Abstract
Angiogenesis, a process that is predominantly driven by the vascular endothelial growth factor (VEGF) signaling pathway, plays an essential role in tumor progression and metastasis. Accordingly, a range of anti-angiogenic agents, most of which block VEGF or its receptor, have been approved for the treatment of various malignant diseases. However, the clinical benefits of anti-angiogenic therapy are relatively modest for several reasons, some of which are related to the development of therapy resistance. Since anti-angiogenic agents target the tumor-supporting vascular system rather than the tumor cells themselves, resistance is dependent on the interplay between the host- and tumor-mediated pathways. In general, the activation of various evasive mechanisms allows for sustained tumor vascularization and growth despite the therapeutic blockade of the drug target. These mechanisms include the upregulation of bypass angiogenic pathways, pro-angiogenic activity of infiltrating stromal cells and alternative vascularization processes. In addition, off-target effects of anti-angiogenic drugs have implications for tumor aggressiveness. In this chapter, we discuss the molecular and cellular mechanisms contributing to therapy resistance as well as possible strategies to improve the clinical outcome.
Abbreviations
- BMDC:
-
Bone marrow-derived cell
- CAF:
-
Cancer-associated fibroblast
- CRC:
-
Colorectal cancer
- ECM:
-
Extracellular matrix
- EGF:
-
Epidermal growth factor
- EMT:
-
Epithelial-mesenchymal transition
- FDA:
-
Food and Drug Administration
- FGF:
-
Fibroblast growth factor
- GBM:
-
Glioblastoma multiforme
- G-CSF:
-
Granulocyte colony stimulating factor
- GIST:
-
Gastrointestinal stromal tumor
- HCC:
-
Hepatocellular carcinoma
- HGF:
-
Hepatocyte growth factor
- HIF-1:
-
Hypoxia inducible factor-1
- MDSC:
-
Myeloid-derived suppressor cell
- NSCLC:
-
Non-small-cell lung cancer
- OS:
-
Overall survival
- PDGF:
-
Platelet-derived growth factor
- PFS:
-
Progression-free survival
- PlGF:
-
Placental growth factor
- PNET:
-
Pancreatic neuroendocrine tumor
- RCC:
-
Renal cell carcinoma
- SCF:
-
Stem cell factor
- SDF-1α:
-
Stromal derived factor-1α
- TAM:
-
Tumor-associated macrophage
- TEM:
-
Tie2-expressing monocyte
- TH17:
-
T helper type 17
- TKI:
-
Tyrosine kinase inhibitor
- VEGF:
-
Vascular endothelial growth factor
- VEGFR:
-
Vascular endothelial growth factor receptor
References
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.
Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285:1182–6.
Ellis LM, Hicklin DJ. VEGF-targeted therapy: mechanisms of anti-tumour activity. Nat Rev Cancer. 2008;8:579–91.
Vasudev NS, Reynolds AR. Anti-angiogenic therapy for cancer: current progress, unresolved questions and future directions. Angiogenesis. 2014;17:471–94.
Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis. Nature. 2011;473:298–307.
Lee S, Chen TT, Barber CL, Jordan MC, Murdock J, Desai S, Ferrara N, Nagy A, Roos KP, Iruela-Arispe ML. Autocrine VEGF signaling is required for vascular homeostasis. Cell. 2007;130:691–703.
Stockmann C, Doedens A, Weidemann A, Zhang N, Takeda N, Greenberg JI, Cheresh DA, Johnson RS. Deletion of vascular endothelial growth factor in myeloid cells accelerates tumorigenesis. Nature. 2008;456:814–8.
Kerbel RS. Tumor angiogenesis. N Engl J Med. 2008;358:2039–49.
Boere IA, Hamberg P, Sleijfer S. It takes two to Tango: combinations of conventional cytotoxics with compounds targeting the vascular endothelial growth factor-vascular endothelial growth factor receptor pathway in patients with solid malignancies. Cancer Sci. 2010;101:7–15.
Ebos JM, Kerbel RS. Antiangiogenic therapy: impact on invasion, disease progression, and metastasis. Nat Rev Clin Oncol. 2011;8:210–21.
Allegra CJ, Yothers G, O'Connell MJ, Sharif S, Petrelli NJ, Colangelo LH, Atkins JN, Seay TE, Fehrenbacher L, Goldberg RM, O'Reilly S, Chu L, Azar CA, Lopa S, Wolmark N. Phase III Trial assessing bevacizumab in stages II and III carcinoma of the colon: results of Nsabp protocol C-08. J Clin Oncol. 2011;29:11–6.
Allegra CJ, Yothers G, O'Connell MJ, Sharif S, Petrelli NJ, Lopa SH, Wolmark N. Bevacizumab in stage II–III colon cancer: 5-year update of the national surgical adjuvant breast and bowel project C-08 trial. J Clin Oncol. 2013;31:359–64.
de Gramont A, Van Cutsem E, Schmoll HJ, Tabernero J, Clarke S, Moore MJ, Cunningham D, Cartwright TH, Hecht JR, Rivera F, Im SA, Bodoky G, Salazar R, Maindrault-Goebel F, Shacham-Shmueli E, Bajetta E, Makrutzki M, Shang A, Andre T, Hoff PM. Bevacizumab Plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (Avant): A Phase 3 randomised controlled trial. Lancet Oncol. 2012;13:1225–33.
von Minckwitz G, Loibl S, Untch M, Eidtmann H, Rezai M, Fasching PA, Tesch H, Eggemann H, Schrader I, Kittel K, Hanusch C, Huober J, Solbach C, Jackisch C, Kunz G, Blohmer JU, Hauschild M, Fehm T, Nekljudova V, Gerber B. Survival after neoadjuvant chemotherapy with or without bevacizumab or everolimus for Her2-negative primary breast cancer (Gbg 44-Geparquinto) dagger. Ann Oncol. 2014;25:2363–72.
