Abstract
Prostate cancer, the most common cancer diagnosed in men, has been investigated extensively concerning the use of anti-angiogenics. There is a significant amount of preclinical and early clinical data about the potential value of this class of drugs as is the case with many other solid cancer types. Vascular endothelial growth factors and their receptors (VEGF/VEGFRs) seem to be key players in neo-angiogenesis and its expression can be regulated by androgen receptor signaling. Platelet-derived growth factor receptor alpha (PDGFR-α) is of lesser importance in primary prostate cancer; however, PDGFR-A might be involved in the formation of bone metastases. Other mechanisms of pro- and anti-angiogenic factors will be described herein.
The clinical development focused mainly on metastatic, castration-resistant prostate cancer. Phase I/II trials showed consistently interesting results in terms of response rates or reduction of tumor growth. Yet, randomized studies failed to demonstrate a significant overall survival benefit despite increased progression-free survival or clinical signs of activity, such as reduced need for analgesic drugs. This chapter will provide an overview of angiogenesis in prostate cancer and on the development of angiogenesis inhibitors, in particular bevacizumab, sunitinib, tasquinimod, lenalidomide, and cabozantinib.
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Algire GH, Chalkley HW (1945) Vascular reactions of normal and malignant tissues in vivo. I. Vascular reactions of mice to wounds and to normal and neoplastic implants. J Natl Cancer Inst 6:73–85
Algire GH, Legallais FY (1948) The transparent chamber technique in the mouse in the study of tumor histo-physiology. Fed Proc 7:268
Anastasiadis AG, Stisser BC, Ghafar MA et al (2002) Tumor hypoxia and the progression of prostate cancer. Curr Urol Rep 3:222–228
Asahara T, Murohara T, Sullivan A et al (1997) Isolation of putative progenitor endothelial cells for angiogenesis. Science 275:964–967
Bates DO, Cui TG, Doughty JM et al (2002) VEGF165b, an inhibitory splice variant of vascular endothelial growth factor, is down-regulated in renal cell carcinoma. Cancer Res 62:4123–4131
Beardsley EK, Hotte SJ, North S et al (2012) A phase II study of sorafenib in combination with bicalutamide in patients with chemotherapy-naive castration resistant prostate cancer. Investig New Drugs 30:1652–1659
Bergers G, Hanahan D (2008) Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 8:592–603
Boll K, Reiche K, Kasack K et al (2013) MiR-130a, miR-203 and miR-205 jointly repress key oncogenic pathways and are downregulated in prostate carcinoma. Oncogene 32:277–285
Bratt O, Haggman M, Ahlgren G et al (2009) Open-label, clinical phase I studies of tasquinimod in patients with castration-resistant prostate cancer. Br J Cancer 101:1233–1240
Carducci M, Armstrong A, Pili R et al (2015) A phase 3, randomized, double-blind, placebo-controlled study of tasquinimod (TASQ) in men with metastatic castrate resistant prostate cancer (mCRPC). Eur J Cancer 51:S713–S714
Cash J, Korchnak A, Gorman J et al (2007) VEGF transcription and mRNA stability are altered by WT1 not DDS(R384W) expression in LNCaP cells. Oncol Rep 17:1413–1419
Chen L, Qiu X, Wang R et al (2014) The efficacy and safety of docetaxel plus thalidomide vs. docetaxel alone in patients with androgen-independent prostate cancer: a systematic review. Sci Report 4:4818
Choueiri TK, Escudier B, Powles T et al (2016) Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol 17:917–927
