Anti-angiogenic drugs in cancer therapeutics: a review of the latest preclinical and clinical studies of anti-angiogenic agents with anticancer potential

Abstract

Cancer is a group of diseases with significant morbidity and mortality. In cancer cells, where energy requirements are exceptionally high, angiogenesis, which is the sprouting of new blood vessels from pre-existing ones, is an important process for tumour survival and progression. Hence, extensive research in recent years focuses on the discovery of new anticancer drugs that target angiogenesis. Several methodologies have been developed preclinically, including the inhibition of pro-angiogenic factors and their receptors via micromolecular agents or monoclonal antibodies and the inhibition of other compensatory pathways beyond the traditional angiogenic ones. The purpose of the literature review is to present new anticancer drugs that target the process of angiogenesis and have been under preclinical or clinical investigation during the last five years. Many new anticancer drugs targeting angiogenesis are identified in the literature. The results of the in vitro and in vivo evaluation of these drugs show that, apart from inhibiting angiogenesis, they also affect cancer cell proliferation and tumour growth. Recent clinical studies show that these drugs increase the overall or disease-free survival of patients, even those with persistent, chemotherapy-resistant and metastatic types of cancer, although treatment-related side effects are not uncommon. Drugs that target the process of angiogenesis are likely to be the future of anticancer therapy, especially in cases where more traditional treatments do not produce the desired results and where combination regimens of anti-angiogenic agents with standard chemotherapeutics increase patient survival.

Keywords

Angiogenesis / cancer / anti-angiogenic drugs / anticancer drugs / chemotherapy / malignant angiogenesis / angiogenic inhibitors

References

[1] Mattiuzzi C.Current cancer epidemiology.J Epidemiol Glob Health2019;9:217-22 PMCID:PMC7310786

[2] Guerra A,Mangir N,Natal Jorge R.Simulation of the process of angiogenesis: quantification and assessment of vascular patterning in the chicken chorioallantoic membrane.Comput Biol Med2021;136:104647

[3] Naito H,Takakura N.Mechanisms of new blood-vessel formation and proliferative heterogeneity of endothelial cells.Int Immunol2020;32:295-305

[4] Carmeliet P.Mechanisms of angiogenesis and arteriogenesis.Nat Med2000;6:389-95

[5] Folkman J,Becker FF.Growth and metastasis of tumor in organ culture.Cancer1963;16:453-67

[6] de Heer EC,Harris AL.HIFs, angiogenesis, and metabolism: elusive enemies in breast cancer.J Clin Invest2020;130:5074-87 PMCID:PMC7524491

[7] Lugano R,Dimberg A.Tumor angiogenesis: causes, consequences, challenges and opportunities.Cell Mol Life Sci2020;77:1745-70 PMCID:PMC7190605

[8] Rajabi M.The role of angiogenesis in cancer treatment.Biomedicines2017;5:34 PMCID:PMC5489820

[9] Melincovici CS,Şuşman S.Vascular endothelial growth factor (VEGF)-key factor in normal and pathological angiogenesis.Rom J Morphol Embryol2018;59:455-67

[10] Bai Y,Zhou J,Zhang L.Sequential delivery of VEGF, FGF-2 and PDGF from the polymeric system enhance HUVECs angiogenesis in vitro and CAM angiogenesis.Cell Immunol2018;323:19-32

[11] Armani G,Pagani A.The heterogeneity of cancer endothelium: the relevance of angiogenesis and endothelial progenitor cells in cancer microenvironment.Microvasc Res2021;138:104189

[12] Huang XL,Wang J.Role of receptor tyrosine kinases mediated signal transduction pathways in tumor growth and angiogenesis-New insight and futuristic vision.Int J Biol Macromol2021;180:739-52

[13] Leung DW,Kuang WJ,Ferrara N.Vascular endothelial growth factor is a secreted angiogenic mitogen.Science1989;246:1306-9

[14] Montesano R,Baird A,Orci L.Basic fibroblast growth factor induces angiogenesis in vitro.Proc Natl Acad Sci U S A1986;83:7297-301 PMCID:PMC386703

[15] Fett JW,Lobb RR.Isolation and characterization of angiogenin, an angiogenic protein from human carcinoma cells.Biochemistry1985;24:5480-6