Bear HD, Tang G, Rastogi P, Geyer CE Jr, Liu Q, Robidoux A, Baez-Diaz L, Brufsky AM, Mehta RS, Fehrenbacher L, Young JA, Senecal FM, Gaur R, Margolese RG, Adams PT, Gross HM, Costantino JP, Paik S, Swain SM, Mamounas EP, Wolmark N. Neoadjuvant plus adjuvant bevacizumab in early breast cancer (Nsabp B-40 [Nrg Oncology]): secondary outcomes of a phase 3. Randomised Controlled Trial Lancet Oncol. 2015;16:1037–48.
Jain RK. Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. Cancer Cell. 2014;26:605–22.
Shaked Y, Ciarrocchi A, Franco M, Lee CR, Man S, Cheung AM, Hicklin DJ, Chaplin D, Foster FS, Benezra R, Kerbel RS. Therapy-induced acute recruitment of circulating endothelial progenitor cells to tumors. Science. 2006;313:1785–7.
Shaked Y, Henke E, Roodhart JM, Mancuso P, Langenberg MH, Colleoni M, Daenen LG, Man S, Xu P, Emmenegger U, Tang T, Zhu Z, Witte L, Strieter RM, Bertolini F, Voest EE, Benezra R, Kerbel RS. Rapid chemotherapy-induced acute endothelial progenitor cell mobilization: implications for antiangiogenic drugs as chemosensitizing agents. Cancer Cell. 2008;14:263–73.
Shaked Y, Kerbel RS. Antiangiogenic strategies on defense: on the possibility of blocking rebounds by the tumor vasculature after chemotherapy. Cancer Res. 2007;67:7055–8.
Smith NR, Baker D, Farren M, Pommier A, Swann R, Wang X, Mistry S, McDaid K, Kendrew J, Womack C, Wedge SR, Barry ST. Tumor stromal architecture can define the intrinsic tumor response to VEGF-targeted therapy. Clin Cancer Res. 2013;19:6943–56.
Bergers G, Hanahan D. Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer. 2008;8:592–603.
Cree IA, Charlton P. Molecular chess? Hallmarks of anti-cancer drug resistance. BMC Cancer. 2017;17:10.
Boehm T, Folkman J, Browder T, O'Reilly MS. Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance. Nature. 1997;390:404–7.
Yang Y, Sun M, Wang L, Jiao B. Hifs, angiogenesis, and cancer. J Cell Biochem. 2013;114:967–74.
Casanovas O, Hicklin DJ, Bergers G, Hanahan D. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell. 2005;8:299–309.
Fischer C, Jonckx B, Mazzone M, Zacchigna S, Loges S, Pattarini L, Chorianopoulos E, Liesenborghs L, Koch M, De Mol M, Autiero M, Wyns S, Plaisance S, Moons L, van Rooijen N, Giacca M, Stassen JM, Dewerchin M, Collen D, Carmeliet P. Anti-Plgf inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels. Cell. 2007;131:463–75.
Crawford Y, Kasman I, Yu L, Zhong C, Wu X, Modrusan Z, Kaminker J, Ferrara N. Pdgf-C mediates the angiogenic and tumorigenic properties of fibroblasts associated with tumors refractory to anti-VEGF treatment. Cancer Cell. 2009;15:21–34.
Shojaei F, Lee JH, Simmons BH, Wong A, Esparza CO, Plumlee PA, Feng J, Stewart AE, Hu-Lowe DD, Christensen JG. Hgf/C-Met acts as an alternative angiogenic pathway in sunitinib-resistant tumors. Cancer Res. 2010;70:10090–100.
Shojaei F, Simmons BH, Lee JH, Lappin PB, Christensen JG. Hgf/C-Met pathway is one of the mediators of sunitinib-induced tumor cell type-dependent metastasis. Cancer Lett. 2012;320:48–55.
Cascone T, Herynk MH, Xu L, Du Z, Kadara H, Nilsson MB, Oborn CJ, Park YY, Erez B, Jacoby JJ, Lee JS, Lin HY, Ciardiello F, Herbst RS, Langley RR, Heymach JV. Upregulated stromal Egfr and vascular remodeling in mouse xenograft models of angiogenesis inhibitor-resistant human lung adenocarcinoma. J Clin Invest. 2011;121:1313–28.
Huang D, Ding Y, Zhou M, Rini BI, Petillo D, Qian CN, Kahnoski R, Futreal PA, Furge KA, Teh BT. Interleukin-8 mediates resistance to antiangiogenic agent sunitinib in renal cell carcinoma. Cancer Res. 2010;70:1063–71.
Shojaei F, Wu X, Qu X, Kowanetz M, Yu L, Tan M, Meng YG, Ferrara N. G-Csf-initiated myeloid cell mobilization and angiogenesis mediate tumor refractoriness to anti-VEGF therapy in mouse models. Proc Natl Acad Sci U S A. 2009;106:6742–7.
van Beijnum JR, Nowak-Sliwinska P, Huijbers EJ, Thijssen VL, Griffioen AW. The great escape; the hallmarks of resistance to antiangiogenic therapy. Pharmacol Rev. 2015;67:441–61.
Shaked Y. Balancing efficacy of and host immune responses to cancer therapy: the Yin and Yang effects. Nat Rev Clin Oncol. 2016;13:611–26.
Batchelor TT, Sorensen AG, di Tomaso E, Zhang WT, Duda DG, Cohen KS, Kozak KR, Cahill DP, Chen PJ, Zhu M, Ancukiewicz M, Mrugala MM, Plotkin S, Drappatz J, Louis DN, Ivy P, Scadden DT, Benner T, Loeffler JS, Wen PY, Jain RK. Azd2171, a Pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell. 2007;11:83–95.
Kopetz S, Hoff PM, Morris JS, Wolff RA, Eng C, Glover KY, Adinin R, Overman MJ, Valero V, Wen S, Lieu C, Yan S, Tran HT, Ellis LM, Abbruzzese JL, Heymach JV. Phase II trial of infusional fluorouracil, irinotecan, and bevacizumab for metastatic colorectal cancer: efficacy and circulating angiogenic biomarkers associated with therapeutic resistance. J Clin Oncol. 2010;28:453–9.
Motzer RJ, Michaelson MD, Redman BG, Hudes GR, Wilding G, Figlin RA, Ginsberg MS, Kim ST, Baum CM, DePrimo SE, Li JZ, Bello CL, Theuer CP, George DJ, Rini BI. Activity of Su11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol. 2006;24:16–24.