Christensen M, Najy AJ, Snyder M et al (2014) A critical role of the PTEN/PDGF signaling network for the regulation of radiosensitivity in adenocarcinoma of the prostate. Int J Radiat Oncol Biol Phys 88:151–158
Chu QS (2009) Aflibercept (AVE0005): an alternative strategy for inhibiting tumour angiogenesis by vascular endothelial growth factors. Expert Opin Biol Ther 9:263–271
Crawford ED, Higano CS, Shore ND et al (2015) Treating patients with metastatic castration resistant prostate cancer: a comprehensive review of available therapies. J Urol 194:1537–1547
Dahut WL, Gulley JL, Arlen PM et al (2004) Randomized phase II trial of docetaxel plus thalidomide in androgen-independent prostate cancer. J Clin Oncol 22:2532–2539
Dalrymple SL, Becker RE, Isaacs JT (2007) The quinoline-3-carboxamide anti-angiogenic agent, tasquinimod, enhances the anti-prostate cancer efficacy of androgen ablation and taxotere without effecting serum PSA directly in human xenografts. Prostate 67:790–797
D’Amato RJ, Loughnan MS, Flynn E et al (1994) Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci U S A 91:4082–4085
Dayyani F, Gallick GE, Logothetis CJ et al (2011) Novel therapies for metastatic castrate-resistant prostate cancer. J Natl Cancer Inst 103:1665–1675
Di Lorenzo G, Figg WD, Fossa SD et al (2008) Combination of bevacizumab and docetaxel in docetaxel-pretreated hormone-refractory prostate cancer: a phase 2 study. Eur Urol 54:1089–1094
Eisermann K, Broderick CJ, Bazarov A et al (2013) Androgen up-regulates vascular endothelial growth factor expression in prostate cancer cells via an Sp1 binding site. Mol Cancer 12:7
Elisei R, Schlumberger MJ, Muller SP et al (2013) Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol 31:3639–3646
Fagiani E, Christofori G (2013) Angiopoietins in angiogenesis. Cancer Lett 328:18–26
Farooqi AA, Siddik ZH (2015) Platelet-derived growth factor (PDGF) signalling in cancer: rapidly emerging signalling landscape. Cell Biochem Funct 33:257–265
Ferlay J, Soerjomataram I, Dikshit R et al (2015) Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136:E359–E386
Ferrara N (2002) VEGF and the quest for tumour angiogenesis factors. Nat Rev Cancer 2:795–803
Figg WD, Arlen P, Gulley J et al (2001) A randomized phase II trial of docetaxel (taxotere) plus thalidomide in androgen-independent prostate cancer. Semin Oncol 28:62–66
Fizazi K, Ulys A, Sengelov L et al (2016) A randomized, double-blind, placebo-controlled phase II study of maintenance therapy with tasquinimod (TASQ) in patients (pts) with mCRPC responsive to or stabilized during first-line docetaxel chemotherapy. J Clin Oncol 34:201
Folkman J, Hanahan D (1991) Switch to the angiogenic phenotype during tumorigenesis. Princess Takamatsu Symp 22:339–347
Folkman J, Merler E, Abernathy C et al (1971) Isolation of a tumor factor responsible for angiogenesis. J Exp Med 133:275–288
Fritzsche S, Kenzelmann M, Hoffmann MJ et al (2006) Concomitant down-regulation of SPRY1 and SPRY2 in prostate carcinoma. Endocr Relat Cancer 13:839–849
Furusato M, Wakui S, Sasaki H et al (1994) Tumour angiogenesis in latent prostatic carcinoma. Br J Cancer 70:1244–1246
Giri D, Ropiquet F, Ittmann M (1999) Alterations in expression of basic fibroblast growth factor (FGF) 2 and its receptor FGFR-1 in human prostate cancer. Clin Cancer Res 5:1063–1071
Green MM, Hiley CT, Shanks JH et al (2007) Expression of vascular endothelial growth factor (VEGF) in locally invasive prostate cancer is prognostic for radiotherapy outcome. Int J Radiat Oncol Biol Phys 67:84–90