[16] Schreiber AB,Derynck R.Transforming growth factor-alpha: a more potent angiogenic mediator than epidermal growth factor.Science1986;232:1250-3

[17] Roberts AB,Assoian RK.Transforming growth factor type beta: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro.Proc Natl Acad Sci U S A1986;83:4167-71 PMCID:PMC323692

[18] Fràter-Schröder M,Hallmann R,Böhlen P.Tumor necrosis factor type alpha, a potent inhibitor of endothelial cell growth in vitro, is angiogenic in vivo.Proc Natl Acad Sci U S A1987;84:5277-81 PMCID:PMC298838

[19] Ishikawa F,Hellman U.Identification of angiogenic activity and the cloning and expression of platelet-derived endothelial cell growth factor.Nature1989;338:557-62

[20] Bussolino F,Wang JM.In vitro and in vivo activation of endothelial cells by colony-stimulating factors.J Clin Invest1991;87:986-95 PMCID:PMC329891

[21] Zhao J,Shu B.Granulocyte/macrophage colony-stimulating factor influences angiogenesis by regulating the coordinated expression of VEGF and the Ang/Tie system.PLoS One2014;9:e92691 PMCID:PMC3962430

[22] Zheng Q,Cheng X.Granulocyte-macrophage colony-stimulating factor increases tumor growth and angiogenesis directly by promoting endothelial cell function and indirectly by enhancing the mobilization and recruitment of proangiogenic granulocytes.Tumour Biol2017;39:1010428317692232

[23] Zhou Y,Zhao Y,Zhang S.Placental growth factor enhances angiogenesis in human intestinal microvascular endothelial cells via PI3K/Akt pathway: potential implications of inflammation bowel disease.Biochem Biophys Res Commun2016;470:967-74

[24] Kitadai Y,Haruma K.Transfection of interleukin-8 increases angiogenesis and tumorigenesis of human gastric carcinoma cells in nude mice.Br J Cancer1999;81:647-53 PMCID:PMC2362886

[25] Kaga T,Sakaguchi M,Taniyama Y.Hepatocyte growth factor stimulated angiogenesis without inflammation: differential actions between hepatocyte growth factor, vascular endothelial growth factor and basic fibroblast growth factor.Vascul Pharmacol2012;57:3-9

[26] Gospodarowicz D,Thakral T.The angiogenic activity of the fibroblast and epidermal growth factor.Experimental Eye Research1979;28:501-14

[27] Yokoi A,Huang J.Human epidermal growth factor receptor signaling contributes to tumor growth via angiogenesis in her2/neu-expressing experimental Wilms’ tumor.Journal of Pediatric Surgery2003;38:1569-73

[28] Palinski W,Camerlingo R.Lysosome purinergic receptor P2X4 regulates neoangiogenesis induced by microvesicles from sarcoma patients.Cell Death Dis2021;12:797 PMCID:PMC8371002

[29] Pavlakovic H,Schweigerer L.Multiple angiogenesis stimulators in a single malignancy: implications for anti-angiogenic tumour therapy.Angiogenesis2001;4:259-62

[30] Shibuya M.Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) signaling in angiogenesis: a crucial target for anti- and pro-angiogenic therapies.Genes Cancer2011;2:1097-105 PMCID:PMC3411125

[31] Muller YA,Christinger HW,Cunningham BC.Vascular endothelial growth factor: crystal structure and functional mapping of the kinase domain receptor binding site.Proc Natl Acad Sci U S A1997;94:7192-7 PMCID:PMC23789

[32] Shibuya M.Role of VEGF-flt receptor system in normal and tumor angiogenesis.Adv Cancer Res1995;67:281-316

[33] Li L,Xu C.VEGF promotes endothelial progenitor cell differentiation and vascular repair through connexin 43.Stem Cell Res Ther2017;8:237 PMCID:PMC5655878

[34] Zhu D,Zhang Z.Recent advances of nanotechnology-based tumor vessel-targeting strategies.J Nanobiotechnology2021;19:435 PMCID:PMC8686559

[35] El-Kenawi AE.Angiogenesis inhibitors in cancer therapy: mechanistic perspective on classification and treatment rationales.Br J Pharmacol2013;170:712-29 PMCID:PMC3799588

[36] Mundel TM.Type IV collagen-derived angiogenesis inhibitors.Microvasc Res2007;74:85-9 PMCID:PMC3998721