Porta C, Paglino C, Imarisio I, Ganini C, Sacchi L, Quaglini S, Giunta V, De Amici M. Changes in circulating pro-angiogenic cytokines, other than VEGF, before progression to sunitinib therapy in advanced renal cell carcinoma patients. Oncology. 2013;84:115–22.
Rosen LS, Kurzrock R, Mulay M, Van Vugt A, Purdom M, Ng C, Silverman J, Koutsoukos A, Sun YN, Bass MB, Xu RY, Polverino A, Wiezorek JS, Chang DD, Benjamin R, Herbst RS. Safety, pharmacokinetics, and efficacy of Amg 706, an oral multikinase inhibitor, in patients with advanced solid tumors. J Clin Oncol. 2007;25:2369–76.
Willett CG, Boucher Y, Duda DG, di Tomaso E, Munn LL, Tong RT, Kozin SV, Petit L, Jain RK, Chung DC, Sahani DV, Kalva SP, Cohen KS, Scadden DT, Fischman AJ, Clark JW, Ryan DP, Zhu AX, Blaszkowsky LS, Shellito PC, Mino-Kenudson M, Lauwers GY. Surrogate markers for antiangiogenic therapy and dose-limiting toxicities for bevacizumab with radiation and chemotherapy: continued experience of a Phase I Trial in rectal cancer patients. J Clin Oncol. 2005;23:8136–9.
Hanahan D, Coussens LM. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell. 2012;21:309–22.
Du R, Lu KV, Petritsch C, Liu P, Ganss R, Passegue E, Song H, Vandenberg S, Johnson RS, Werb Z, Bergers G. Hif1alpha induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell. 2008;13:206–20.
Shojaei F, Wu X, Malik AK, Zhong C, Baldwin ME, Schanz S, Fuh G, Gerber HP, Ferrara N. Tumor refractoriness to anti-VEGF treatment is mediated by Cd11b+Gr1+ Myeloid Cells. Nat Biotechnol. 2007;25:911–20.
Shojaei F, Wu X, Zhong C, Yu L, Liang XH, Yao J, Blanchard D, Bais C, Peale FV, van Bruggen N, Ho C, Ross J, Tan M, Carano RA, Meng YG, Ferrara N. Bv8 regulates myeloid-cell-dependent tumour angiogenesis. Nature. 2007;450:825–31.
Carbone C, Moccia T, Zhu C, Paradiso G, Budillon A, Chiao PJ, Abbruzzese JL, Melisi D. Anti-VEGF treatment-resistant pancreatic cancers secrete proinflammatory factors that contribute to malignant progression by inducing an Emt cell phenotype. Clin Cancer Res. 2011;17:5822–32.
Hasnis E, Alishekevitz D, Gingis-Veltski S, Bril R, Fremder E, Voloshin T, Raviv Z, Karban A, Shaked Y. Anti-Bv8 antibody and metronomic gemcitabine improve pancreatic adenocarcinoma treatment outcome following weekly gemcitabine therapy. Neoplasia. 2014;16:501–10.
Chung AS, Wu X, Zhuang G, Ngu H, Kasman I, Zhang J, Vernes JM, Jiang Z, Meng YG, Peale FV, Ouyang W, Ferrara N. An Interleukin-17-mediated paracrine network promotes tumor resistance to anti-angiogenic therapy. Nat Med. 2013;19:1114–23.
De Palma M, Lewis CE. Macrophage regulation of tumor responses to anticancer therapies. Cancer Cell. 2013;23:277–86.
Rolny C, Mazzone M, Tugues S, Laoui D, Johansson I, Coulon C, Squadrito ML, Segura I, Li X, Knevels E, Costa S, Vinckier S, Dresselaer T, Akerud P, De Mol M, Salomaki H, Phillipson M, Wyns S, Larsson E, Buysschaert I, Botling J, Himmelreich U, Van Ginderachter JA, De Palma M, Dewerchin M, Claesson-Welsh L, Carmeliet P. Hrg inhibits tumor growth and metastasis by inducing macrophage polarization and vessel normalization through downregulation of Plgf. Cancer Cell. 2011;19:31–44.
Zhang W, Zhu XD, Sun HC, Xiong YQ, Zhuang PY, Xu HX, Kong LQ, Wang L, Wu WZ, Tang ZY. Depletion of tumor-associated macrophages enhances the effect of sorafenib in metastatic liver cancer models by antimetastatic and antiangiogenic effects. Clin Cancer Res. 2010;16:3420–30.
Lewis CE, De Palma M, Naldini L. Tie2-expressing monocytes and tumor angiogenesis: regulation by hypoxia and angiopoietin-2. Cancer Res. 2007;67:8429–32.
Coffelt SB, Tal AO, Scholz A, De Palma M, Patel S, Urbich C, Biswas SK, Murdoch C, Plate KH, Reiss Y, Lewis CE. Angiopoietin-2 regulates gene expression in Tie2-expressing monocytes and augments their inherent proangiogenic functions. Cancer Res. 2010;70:5270–80.
Welford AF, Biziato D, Coffelt SB, Nucera S, Fisher M, Pucci F, Di Serio C, Naldini L, De Palma M, Tozer GM, Lewis CE. Tie2-expressing macrophages limit the therapeutic efficacy of the vascular-disrupting agent combretastatin A4 phosphate in mice. J Clin Invest. 2011;121:1969–73.
De Palma M, Venneri MA, Galli R, Sergi Sergi L, Politi LS, Sampaolesi M, Naldini L. Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell. 2005;8:211–26.
Kienast Y, Klein C, Scheuer W, Raemsch R, Lorenzon E, Bernicke D, Herting F, Yu S, The HH, Martarello L, Gassner C, Stubenrauch KG, Munro K, Augustin HG, Thomas M. Ang-2-VEGF-A Crossmab, a novel bispecific human IgG1 antibody blocking VEGF-A and Ang-2 functions simultaneously, mediates potent antitumor, antiangiogenic, and antimetastatic efficacy. Clin Cancer Res. 2013;19:6730–40.
