ct2/show/NCT02683824 (Accessed May 01, 2018)
[82]
Reynolds, L.E.; Wyder, L.; Lively, J.C.; Taverna, D.; Robinson, S.D.; Huang, X.; Sheppard, D.; Hynes, R.O.; Hodivala-Dilke, K.M. Enhanced pathological angiogenesis in mice lacking beta3 integrin or beta3 and beta5 integrins. Nat. Med., 2002, 8, 27-34.
[83]
Reynolds, A.R.; Reynolds, L.E.; Nagel, T.E.; Lively, J.C.; Robinson, S.D.; Hicklin, D.J.; Bodary, S.C.; Hodivala-Dilke, K.M. Elevated flk1 (vascular endothelial growth factor receptor 2) signaling mediates enhanced angiogenesis in beta3-integrin-deficient mice. Cancer Res., 2004, 64, 8643-8650.
[84]
Reynolds, A.R.; Hart, I.R.; Watson, A.R.; Welti, J.C.; Silva, R.G.; Robinson, S.D.; Da Violante, G.; Gourlaouen, M.; Salih, M.; Jones, M.C. Stimulation of tumor growth and angiogenesis by lowconcentrations of rgd-mimetic integrin inhibitors. Nat. Med., 2009, 15, 392-400.
[85]
Wong, P.P.; Demircioglu, F.; Ghazaly, E.; Alrawashdeh, W.; Stratford, M.R.; Scudamore, C.L.; Cereser, B.; Crnogorac-Jurcevic, T.; McDonald, S.; Elia, G.; Hagemann, T.; Kocher, H.M.; Hodivala-Dilke, K.M. Dual-action combination therapy enhances angiogenesis while reducing tumor growth and spread. Cancer Cell, 2015, 27, 123-137.
[86]
Hezel, A.F.; Deshpande, V.; Zimmerman, S.M.; Contino, G.; Alagesan, B.; O’Dell, M.R.; Rivera, L.B.; Harper, J.; Lonning, S.; Brekken, R.A.; Bardeesy, N. TGF-beta and alphavbeta6 integrin act in a common pathway to suppress pancreatic cancer progression. Cancer Res., 2012, 72, 4840-4845.
[87]
Campbell, M.R.; Zhang, H.; Ziaee, S.; Ruiz-Saenz, A.; Gulizia, N.; Oeffinger, J.; Amin, D.N.; Ahuja, D.; Moasser, M.M.; Park, C.C. Effective treatment of HER2-amplified breast cancer by targeting HER3 and β1 integrin. Breast Cancer Res. Treat., 2016, 155(3), 431-440.
[88]
Skopec, R. Integrin inhibitor drugs: New therapy against metastasis. J. Biol. Biomark. Diagn, 2016, 7(5), 1-3.


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 19
ISSUE: 5
Year: 2019
Page: [580 - 586]
Pages: 7
DOI: 10.2174/1871520618666181119103413
Price: $58

Article Metrics

PDF: 33
HTML: 5