[37] Abdollahi A,Maercker C.Endostatin’s antiangiogenic signaling network.Molecular Cell2004;13:649-63

[38] Ranjit PM,Vishnupriya S,Girish K. Endogenous angiogenesis inhibitor endostatin: an overview. Asian Journal of Pharmaceutical and Clinical Research 2012;5:1-8. Available from: https://xueshu.baidu.com/usercenter/paper/show?paperid=cdfa6789882c0b11995e7c9aed8209c7&site=xueshu_se&hitarticle=1. [Last accessed on 26 Apr 2022]

[39] Kerbel R.Clinical translation of angiogenesis inhibitors.Nat Rev Cancer2002;2:727-39

[40] Ribatti D.Endogenous inhibitors of angiogenesis: a historical review.Leuk Res2009;33:638-44

[41] Rao N,Ge R.Novel endogenous angiogenesis inhibitors and their therapeutic potential.Acta Pharmacol Sin2015;36:1177-90 PMCID:PMC4648174

[42] Ferrara N.VEGF as a therapeutic target in cancer.Oncology2005;69 Suppl 3:11-6

[43] Frezzetti D,Maiello MR.VEGF as a potential target in lung cancer.Expert Opin Ther Targets2017;21:959-66

[44] Carmeliet P.Molecular mechanisms and clinical applications of angiogenesis.Nature2011;473:298-307 PMCID:PMC4049445

[45] Xu G.Angiogenesis inhibition in the in vivo antineoplastic effect of manumycin and paclitaxel against anaplastic thyroid carcinoma.2001;86:1769-77

[46] Xu N,Luo T. Low-dose paclitaxel combined with thalidomide inhibits angiogenesis in mice bearing S180 sarcoma. Chinese Journal of Clinical Oncology 2020;47:7-11. (in Chinese) Available from: https://xueshu.baidu.com/usercenter/paper/show?paperid=1j620ed0bf510m10dv0a08y0km339097&site=xueshu_se&hitarticle=1. [Last accessed on 26 Apr 2022]

[47] Zhang QY,Wang ZH. Effect of ginsenoside Rg3 combined with cyclophosphamide on angiogenesis in rats with EMT-6 breast cancer.Chinese Journal of Clinical Rehabilitation 2004. Available from: https://xueshu.baidu.com/usercenter/paper/show?paperid=ac39f44b384ddaf8af60bee674f81bbe&site=xueshu_se&hitarticle=1. [Last accessed on 26 Apr 2022]

[48] Ezoe K,Yabuuchi A.Long-term adverse effects of cyclophosphamide on follicular growth and angiogenesis in mouse ovaries.Reprod Biol2014;14:238-42

[49] Ciardiello F,Bianco R.Inhibition of growth factor production and angiogenesis in human cancer cells by ZD1839 (Iressa), a selective epidermal growth factor receptor tyrosine kinase inhibitor.Clin Cancer Res2001;7:1459-65

[50] Hirata A,Kometani T.ZD1839 (Iressa) induces antiangiogenic effects through inhibition of epidermal growth factor receptor tyrosine kinase.Cancer Res2002;62:2554-60

[51] Fallahi P,Galdiero MR.Molecular targets of tyrosine kinase inhibitors in thyroid cancer.Semin Cancer Biol2022;79:180-96

[52] Papadimitriou M.Antiangiogenic tyrosine kinase inhibitors in metastatic colorectal cancer: focusing on regorafenib.Anticancer Res2021;41:567-82

[53] Dan H,Huang X,Xing Y.CM082, a novel VEGF receptor tyrosine kinase inhibitor, can inhibit angiogenesis in vitro and in vivo.Microvasc Res2021;136:104146

[54] Dai MD,Fan J.DW14383 is an irreversible pan-FGFR inhibitor that suppresses FGFR-dependent tumor growth in vitro and in vivo.Acta Pharmacol Sin2021;42:1498-506 PMCID:PMC8379184

[55] Yang JC,Sherry RM.A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer.N Engl J Med2003;349:427-34 PMCID:PMC2275324

[56] Willett CG,di Tomaso E.Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer.Nat Med2004;10:145-7 PMCID:PMC2693485

[57] Heinemann V.Bevacizumab plus irinotecan-based regimens in the treatment of metastatic colorectal cancer.Oncology2010;79:118-28