Peterson TE, Kirkpatrick ND, Huang Y, Farrar CT, Marijt KA, Kloepper J, Datta M, Amoozgar Z, Seano G, Jung K, Kamoun WS, Vardam T, Snuderl M, Goveia J, Chatterjee S, Batista A, Muzikansky A, Leow CC, Xu L, Batchelor TT, Duda DG, Fukumura D, Jain RK. Dual inhibition of Ang-2 and VEGF receptors normalizes tumor vasculature and prolongs survival in glioblastoma by altering macrophages. Proc Natl Acad Sci U S A. 2016;113:4470–5.
Wu FT, Man S, Xu P, Chow A, Paez-Ribes M, Lee CR, Pirie-Shepherd SR, Emmenegger U, Kerbel RS. Efficacy of cotargeting Angiopoietin-2 and the VEGF pathway in the adjuvant postsurgical setting for early breast, colorectal, and renal cancers. Cancer Res. 2016;76:6988–7000.
Armulik A, Abramsson A, Betsholtz C. Endothelial/pericyte interactions. Circ Res. 2005;97:512–23.
Thomas M, Kienast Y, Scheuer W, Bahner M, Kaluza K, Gassner C, Herting F, Brinkmann U, Seeber S, Kavlie A, Welschof M, Ries S, Weidner KM, Regula JT, Klein C. A novel Angiopoietin-2 selective fully human antibody with potent anti-tumoral and anti-angiogenic efficacy and superior side effect profile compared to pan-angiopoietin-1/−2 inhibitors. PLoS One. 2013;8:e54923.
Kumar S, Mokhtari RB, Oliveira ID, Islam S, Toledo SR, Yeger H, Baruchel S. Tumor dynamics in response to antiangiogenic therapy with oral metronomic topotecan and pazopanib in neuroblastoma xenografts. Transl Oncol. 2013;6:493–503.
Mancuso MR, Davis R, Norberg SM, O’Brien S, Sennino B, Nakahara T, Yao VJ, Inai T, Brooks P, Freimark B, Shalinsky DR, Hu-Lowe DD, McDonald DM. Rapid vascular regrowth in tumors after reversal of VEGF inhibition. J Clin Invest. 2006;116:2610–21.
Franco M, Roswall P, Cortez E, Hanahan D, Pietras K. Pericytes promote endothelial cell survival through induction of autocrine VEGF-a signaling and Bcl-W Expression. Blood. 2011;118:2906–17.
Erber R, Thurnher A, Katsen AD, Groth G, Kerger H, Hammes HP, Menger MD, Ullrich A, Vajkoczy P. Combined inhibition of VEGF and PDGF signaling enforces tumor vessel regression by interfering with pericyte-mediated endothelial cell survival mechanisms. FASEB J. 2004;18:338–40.
Bergers G, Song S, Meyer-Morse N, Bergsland E, Hanahan D. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest. 2003;111:1287–95.
Pietras K, Hanahan D. A multitargeted, metronomic, and maximum-tolerated dose “Chemo-Switch” regimen is antiangiogenic, producing objective responses and survival benefit in a mouse model of cancer. J Clin Oncol. 2005;23:939–52.
Xian X, Hakansson J, Stahlberg A, Lindblom P, Betsholtz C, Gerhardt H, Semb H. Pericytes limit tumor cell metastasis. J Clin Invest. 2006;116:642–51.
Cooke VG, LeBleu VS, Keskin D, Khan Z, O'Connell JT, Teng Y, Duncan MB, Xie L, Maeda G, Vong S, Sugimoto H, Rocha RM, Damascena A, Brentani RR, Kalluri R. Pericyte depletion results in hypoxia-associated epithelial-to-mesenchymal transition and metastasis mediated by met signaling pathway. Cancer Cell. 2012;21:66–81.
Pinto MP, Sotomayor P, Carrasco-Avino G, Corvalan AH, Owen GI. Escaping antiangiogenic therapy: strategies employed by cancer cells. Int J Mol Sci. 2016;17
Donnem T, Hu J, Ferguson M, Adighibe O, Snell C, Harris AL, Gatter KC, Pezzella F. Vessel co-option in primary human tumors and metastases: an obstacle to effective anti-angiogenic treatment? Cancer Med. 2013;2:427–36.
de Groot JF, Fuller G, Kumar AJ, Piao Y, Eterovic K, Ji Y, Conrad CA. Tumor invasion after treatment of glioblastoma with bevacizumab: radiographic and pathologic correlation in humans and mice. Neuro-Oncology. 2010;12:233–42.
di Tomaso E, Snuderl M, Kamoun WS, Duda DG, Auluck PK, Fazlollahi L, Andronesi OC, Frosch MP, Wen PY, Plotkin SR, Hedley-Whyte ET, Sorensen AG, Batchelor TT, Jain RK. Glioblastoma recurrence after cediranib therapy in patients: lack of “rebound” revascularization as mode of escape. Cancer Res. 2011;71:19–28.
Narayana A, Kelly P, Golfinos J, Parker E, Johnson G, Knopp E, Zagzag D, Fischer I, Raza S, Medabalmi P, Eagan P, Gruber ML. Antiangiogenic therapy using bevacizumab in recurrent high-grade glioma: impact on local control and patient survival. J Neurosurg. 2009;110:173–80.
Norden AD, Young GS, Setayesh K, Muzikansky A, Klufas R, Ross GL, Ciampa AS, Ebbeling LG, Levy B, Drappatz J, Kesari S, Wen PY. Bevacizumab for recurrent malignant gliomas: efficacy, toxicity, and patterns of recurrence. Neurology. 2008;70:779–87.
Rubenstein JL, Kim J, Ozawa T, Zhang M, Westphal M, Deen DF, Shuman MA. Anti-VEGF antibody treatment of glioblastoma prolongs survival but results in increased vascular cooption. Neoplasia. 2000;2:306–14.