Greene HSN (1950) The heterologous transplantation of human melanomas. Yale J Biol Med 22:611–620
Henry JY, Lu L, Adams M et al (2012) Lenalidomide enhances the anti-prostate cancer activity of docetaxel in vitro and in vivo. Prostate 72:856–867
Hernandez S, de Muga S, Agell L et al (2009) FGFR3 mutations in prostate cancer: association with low-grade tumors. Mod Pathol 22:848–856
Huang CN, Huang SP, Pao JB et al (2012a) Genetic polymorphisms in androgen receptor-binding sites predict survival in prostate cancer patients receiving androgen-deprivation therapy. Ann Oncol 23:707–713
Huang W, Fridman Y, Bonfil RD et al (2012b) A novel function for platelet-derived growth factor D: induction of osteoclastic differentiation for intraosseous tumor growth. Oncogene 31:4527–4535
Isambert N, Freyer G, Zanetta S et al (2012) Phase I dose-escalation study of intravenous aflibercept in combination with docetaxel in patients with advanced solid tumors. Clin Cancer Res 18:1743–1750
Kaplan RN, Riba RD, Zacharoulis S et al (2005) VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438:820–827
Kelly WK, Halabi S, Carducci M et al (2012) Randomized, double-blind, placebo-controlled phase III trial comparing docetaxel and prednisone with or without bevacizumab in men with metastatic castration-resistant prostate cancer: CALGB 90401. J Clin Oncol 30:1534–1540
Kim R, Emi M, Tanabe K (2007) Cancer immunoediting from immune surveillance to immune escape. Immunology 121:1–14
Kitagawa Y, Dai J, Zhang J et al (2005) Vascular endothelial growth factor contributes to prostate cancer-mediated osteoblastic activity. Cancer Res 65:10921–10929
Koppenol WH, Bounds PL, Dang CV (2011) Otto Warburg’s contributions to current concepts of cancer metabolism. Nat Rev Cancer 11:325–337
Kwabi-Addo B, Ozen M, Ittmann M (2004) The role of fibroblast growth factors and their receptors in prostate cancer. Endocr Relat Cancer 11:709–724
Kwart AM, Sims JE (1978) Blood vascular invasion: a poor prognostic factor in adenocarcinoma of the prostate. J Urol 119:138–140
Lambrechts D, Storkebaum E, Morimoto M et al (2003) VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death. Nat Genet 34:383–394
Lind AJ, Wikstrom P, Granfors T et al (2005) Angiopoietin 2 expression is related to histological grade, vascular density, metastases, and outcome in prostate cancer. Prostate 62:394–399
Mavrou A, Brakspear K, Hamdollah-Zadeh M et al (2015) Serine-arginine protein kinase 1 (SRPK1) inhibition as a potential novel targeted therapeutic strategy in prostate cancer. Oncogene 34:4311–4319
McIntyre A, Harris AL (2015) Metabolic and hypoxic adaptation to anti-angiogenic therapy: a target for induced essentiality. EMBO Mol Med 7:368–379
Mehta R, Kyshtoobayeva A, Kurosaki T et al (2001) Independent association of angiogenesis index with outcome in prostate cancer. Clin Cancer Res 7:81–88
Mellman I, Coukos G, Dranoff G (2011) Cancer immunotherapy comes of age. Nature 480:480–489
Michaelson MD, Oudard S, Ou YC et al (2014) Randomized, placebo-controlled, phase III trial of sunitinib plus prednisone versus prednisone alone in progressive, metastatic, castration-resistant prostate cancer. J Clin Oncol 32:76–82
Miles DW, Chan A, Dirix LY et al (2010) Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol 28:3239–3247
Morrissey C, Dowell A, Koreckij TD et al (2010) Inhibition of angiopoietin-2 in LuCaP 23.1 prostate cancer tumors decreases tumor growth and viability. Prostate 70:1799–1808
Nabhan C, Patel A, Villines D et al (2014) Lenalidomide monotherapy in chemotherapy-naive, castration-resistant prostate cancer patients: final results of a phase II study. Clin Genitourin Cancer 12:27–32