[58] Cui F,Wan C,Luo RC.Clinical research of bevacizumab in combination with irinotecan, fluorouracil and leucovorin for advanced metastatic colorectal cancer.Zhonghua Wei Chang Wai Ke Za Zhi2009;12:374-7

[59] Kabbinavar F,Fehrenbacher L.Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer.J Clin Oncol2003;21:60-5

[60] Dank M,Piko B.First-line bevacizumab-paclitaxel in 220 patients with metastatic breast cancer: results from the AVAREG study.Anticancer Res2014;34:1275-80

[61] Johnson DH,Novotny WF.Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer.J Clin Oncol2004;22:2184-91

[62] Soria JC,Reck M.Meta-analysis of Bevacizumab in Advanced NSCLC Collaborative GroupSystematic review and meta-analysis of randomised, phase II/III trials adding bevacizumab to platinum-based chemotherapy as first-line treatment in patients with advanced non-small-cell lung cancer.Ann Oncol2013;24:20-30

[63] Yu SR,Xia GH.Combination of bevacizumab and platinum-based chemotherapy as first-line therapy for advanced non-squamous NSCLC.Journal of Practical Oncology2015;30:418-22

[64] Spratlin JL,Mackey JR.Ramucirumab (IMC-1121B): a novel attack on angiogenesis.Future Oncol2010;6:1085-94

[65] Mcintyre JA. Panitumumab: oncolytic prop inn anti-EGFR human monoclonal antibody. Drugs of the Future 2004. Available from: https://xueshu.baidu.com/usercenter/paper/show?paperid=af47c87a085e47a6dd730f339a94aa3e&site=xueshu_se&hitarticle=1. [Last accessed on 26 Apr 2022]

[66] Pueyo G,Figueras A.Cetuximab may inhibit tumor growth and angiogenesis induced by ionizing radiation: a preclinical rationale for maintenance treatment after radiotherapy.Oncologist2010;15:976-86 PMCID:PMC3228040

[67] Bugyik E,Reiniger L.Lack of angiogenesis in experimental brain metastases.J Neuropathol Exp Neurol2011;70:979-91

[68] Valiente M,Jin X.Serpins promote cancer cell survival and vascular co-option in brain metastasis.Cell2014;156:1002-16 PMCID:PMC3988473

[69] Bridgeman VL,Foo S.Vessel co-option is common in human lung metastases and mediates resistance to anti-angiogenic therapy in preclinical lung metastasis models.J Pathol2017;241:362-74 PMCID:PMC5248628

[70] Stessels F,Van der Auwera I.Breast adenocarcinoma liver metastases, in contrast to colorectal cancer liver metastases, display a non-angiogenic growth pattern that preserves the stroma and lacks hypoxia.Br J Cancer2004;90:1429-36 PMCID:PMC2409675

[71] Vermeulen PB,Salgado R.Liver metastases from colorectal adenocarcinomas grow in three patterns with different angiogenesis and desmoplasia.J Pathol2001;195:336-42

[72] Winkler F.Hostile takeover: how tumours hijack pre-existing vascular environments to thrive.J Pathol2017;242:267-72

[73] Kuczynski EA,Bar-Zion A.Co-option of liver vessels and not sprouting angiogenesis drives acquired sorafenib resistance in hepatocellular carcinoma.J Natl Cancer Inst2016;108:djw030 PMCID:PMC5017954

[74] Leenders WP,Verrijp K.Antiangiogenic therapy of cerebral melanoma metastases results in sustained tumor progression via vessel co-option.Clin Cancer Res2004;10:6222-30

[75] Frentzas S,Bridgeman VL.Vessel co-option mediates resistance to anti-angiogenic therapy in liver metastases.Nat Med2016;22:1294-302 PMCID:PMC5104270

[76] Kuczynski EA.Vessel co-option and resistance to anti-angiogenic therapy.Angiogenesis2020;23:55-74

[77] Casanovas O,Bergers G.Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors.Cancer Cell2005;8:299-309

[78] Ebos JM,Christensen JG,Kerbel RS.Multiple circulating proangiogenic factors induced by sunitinib malate are tumor-independent and correlate with antitumor efficacy.Proc Natl Acad Sci U S A2007;104:17069-74 PMCID:PMC2040401