Kuczynski EA, Yin M, Bar-Zion A, Lee CR, Butz H, Man S, Daley F, Vermeulen PB, Yousef GM, Foster FS, Reynolds AR, Kerbel RS. Co-option of liver vessels and not sprouting angiogenesis drives acquired sorafenib resistance in hepatocellular carcinoma. J Natl Cancer Inst. 2016;108:djw030. https://doi.org/10.1093/jnci/djw030.
Jeong HS, Jones D, Liao S, Wattson DA, Cui CH, Duda DG, Willett CG, Jain RK, Padera TP. Investigation of the lack of angiogenesis in the formation of lymph node metastases. J Natl Cancer Inst. 2015;107:699. https://doi.org/10.1111/cup.12571.
Leenders WP, Kusters B, Verrijp K, Maass C, Wesseling P, Heerschap A, Ruiter D, Ryan A, de Waal R. Antiangiogenic therapy of cerebral melanoma metastases results in sustained tumor progression via vessel co-option. Clin Cancer Res. 2004;10:6222–30.
Frentzas S, Simoneau E, Bridgeman VL, Vermeulen PB, Foo S, Kostaras E, Nathan MR, Wotherspoon A, Gao ZH, Shi Y, Van den Eynden G, Daley F, Peckitt C, Tan X, Salman A, Lazaris A, Gazinska P, Berg TJ, Eltahir Z, Ritsma L, van Rheenen J, Khashper A, Brown G, Nystrom H, Sund M, Van Laere S, Loyer E, Dirix L, Cunningham D, Metrakos P, Reynolds AR. Vessel co-option mediates resistance to anti-angiogenic therapy in liver metastases. Nat Med. 2016;22:1294–302.
Bridgeman VL, Vermeulen PB, Foo S, Bilecz A, Daley F, Kostaras E, Nathan MR, Wan E, Frentzas S, Schweiger T, Hegedus B, Hoetzenecker K, Renyi-Vamos F, Kuczynski EA, Vasudev NS, Larkin J, Gore M, Dvorak HF, Paku S, Kerbel RS, Dome B, Reynolds AR. Vessel co-option is common in human lung metastases and mediates resistance to anti-angiogenic therapy in preclinical lung metastasis models. J Pathol. 2016;241:362.
Kirschmann DA, Seftor EA, Hardy KM, Seftor RE, Hendrix MJ. Molecular pathways: vasculogenic mimicry in tumor cells: diagnostic and therapeutic implications. Clin Cancer Res. 2012;18:2726–32.
Maniotis AJ, Folberg R, Hess A, Seftor EA, Gardner LM, Pe'er J, Trent JM, Meltzer PS, Hendrix MJ. Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry. Am J Pathol. 1999;155:739–52.
Paulis YW, Soetekouw PM, Verheul HM, Tjan-Heijnen VC, Griffioen AW. Signalling pathways in vasculogenic mimicry. Biochim Biophys Acta. 2010;1806:18–28.
Ricci-Vitiani L, Pallini R, Biffoni M, Todaro M, Invernici G, Cenci T, Maira G, Parati EA, Stassi G, Larocca LM, De Maria R. Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells. Nature. 2010;468:824–8.
Wang R, Chadalavada K, Wilshire J, Kowalik U, Hovinga KE, Geber A, Fligelman B, Leversha M, Brennan C, Tabar V. Glioblastoma stem-like cells give rise to tumour endothelium. Nature. 2010;468:829–33.
van der Schaft DW, Seftor RE, Seftor EA, Hess AR, Gruman LM, Kirschmann DA, Yokoyama Y, Griffioen AW, Hendrix MJ. Effects of angiogenesis inhibitors on vascular network formation by human endothelial and melanoma cells. J Natl Cancer Inst. 2004;96:1473–7.
Soda Y, Marumoto T, Friedmann-Morvinski D, Soda M, Liu F, Michiue H, Pastorino S, Yang M, Hoffman RM, Kesari S, Verma IM. Transdifferentiation of glioblastoma cells into vascular endothelial cells. Proc Natl Acad Sci U S A. 2011;108:4274–80.
Xu Y, Li Q, Li XY, Yang QY, Xu WW, Liu GL. Short-term anti-vascular endothelial growth factor treatment elicits vasculogenic mimicry formation of tumors to accelerate metastasis. J Exp Clin Cancer Res. 2012;31:16.
Schnegg CI, Yang MH, Ghosh SK, Hsu MY. Induction of vasculogenic mimicry overrides VEGF-a silencing and enriches stem-like cancer cells in melanoma. Cancer Res. 2015;75:1682–90.
Sun B, Zhang D, Zhang S, Zhang W, Guo H, Zhao X. Hypoxia influences vasculogenic mimicry channel formation and tumor invasion-related protein expression in melanoma. Cancer Lett. 2007;249:188–97.
Ebos JM, Lee CR, Cruz-Munoz W, Bjarnason GA, Christensen JG, Kerbel RS. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell. 2009;15:232–9.
Paez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Vinals F, Inoue M, Bergers G, Hanahan D, Casanovas O. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell. 2009;15:220–31.
Ebos JM, Lee CR, Christensen JG, Mutsaers AJ, Kerbel RS. Multiple circulating proangiogenic factors induced by sunitinib malate are tumor-independent and correlate with antitumor efficacy. Proc Natl Acad Sci U S A. 2007;104:17069–74.
Norden-Zfoni A, Desai J, Manola J, Beaudry P, Force J, Maki R, Folkman J, Bello C, Baum C, DePrimo SE, Shalinsky DR, Demetri GD, Heymach JV. Blood-based biomarkers of Su11248 activity and clinical outcome in patients with metastatic imatinib-resistant gastrointestinal stromal tumor. Clin Cancer Res. 2007;13:2643–50.
Zurita AJ, Khajavi M, Wu HK, Tye L, Huang X, Kulke MH, Lenz HJ, Meropol NJ, Carley W, DePrimo SE, Lin E, Wang X, Harmon CS, Heymach JV. Circulating cytokines and monocyte subpopulations as biomarkers of outcome and biological activity in sunitinib-treated patients with advanced neuroendocrine tumours. Br J Cancer. 2015;112:1199–205.
Ebos JM, Lee CR, Kerbel RS. Tumor and host-mediated pathways of resistance and disease progression in response to antiangiogenic therapy. Clin Cancer Res. 2009;15:5020–5.