Ng SS, MacPherson GR, Gutschow M et al (2004) Antitumor effects of thalidomide analogs in human prostate cancer xenografts implanted in immunodeficient mice. Clin Cancer Res 10:4192–4197
Ning YM, Gulley JL, Arlen PM et al (2010) Phase II trial of bevacizumab, thalidomide, docetaxel, and prednisone in patients with metastatic castration-resistant prostate cancer. J Clin Oncol 28:2070–2076
Nyberg P, Xie L, Kalluri R (2005) Endogenous inhibitors of angiogenesis. Cancer Res 65:3967–3979
Ocana A, Amir E, Vera F et al (2011) Addition of bevacizumab to chemotherapy for treatment of solid tumors: similar results but different conclusions. J Clin Oncol 29:254–256
Olsson A, Nakhle J, Sundstedt A et al (2015) Tasquinimod triggers an early change in the polarization of tumor associated macrophages in the tumor microenvironment. J Immunother Cancer 3:53
Patel JN, Jiang C, Hertz DL et al (2015) Bevacizumab and the risk of arterial and venous thromboembolism in patients with metastatic, castration-resistant prostate cancer treated on Cancer and Leukemia Group B (CALGB) 90401 (Alliance). Cancer 121:1025–1031
Paulsson J, Sjoblom T, Micke P et al (2009) Prognostic significance of stromal platelet-derived growth factor beta-receptor expression in human breast cancer. Am J Pathol 175:334–341
Pennacchietti S, Michieli P, Galluzzo M et al (2003) Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell 3:347–361
Perlmutter MA, Lepor H (2007) Androgen deprivation therapy in the treatment of advanced prostate cancer. Rev Urol 9(Suppl 1):S3–S8
Petrylak DP, Vogelzang NJ, Budnik N et al (2015) Docetaxel and prednisone with or without lenalidomide in chemotherapy-naive patients with metastatic castration-resistant prostate cancer (MAINSAIL): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol 16:417–425
Picus J, Halabi S, Kelly WK et al (2011) A phase 2 study of estramustine, docetaxel, and bevacizumab in men with castrate-resistant prostate cancer: results from Cancer and Leukemia Group B Study 90006. Cancer 117:526–533
Pili R, Haggman M, Stadler WM et al (2011) Phase II randomized, double-blind, placebo-controlled study of tasquinimod in men with minimally symptomatic metastatic castrate-resistant prostate cancer. J Clin Oncol 29:4022–4028
Pircher A, Wellbrock J, Fiedler W et al (2014) New antiangiogenic strategies beyond inhibition of vascular endothelial growth factor with special focus on axon guidance molecules. Oncology 86:46–52
Rapisarda A, Melillo G (2009) Role of the hypoxic tumor microenvironment in the resistance to anti-angiogenic therapies. Drug Resist Updat 12:74–80
Rigamonti N, Kadioglu E, Keklikoglou I et al (2014) Role of angiopoietin-2 in adaptive tumor resistance to VEGF signaling blockade. Cell Rep 8:696–706
Ropiquet F, Giri D, Kwabi-Addo B et al (2000) Increased expression of fibroblast growth factor 6 in human prostatic intraepithelial neoplasia and prostate cancer. Cancer Res 60:4245–4250
Ruoslahti E (2002) Specialization of tumour vasculature. Nat Rev Cancer 2:83–90
Sanborn SL, Gibbons J, Krishnamurthi S et al (2009) Phase I trial of docetaxel given every 3 weeks and daily lenalidomide in patients with advanced solid tumors. Investig New Drugs 27:453–460
Scher HI, Morris MJ, Basch E et al (2011) End points and outcomes in castration-resistant prostate cancer: from clinical trials to clinical practice. J Clin Oncol 29:3695–3704
Schweizer MT, Carducci MA (2013) From bevacizumab to tasquinimod: angiogenesis as a therapeutic target in prostate cancer. Cancer J 19:99–106