[79] Croci DO,Dalotto-Moreno T.Glycosylation-dependent lectin-receptor interactions preserve angiogenesis in anti-VEGF refractory tumors.Cell2014;156:744-58

[80] Pisarsky L,Fagiani E.Targeting metabolic symbiosis to overcome resistance to anti-angiogenic therapy.Cell Rep2016;15:1161-74 PMCID:PMC4870473

[81] Zhai B,Jiang X.Inhibition of Akt reverses the acquired resistance to sorafenib by switching protective autophagy to autophagic cell death in hepatocellular carcinoma.Mol Cancer Ther2014;13:1589-98

[82] Chandra A,Yagnik G.Autophagy as a mechanism for anti-angiogenic therapy resistance.Semin Cancer Biol2020;66:75-88 PMCID:PMC7047534

[83] Giuliano S,Dufies M.Resistance to sunitinib in renal clear cell carcinoma results from sequestration in lysosomes and inhibition of the autophagic flux.Autophagy2015;11:1891-904 PMCID:PMC4824581

[84] Wu S,Shen R.Drug resistance-related sunitinib sequestration in autophagolysosomes of endothelial cells.Int J Oncol2020;56:113-22 PMCID:PMC6910192

[85] Wen Y,Umamaheswaran S.Endothelial p130cas confers resistance to anti-angiogenesis therapy.Cell Rep2022;38:110301 PMCID:PMC8860355

[86] Tang D,Wang S.Cancer-associated fibroblasts promote angiogenesis in gastric cancer through galectin-1 expression.Tumour Biol2016;37:1889-99

[87] Hosaka K,Seki T.Pericyte-fibroblast transition promotes tumor growth and metastasis.Proc Natl Acad Sci U S A2016;113:E5618-27 PMCID:PMC5035870

[88] Orlidge A.Inhibition of capillary endothelial cell growth by pericytes and smooth muscle cells.J Cell Biol1987;105:1455-62 PMCID:PMC2114828

[89] Bussolati B,Camussi G.Characterization of molecular and functional alterations of tumor endothelial cells to design anti-angiogenic strategies.Curr Vasc Pharmacol2010;8:220-32

[90] Bussolati B,Russo S,Camussi G.Altered angiogenesis and survival in human tumor-derived endothelial cells.FASEB J2003;17:1159-61

[91] Hida K,Amin DN.Tumor-associated endothelial cells with cytogenetic abnormalities.Cancer Res2004;64:8249-55

[92] Maishi N,Kikuchi H,Hida K.Tumor endothelial heterogeneity in cancer progression.Cancers (Basel)2019;11:1511 PMCID:PMC6826555

[93] Holmgren L,Folkman J.Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression.Nat Med1995;1:149-53

[94] Conley SJ,Kakarala P.Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia.Proc Natl Acad Sci U S A2012;109:2784-9 PMCID:PMC3286974

[95] Cheng L,Zhou W.Glioblastoma stem cells generate vascular pericytes to support vessel function and tumor growth.Cell2013;153:139-52 PMCID:PMC3638263

[96] Mohammed RA,El-Shikh S,Ellis IO.Prognostic significance of vascular endothelial cell growth factors -A, -C and -D in breast cancer and their relationship with angio- and lymphangiogenesis.Br J Cancer2007;96:1092-100 PMCID:PMC2360132

[97] Zarrin B,Vaseghi G.Acquired tumor resistance to antiangiogenic therapy: mechanisms at a glance.J Res Med Sci2017;22:117 PMCID:PMC5680657

[98] Montemagno C.Resistance to anti-angiogenic therapies: a mechanism depending on the time of exposure to the drugs.Front Cell Dev Biol2020;8:584 PMCID:PMC7381352

[99] Lopes-Coelho F,Pereira SA.Anti-angiogenic therapy: current challenges and future perspectives.Int J Mol Sci2021;22:3765 PMCID:PMC8038573

[100] Kienast Y,Scheuer W.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 Res2013;19:6730-40

[101] Brown JL,Pinzon-Ortiz M.A human monoclonal anti-ANG2 antibody leads to broad antitumor activity in combination with VEGF inhibitors and chemotherapy agents in preclinical models.Mol Cancer Ther2010;9:145-56

[102] Gyanchandani R,Myers JN.A proangiogenic signature is revealed in FGF-mediated bevacizumab-resistant head and neck squamous cell carcinoma.Mol Cancer Res2013;11:1585-96 PMCID:PMC3955724