Chung AS, Kowanetz M, Wu X, Zhuang G, Ngu H, Finkle D, Komuves L, Peale F, Ferrara N. Differential drug class-specific metastatic effects following treatment with a panel of angiogenesis inhibitors. J Pathol. 2012;227:404–16.
Welti JC, Powles T, Foo S, Gourlaouen M, Preece N, Foster J, Frentzas S, Bird D, Sharpe K, van Weverwijk A, Robertson D, Soffe J, Erler JT, Pili R, Springer CJ, Mather SJ, Reynolds AR. Contrasting effects of sunitinib within in vivo models of metastasis. Angiogenesis. 2012;15:623–41.
Nguyen DX, Bos PD, Massague J. Metastasis: from dissemination to organ-specific colonization. Nat Rev Cancer. 2009;9:274–84.
Maione F, Capano S, Regano D, Zentilin L, Giacca M, Casanovas O, Bussolino F, Serini G, Giraudo E. Semaphorin 3a overcomes cancer hypoxia and metastatic dissemination induced by antiangiogenic treatment in mice. J Clin Invest. 2012;122:1832–48.
Sennino B, Ishiguro-Oonuma T, Wei Y, Naylor RM, Williamson CW, Bhagwandin V, Tabruyn SP, You WK, Chapman HA, Christensen JG, Aftab DT, McDonald DM. Suppression of tumor invasion and metastasis by concurrent inhibition of C-Met and VEGF signaling in pancreatic neuroendocrine tumors. Cancer Discov. 2012;2:270–87.
Blagoev KB, Wilkerson J, Stein WD, Motzer RJ, Bates SE, Fojo AT. Sunitinib does not accelerate tumor growth in patients with metastatic renal cell carcinoma. Cell Rep. 2013;3:277–81.
Miles D, Harbeck N, Escudier B, Hurwitz H, Saltz L, Van Cutsem E, Cassidy J, Mueller B, Sirzen F. Disease course patterns after discontinuation of bevacizumab: pooled analysis of randomized phase III trials. J Clin Oncol. 2011;29:83–8.
Desar IM, Mulder SF, Stillebroer AB, van Spronsen DJ, van der Graaf WT, Mulders PF, van Herpen CM. The reverse side of the victory: flare up of symptoms after discontinuation of sunitinib or sorafenib in renal cell cancer patients. A report of three cases. Acta Oncol. 2009;48:927–31.
Wolter P, Beuselinck B, Pans S, Schoffski P. Flare-up: an often unreported phenomenon nevertheless familiar to oncologists prescribing tyrosine kinase inhibitors. Acta Oncol. 2009;48:621–4.
Cacheux W, Boisserie T, Staudacher L, Vignaux O, Dousset B, Soubrane O, Terris B, Mateus C, Chaussade S, Goldwasser F. Reversible tumor growth acceleration following bevacizumab interruption in metastatic colorectal cancer patients scheduled for surgery. Ann Oncol. 2008;19:1659–61.
Paez-Ribes M, Man S, Xu P, Kerbel RS. Potential proinvasive or metastatic effects of preclinical antiangiogenic therapy are prevented by concurrent chemotherapy. Clin Cancer Res. 2015;21:5488–98.
Rovida A, Castiglioni V, Decio A, Scarlato V, Scanziani E, Giavazzi R, Cesca M. Chemotherapy counteracts metastatic dissemination induced by antiangiogenic treatment in mice. Mol Cancer Ther. 2013;12:2237–47.
Francia G, Cruz-Munoz W, Man S, Xu P, Kerbel RS. Mouse models of advanced spontaneous metastasis for experimental therapeutics. Nat Rev Cancer. 2011;11:135–41.
Ledermann JA, Hackshaw A, Kaye S, Jayson G, Gabra H, McNeish I, Earl H, Perren T, Gore M, Persic M, Adams M, James L, Temple G, Merger M, Rustin G. randomized phase ii placebo-controlled trial of maintenance therapy using the oral triple angiokinase inhibitor BIBF 1120 after chemotherapy for relapsed ovarian cancer. J Clin Oncol. 2011;29:3798–804.
Llovet JM, Decaens T, Raoul JL, Boucher E, Kudo M, Chang C, Kang YK, Assenat E, Lim HY, Boige V, Mathurin P, Fartoux L, Lin DY, Bruix J, Poon RT, Sherman M, Blanc JF, Finn RS, Tak WY, Chao Y, Ezzeddine R, Liu D, Walters I, Park JW. Brivanib in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed: results from the randomized phase III BRISK-PS study. J Clin Oncol. 2013;31:3509–16.
Duda DG, Kozin SV, Kirkpatrick ND, Xu L, Fukumura D, Jain RK. Cxcl12 (Sdf1alpha)-Cxcr4/Cxcr7 pathway inhibition: an emerging sensitizer for anticancer therapies? Clin Cancer Res. 2011;17:2074–80.
Ries CH, Cannarile MA, Hoves S, Benz J, Wartha K, Runza V, Rey-Giraud F, Pradel LP, Feuerhake F, Klaman I, Jones T, Jucknischke U, Scheiblich S, Kaluza K, Gorr IH, Walz A, Abiraj K, Cassier PA, Sica A, Gomez-Roca C, de Visser KE, Italiano A, Le Tourneau C, Delord JP, Levitsky H, Blay JY, Ruttinger D. Targeting tumor-associated macrophages with anti-Csf-1r antibody reveals a strategy for cancer therapy. Cancer Cell. 2014;25:846–59.
Ries CH, Hoves S, Cannarile MA, Ruttinger D. Csf-1/Csf-1r Targeting agents in clinical development for cancer therapy. Curr Opin Pharmacol. 2015;23:45–51.
Sandhu SK, Papadopoulos K, Fong PC, Patnaik A, Messiou C, Olmos D, Wang G, Tromp BJ, Puchalski TA, Balkwill F, Berns B, Seetharam S, de Bono JS, Tolcher AW. A first-in-human, first-in-class, phase i study of carlumab (Cnto 888), a human monoclonal antibody against CC-chemokine ligand 2 in patients with solid tumors. Cancer Chemother Pharmacol. 2013;71:1041–50.