Scolnik M, Tykochinsky G, Servadio C et al (1992) The development of vascular supply of normal rat prostate during the sexual maturation: an angiographic study. Prostate 21:1–14
Sennino B, Ishiguro-Oonuma T, Wei Y et al (2012) Suppression of tumor invasion and metastasis by concurrent inhibition of c-Met and VEGF signaling in pancreatic neuroendocrine tumors. Cancer Discov 2:270–287
Sfar S, Hassen E, Saad H et al (2006) Association of VEGF genetic polymorphisms with prostate carcinoma risk and clinical outcome. Cytokine 35:21–28
Sieveking DP, Lim P, Chow RW et al (2010) A sex-specific role for androgens in angiogenesis. J Exp Med 207:345–352
Smith DC, Smith MR, Sweeney C et al (2013) Cabozantinib in patients with advanced prostate cancer: results of a phase II randomized discontinuation trial. J Clin Oncol 31:412–419
Smith MR, Sweeney CJ, Corn PG et al (2014) Cabozantinib in chemotherapy-pretreated metastatic castration-resistant prostate cancer: results of a phase II nonrandomized expansion study. J Clin Oncol 32:3391–3399
Smith M, Bono JD, Sternberg C et al (2016) Phase III study of cabozantinib in previously treated metastatic castration-resistant prostate cancer: COMET-1. J Clin Oncol 34:3005–3013
Song S, Ewald AJ, Stallcup W et al (2005) PDGFRbeta+ perivascular progenitor cells in tumours regulate pericyte differentiation and vascular survival. Nat Cell Biol 7:870–879
Sonpavde G, Periman PO, Bernold D et al (2010) Sunitinib malate for metastatic castration-resistant prostate cancer following docetaxel-based chemotherapy. Ann Oncol 21:319–324
Sulzbacher I, Dominkus M, Pichlhofer B et al (2009) Expression of platelet-derived growth factor-alpha receptor and c-kit in giant cell tumours of bone. Pathology 41:630–633
Szczyrba J, Nolte E, Hart M et al (2013) Identification of ZNF217, hnRNP-K, VEGF-A and IPO7 as targets for microRNAs that are downregulated in prostate carcinoma. Int J Cancer 132:775–784
Tannock IF, Fizazi K, Ivanov S et al (2013) Aflibercept versus placebo in combination with docetaxel and prednisone for treatment of men with metastatic castration-resistant prostate cancer (VENICE): a phase 3, double-blind randomised trial. Lancet Oncol 14:760–768
Turner N, Grose R (2010) Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer 10:116–129
Ustach CV, Huang W, Conley-LaComb MK et al (2010) A novel signaling axis of matriptase/PDGF-D/ss-PDGFR in human prostate cancer. Cancer Res 70:9631–9640
Van Cutsem E, Tabernero J, Lakomy R et al (2012) 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 30:3499–3506
Vargesson N (2015) Thalidomide-induced teratogenesis: history and mechanisms. Birth Defects Res C Embryo Today 105:140–156
Wakui S, Furusato M, Itoh T et al (1992) Tumour angiogenesis in prostatic carcinoma with and without bone marrow metastasis: a morphometric study. J Pathol 168:257–262
Welti J, Loges S, Dimmeler S et al (2013) Recent molecular discoveries in angiogenesis and antiangiogenic therapies in cancer. J Clin Invest 123:3190–3200
Yue X, Wang P, Xu J et al (2012) MicroRNA-205 functions as a tumor suppressor in human glioblastoma cells by targeting VEGF-A. Oncol Rep 27:1200–1206
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Homicsko, K., Berthold, D. (2017). The Value of Anti-angiogenics in Prostate Cancer Therapy. In: Marmé, D. (eds) Tumor Angiogenesis. Springer, Cham. https://doi.org/10.1007/978-3-319-31215-6_28-1
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DOI: https://doi.org/10.1007/978-3-319-31215-6_28-1
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