[103] Powell MA,Goodfellow PJ.A phase II trial of brivanib in recurrent or persistent endometrial cancer: an NRG Oncology/Gynecologic Oncology Group Study.Gynecol Oncol2014;135:38-43 PMCID:PMC4278402

[104] Shimizu S,Hikita H.Inhibition of autophagy potentiates the antitumor effect of the multikinase inhibitor sorafenib in hepatocellular carcinoma.Int J Cancer2012;131:548-57

[105] Motzer RJ,Ye D.Phase II trial of second-line everolimus in patients with metastatic renal cell carcinoma (RECORD-4).Ann Oncol2016;27:441-8 PMCID:PMC5006123

[106] Bamias A,Gavalas N.The combination of bevacizumab/temsirolimus after first-line anti-VEGF therapy in advanced renal-cell carcinoma: a clinical and biomarker study.Int J Clin Oncol2019;24:411-9

[107] Pietras K.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 Oncol2005;23:939-52

[108] Ramadan WS,Altaie AM,Elmoselhi A.Potential therapeutic strategies for lung and breast cancers through understanding the anti-angiogenesis resistance mechanisms.Int J Mol Sci2020;21:565 PMCID:PMC7014257

[109] Song Y,Xie Q,Wang J.Anti-angiogenic agents in combination with immune checkpoint inhibitors: a promising strategy for cancer treatment.Front Immunol2020;11:1956 PMCID:PMC7477085

[110] Ogasawara S,Kondo R,Akiba J.Antiproliferative effect of lenvatinib on human liver cancer cell lines in vitro and in vivo.Anticancer Res2019;39:5973-82

[111] Suyama K.Lenvatinib: a promising molecular targeted agent for multiple cancers.Cancer Control2018;25:1073274818789361 PMCID:PMC6056795

[112] Kudo M,Qin S.Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial.The Lancet2018;391:1163-73

[113] Vogel A,Kudo M.Lenvatinib versus sorafenib for first-line treatment of unresectable hepatocellular carcinoma: patient-reported outcomes from a randomised, open-label, non-inferiority, phase 3 trial.2021;6:649-58

[114] Jin H,Lv Y.EGFR activation limits the response of liver cancer to lenvatinib.Nature2021;595:730-4

[115] Yano S,Dong RP.EGFR tyrosine kinase inhibitor “gefitinib (Iressa)” for cancer therapy.Nihon Yakurigaku Zasshi2003;122:491-7

[116] Han B,Wang Q.Effect of anlotinib as a third-line or further treatment on overall survival of patients with advanced non-small cell lung cancer: the ALTER 0303 phase 3 randomized clinical trial.JAMA Oncol2018;4:1569-75 PMCID:PMC6248083

[117] Chi Y,Hong X.Safety and efficacy of anlotinib, a multikinase angiogenesis inhibitor, in patients with refractory metastatic soft-tissue sarcoma.Clin Cancer Res2018;24:5233-8

[118] Sherman SI.Advances in chemotherapy of differentiated epithelial and medullary thyroid cancers.J Clin Endocrinol Metab2009;94:1493-9

[119] Ruan X,Dong Q.Antitumor effects of anlotinib in thyroid cancer.Endocr Relat Cancer2019;26:153-64 PMCID:PMC6215907

[120] Gao Q,Chen H.Intratumoral injection of anlotinib hydrogel enhances antitumor effects and reduces toxicity in mouse model of lung cancer.Drug Deliv2020;27:1524-34 PMCID:PMC7599023

[121] Goff D,Heckrodt T.Discovery of dual Axl/VEGF-R2 inhibitors as potential anti-angiogenic and anti-metastatic drugs for cancer chemotherapy.Bioorg Med Chem Lett2017;27:3766-71

[122] Holland SJ,Franci C.R428, a selective small molecule inhibitor of Axl kinase, blocks tumor spread and prolongs survival in models of metastatic breast cancer.Cancer Res2010;70:1544-54

[123] Holland SJ,Franci C.Multiple roles for the receptor tyrosine kinase axl in tumor formation.Cancer Res2005;65:9294-303

[124] Colavito SA.AXL as a target in breast cancer therapy.J Oncol2020;2020:5291952 PMCID:PMC7042526