Ruffell B, Coussens LM. Macrophages and therapeutic resistance in cancer. Cancer Cell. 2015;27:462–72.
Rapisarda A, Melillo G. Role of the hypoxic tumor microenvironment in the resistance to anti-angiogenic therapies. Drug Resist Updat. 2009;12:74–80.
Batchelor TT, Gerstner ER, Emblem KE, Duda DG, Kalpathy-Cramer J, Snuderl M, Ancukiewicz M, Polaskova P, Pinho MC, Jennings D, Plotkin SR, Chi AS, Eichler AF, Dietrich J, Hochberg FH, Lu-Emerson C, Iafrate AJ, Ivy SP, Rosen BR, Loeffler JS, Wen PY, Sorensen AG, Jain RK. Improved tumor oxygenation and survival in glioblastoma patients who show increased blood perfusion after cediranib and chemoradiation. Proc Natl Acad Sci U S A. 2013;110:19059–64.
Emblem KE, Mouridsen K, Bjornerud A, Farrar CT, Jennings D, Borra RJ, Wen PY, Ivy P, Batchelor TT, Rosen BR, Jain RK, Sorensen AG. Vessel architectural imaging identifies cancer patient responders to anti-angiogenic therapy. Nat Med. 2013;19:1178–83.
Sorensen AG, Batchelor TT, Zhang WT, Chen PJ, Yeo P, Wang M, Jennings D, Wen PY, Lahdenranta J, Ancukiewicz M, di Tomaso E, Duda DG, Jain RK. A “vascular normalization index” as potential mechanistic biomarker to predict survival after a single dose of cediranib in recurrent glioblastoma patients. Cancer Res. 2009;69:5296–300.
Sorensen AG, Emblem KE, Polaskova P, Jennings D, Kim H, Ancukiewicz M, Wang M, Wen PY, Ivy P, Batchelor TT, Jain RK. Increased survival of glioblastoma patients who respond to antiangiogenic therapy with elevated blood perfusion. Cancer Res. 2012;72:402–7.
Hutt DM, Roth DM, Vignaud H, Cullin C, Bouchecareilh M. The histone deacetylase inhibitor, vorinostat, represses hypoxia inducible factor 1 alpha expression through translational inhibition. PLoS One. 2014;9:e106224.
Aggarwal R, Thomas S, Pawlowska N, Bartelink I, Grabowsky J, Jahan T, Cripps A, Harb A, Leng J, Reinert A, Mastroserio I, Truong TG, Ryan CJ, Munster PN. Inhibiting histone deacetylase as a means to reverse resistance to angiogenesis inhibitors: phase I study of abexinostat plus pazopanib in advanced solid tumor malignancies. J Clin Oncol. 2017.:JCO2016705350;35:1231.
Gabrilovich DI, Chen HL, Girgis KR, Cunningham HT, Meny GM, Nadaf S, Kavanaugh D, Carbone DP. Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat Med. 1996;2:1096–103.
Huang Y, Chen X, Dikov MM, Novitskiy SV, Mosse CA, Yang L, Carbone DP. Distinct roles of VEGFR-1 and VEGFR-2 in the aberrant hematopoiesis associated with elevated levels of VEGF. Blood. 2007;110:624–31.
Terme M, Pernot S, Marcheteau E, Sandoval F, Benhamouda N, Colussi O, Dubreuil O, Carpentier AF, Tartour E, Taieb J. VEGFA-VEGFR pathway blockade inhibits tumor-induced regulatory t-cell proliferation in colorectal cancer. Cancer Res. 2013;73:539–49.
Huang Y, Goel S, Duda DG, Fukumura D, Jain RK. Vascular normalization as an emerging strategy to enhance cancer immunotherapy. Cancer Res. 2013;73:2943–8.
Gabrilovich DI, Ishida T, Nadaf S, Ohm JE, Carbone DP. Antibodies to vascular endothelial growth factor enhance the efficacy of cancer immunotherapy by improving endogenous dendritic cell function. Clin Cancer Res. 1999;5:2963–70.
Hodi FS, Lawrence D, Lezcano C, Wu X, Zhou J, Sasada T, Zeng W, Giobbie-Hurder A, Atkins MB, Ibrahim N, Friedlander P, Flaherty KT, Murphy GF, Rodig S, Velazquez EF, Mihm MC Jr, Russell S, DiPiro PJ, Yap JT, Ramaiya N, Van den Abbeele AD, Gargano M, McDermott D. Bevacizumab plus ipilimumab in patients with metastatic melanoma. Cancer Immunol Res. 2014;2:632–42.
Huang Y, Yuan J, Righi E, Kamoun WS, Ancukiewicz M, Nezivar J, Santosuosso M, Martin JD, Martin MR, Vianello F, Leblanc P, Munn LL, Huang P, Duda DG, Fukumura D, Jain RK, Poznansky MC. Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy. Proc Natl Acad Sci U S A. 2012;109:17561–6.
Ko JS, Zea AH, Rini BI, Ireland JL, Elson P, Cohen P, Golshayan A, Rayman PA, Wood L, Garcia J, Dreicer R, Bukowski R, Finke JH. Sunitinib mediates reversal of myeloid-derived suppressor cell accumulation in renal cell carcinoma patients. Clin Cancer Res. 2009;15:2148–57.
Manegold C, Dingemans AC, Gray JE, Nakagawa K, Nicolson M, Peters S, Reck M, Wu YL, Brustugun OT, Crino L, Felip E, Fennell D, Garrido P, Huber RM, Marabelle A, Moniuszko M, Mornex F, Novello S, Papotti M, Perol M, Smit EF, Syrigos K, van Meerbeeck JP, van Zandwijk N, Chih-Hsin Yang J, Zhou C, Vokes E. The potential of combined immunotherapy and antiangiogenesis for the synergistic treatment of advanced Nsclc. J Thorac Oncol. 2017;12:194–207.
Manning EA, Ullman JG, Leatherman JM, Asquith JM, Hansen TR, Armstrong TD, Hicklin DJ, Jaffee EM, Emens LA. A vascular endothelial growth factor receptor-2 inhibitor enhances antitumor immunity through an immune-based mechanism. Clin Cancer Res. 2007;13:3951–9.
Shrimali RK, Yu Z, Theoret MR, Chinnasamy D, Restifo NP, Rosenberg SA. Antiangiogenic agents can increase lymphocyte infiltration into tumor and enhance the effectiveness of adoptive immunotherapy of cancer. Cancer Res. 2010;70:6171–80.
Clarke JM, Hurwitz HI. Understanding and targeting resistance to anti-angiogenic therapies. J Gastrointest Oncol. 2013;4:253–63.
Miles DW, de Haas SL, Dirix LY, Romieu G, Chan A, Pivot X, Tomczak P, Provencher L, Cortes J, Delmar PR, Scherer SJ. Biomarker results from the avado phase 3 trial of first-line bevacizumab plus docetaxel for Her2-negative metastatic breast cancer. Br J Cancer. 2013;108:1052–60.
Van Cutsem E, de Haas S, Kang YK, Ohtsu A, Tebbutt NC, Ming Xu J, Peng Yong W, Langer B, Delmar P, Scherer SJ, Shah MA. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a biomarker evaluation from the avagast randomized phase iii trial. J Clin Oncol. 2012;30:2119–27.
Hegde PS, Jubb AM, Chen D, Li NF, Meng YG, Bernaards C, Elliott R, Scherer SJ, Chen DS. Predictive impact of circulating vascular endothelial growth factor in four phase III trials evaluating bevacizumab. Clin Cancer Res. 2013;19:929–37.
Jayson GC, Hicklin DJ, Ellis LM. Antiangiogenic therapy--evolving view based on clinical trial results. Nat Rev Clin Oncol. 2012;9:297–303.
Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335–42.
Giantonio BJ, Catalano PJ, Meropol NJ, O'Dwyer PJ, Mitchell EP, Alberts SR, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol. 2007;25:1539–44.
Saltz LB, Clarke S, Diaz-Rubio E, Scheithauer W, Figer A, Wong R, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008;26:2013–9.
Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355:2542–50.
Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, et al. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol. 2009;27:1227–34.
Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, et al. Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL). Ann Oncol. 2010;21(9):1804.
Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Archer L, et al. Phase III trial of bevacizumab plus interferon alfa versus interferon alfa monotherapy in patients with metastatic renal cell carcinoma: final results of CALGB 90206. J Clin Oncol. 2010;28:2137–43.
Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Ou SS, et al. Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol. 2008;26:5422–8.
Escudier B, Bellmunt J, Negrier S, Bajetta E, Melichar B, Bracarda S, et al. Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J Clin Oncol. 2010;28:2144–50.
Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007;370:2103–11.
Perren TJ, Swart AM, Pfisterer J, Ledermann JA, Pujade-Lauraine E, Kristensen G, et al. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med. 2011;365:2484–96.
Oza AM, Cook AD, Pfisterer J, Embleton A, Ledermann JA, Pujade-Lauraine E, et al. Standard chemotherapy with or without bevacizumab for women with newly diagnosed ovarian cancer (ICON7): overall survival results of a phase 3 randomised trial. Lancet Oncol. 2015;16:928–36.
Burger RA, Brady MF, Bookman MA, Fleming GF, Monk BJ, Huang H, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med. 2011;365:2473–83.
Cohen MH, Shen YL, Keegan P, Pazdur R. FDA drug approval summary: bevacizumab (Avastin) as treatment of recurrent glioblastoma multiforme. Oncologist. 2009;14:1131–8.
Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014;15:1224–35.
Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014;383:31–9.
Van Cutsem E, Tabernero J, Lakomy R, Prenen H, Prausova J, Macarulla T, et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol. 2012;30:3499–506.
Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356:125–34.
Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Staehler M, et al. Sorafenib for treatment of renal cell carcinoma: Final efficacy and safety results of the phase III treatment approaches in renal cancer global evaluation trial. J Clin Oncol. 2009;27:3312–8.
Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–90.
Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Oudard S, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009;27:3584–90.
Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356:115–24.
Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah MH, Verweij J, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 2006;368:1329–38.
Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011;364:501–13.
Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol. 2010;28:1061–8.
Sternberg CN, Hawkins RE, Wagstaff J, Salman P, Mardiak J, Barrios CH, et al. A randomised, double-blind phase III study of pazopanib in patients with advanced and/or metastatic renal cell carcinoma: final overall survival results and safety update. Eur J Cancer. 2013;49:1287–96.
Motzer RJ, Escudier B, Tomczak P, Hutson TE, Michaelson MD, Negrier S, et al. Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial. Lancet Oncol. 2013;14:552–62.
Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381:303–12.
Reck M, Kaiser R, Mellemgaard A, Douillard JY, Orlov S, Krzakowski M, et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol. 2014;15:143–55.
Wells SA Jr, Robinson BG, Gagel RF, Dralle H, Fagin JA, Santoro M, et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol. 2012;30:134–41.
Elisei R, Schlumberger MJ, Muller SP, Schoffski P, Brose MS, Shah MH, et al. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol. 2013;31:3639–46.
Acknowledgments
This book chapter is primarily supported by the European Research Council (#260633) and Rappaport Institute funds given to YS. KM is supported by a student fellowship from the Lyon Sachs University of Toronto— Technion Collaboration Fund.
Conflict of Interest
The authors declare that they have no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2018 Springer International Publishing AG, part of Springer Nature
About this chapter
Cite this chapter
Dahan, N., Magidey, K., Shaked, Y. (2018). Resistance to Inhibitors of Angiogenesis. In: Yarden, Y., Elkabets, M. (eds) Resistance to Anti-Cancer Therapeutics Targeting Receptor Tyrosine Kinases and Downstream Pathways. Resistance to Targeted Anti-Cancer Therapeutics, vol 15. Springer, Cham. https://doi.org/10.1007/978-3-319-67932-7_9
Download citation
DOI: https://doi.org/10.1007/978-3-319-67932-7_9
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-67930-3
Online ISBN: 978-3-319-67932-7
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)