[125] Yoshiji H,Yoshii J.Synergistic effect of basic fibroblast growth factor and vascular endothelial growth factor in murine hepatocellular carcinoma.Hepatology2002;35:834-42

[126] Harimoto N,Shirabe K.The significance of fibroblast growth factor receptor 2 expression in differentiation of hepatocellular carcinoma.Oncology2010;78:361-8

[127] Kano MR,Iwata C.VEGF-A and FGF-2 synergistically promote neoangiogenesis through enhancement of endogenous PDGF-B-PDGFRbeta signaling.J Cell Sci2005;118:3759-68

[128] Le TBU,Ho RZW.Bevacizumab augments the antitumor efficacy of infigratinib in hepatocellular carcinoma.Int J Mol Sci2020;21:9405 PMCID:PMC7764786

[129] Prawira A,Vu TC.Ribociclib enhances infigratinib-induced cancer cell differentiation and delays resistance in FGFR-driven hepatocellular carcinoma.Liver Int2021;41:608-20 PMCID:PMC7894323

[130] Lu RM,Liu IJ,Liu YJ.Novel human Ab against vascular endothelial growth factor receptor 2 shows therapeutic potential for leukemia and prostate cancer.Cancer Sci2019;110:3773-87 PMCID:PMC6890446

[131] Zhang J,Shi W.The novel VEGF receptor 2 inhibitor YLL545 inhibits angiogenesis and growth in breast cancer.Oncotarget2016;7:41067-80 PMCID:PMC5173043

[132] Keating GM.Sorafenib: a review in hepatocellular carcinoma.Target Oncol2017;12:243-53

[133] West XZ,Merkulova AA.Oxidative stress induces angiogenesis by activating TLR2 with novel endogenous ligands.Nature2010;467:972-6 PMCID:PMC2990914

[134] Wu C,Tomko N.2-(ω-carboxyethyl)pyrrole antibody as a new inhibitor of tumor angiogenesis and growth.Anticancer Agents Med Chem2017;17:813-20 PMCID:PMC6002755

[135] Li QW,Hao CX.SANT, a novel Chinese herbal monomer combination, decreasing tumor growth and angiogenesis via modulating autophagy in heparanase overexpressed triple-negative breast cancer.J Ethnopharmacol2021;266:113430

[136] Nadir Y,Brenner B.Heparanase, tissue factor, and cancer.Semin Thromb Hemost2008;34:187-94

[137] Chen L. Relationship between expressions of heparanase and basic fibroblast growth factor and clinicopathology of breast cancer tissues. Chinese Journal of Cancer Prevention and Treatment 2010;17:743-745+748. Available from: https://xueshu.baidu.com/usercenter/paper/show?paperid=22fd6776dcd06aea5a4e3876c132fdf9&site=xueshu_se&hitarticle=1. [Last accessed on 26 Apr 2022]

[138] Gawthorpe S,Arif M,Nevill A.Heparanase and COX-2 expression as predictors of lymph node metastasis in large, high-grade breast tumors.Anticancer Res2014;34:2797-800

[139] Zhang PC,Li MM.AT-533, a novel Hsp90 inhibitor, inhibits breast cancer growth and HIF-1α/VEGF/VEGFR-2-mediated angiogenesis in vitro and in vivo.Biochem Pharmacol2020;172:113771

[140] Miyata Y,Neckers L.The therapeutic target Hsp90 and cancer hallmarks.Curr Pharm Des2013;19:347-65 PMCID:PMC7553218

[141] Calderwood SK.Heat shock proteins promote cancer: it’s a protection racket.Trends Biochem Sci2016;41:311-23 PMCID:PMC4911230

[142] Han B,Zhao Y.Anlotinib as a third-line therapy in patients with refractory advanced non-small-cell lung cancer: a multicentre, randomised phase II trial (ALTER0302).Br J Cancer2018;118:654-61 PMCID:PMC5846072

[143] Koumarianou A.Surufatinib-a novel oral agent for neuroendocrine tumours.Nat Rev Endocrinol2021;17:9-10

[144] Xu J,Zhou Z.Surufatinib in advanced extrapancreatic neuroendocrine tumours (SANET-ep): a randomised, double-blind, placebo-controlled, phase 3 study.Lancet Oncol2020;21:1500-12

[145] Xu J,Bai C.Surufatinib in advanced pancreatic neuroendocrine tumours (SANET-p): a randomised, double-blind, placebo-controlled, phase 3 study.The Lancet Oncology2020;21:1489-99

[146] Syed YY.Surufatinib: first approval.Drugs2021;81:727-32

[147] Taylor MH,Makker V.Phase IB/II trial of lenvatinib plus pembrolizumab in patients with advanced renal cell carcinoma, endometrial cancer, and other selected advanced solid tumors.J Clin Oncol2020;38:1154-63 PMCID:PMC7145588

[148] Yasuda S,Yamato I.Simultaneous blockade of programmed death 1 and vascular endothelial growth factor receptor 2 (VEGFR2) induces synergistic anti-tumour effect in vivo.Clin Exp Immunol2013;172:500-6 PMCID:PMC3646450

[149] Atkins MB,Puzanov I.Axitinib in combination with pembrolizumab in patients with advanced renal cell cancer: a non-randomised, open-label, dose-finding, and dose-expansion phase 1b trial.The Lancet Oncology2018;19:405-15 PMCID:PMC6860026

[150] Powles T,Soulières D.Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial.The Lancet Oncology2020;21:1563-73

[151] Riechelmann RP,Bariani GM.Regorafenib in patients with antiangiogenic-naïve and chemotherapy-refractory advanced colorectal cancer: results from a phase IIb trial.Oncologist2019;24:1180-7 PMCID:PMC6738304

[152] Ettrich TJ.Regorafenib. In: Martens UM, editor. Small molecules in oncology. Cham: Springer International Publishing; 2018. p. 45-56.

[153] la Fouchardière C. Regorafenib in the treatment of metastatic colorectal cancer.Future Oncol2018;14:2239-46

[154] Nakazawa T,Takada J.Early increase in α-fetoprotein for predicting unfavorable clinical outcomes in patients with advanced hepatocellular carcinoma treated with sorafenib.Eur J Gastroenterol Hepatol2013;25:683-9

[155] Silva JP,Berger NG.The prognostic utility of baseline alpha-fetoprotein for hepatocellular carcinoma patients.J Surg Oncol2017;116:831-40

[156] Tangkijvanich P,Suwangool P.Clinical characteristics and prognosis of hepatocellular carcinoma: analysis based on serum alpha-fetoprotein levels.J Clin Gastroenterol2000;31:302-8

[157] Zhu AX,Yen C.Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial.The Lancet Oncology2019;20:282-96

[158] Mayer RJ,Falcone A.RECOURSE Study GroupRandomized trial of TAS-102 for refractory metastatic colorectal cancer.N Engl J Med2015;372:1909-19

[159] Tsukihara H,Sakamoto K.Efficacy of combination chemotherapy using a novel oral chemotherapeutic agent, TAS-102, together with bevacizumab, cetuximab, or panitumumab on human colorectal cancer xenografts.Oncol Rep2015;33:2135-42 PMCID:PMC4391594

[160] Kuboki Y,Shinozaki E.TAS-102 plus bevacizumab for patients with metastatic colorectal cancer refractory to standard therapies (C-TASK FORCE): an investigator-initiated, open-label, single-arm, multicentre, phase 1/2 study.The Lancet Oncology2017;18:1172-81

[161] Palazzo A,Munzone E.Phase II trial of bevacizumab plus weekly paclitaxel, carboplatin, and metronomic cyclophosphamide with or without trastuzumab and endocrine therapy as preoperative treatment of inflammatory breast cancer.Clin Breast Cancer2018;18:328-35

[162] Lan C,Xiong Y.Apatinib combined with oral etoposide in patients with platinum-resistant or platinum-refractory ovarian cancer (AEROC): a phase 2, single-arm, prospective study.The Lancet Oncology2018;19:1239-46

[163] Marrero AD,Martínez-Poveda B.Antiangiogenic phytochemicals constituent of diet as promising candidates for chemoprevention of cancer.Antioxidants (Basel)2022;11:302 PMCID:PMC8868078

[164] Hussen BM,Abdullah ST.Signaling pathways modulated by miRNAs in breast cancer angiogenesis and new therapeutics.Pathol Res Pract2022;230:153764

[165] Shoari A,Ahangari Cohan R,Karami E.Anti-angiogenic peptides application in cancer therapy: a review.Res Pharm Sci2021;16:559-74 PMCID:PMC8562409