Advertisement

Tumor Biology

, Volume 37, Issue 3, pp 2833–2839 | Cite as

Cediranib in ovarian cancer: state of the art and future perspectives

  • Ilary Ruscito
  • Maria Luisa Gasparri
  • Claudia Marchetti
  • Caterina De Medici
  • Carlotta Bracchi
  • Innocenza Palaia
  • Sara Imboden
  • Michael D. Mueller
  • Andrea Papadia
  • Ludovico Muzii
  • Pierluigi Benedetti Panici
Review

Abstract

Despite the dramatic improvements achieved in cancer treatment through a better understanding of the tumor biology, ovarian cancer is still characterized by a poor prognosis: most patients diagnosed with this disease will ultimately die from it. In various clinical trials conducted over a time span of two decades, new combinations of conventional chemotherapy regimens have failed to achieve significant improvements in oncologic outcome in ovarian cancer patients. We have now entered an era of “personalized medicine” in which new medications are designed to specifically target molecular pathways involved in carcinogenesis and cancer progression. Encouraging results in different tumor types have been reported, applying an increasing number of target therapies that are still under evaluation. In this setting, one of the most successfully targeted molecular pathways is tumor angiogenesis. Bevacizumab, a monoclonal antibody binding vascular endothelial growth factor (VEGF), has been recently incorporated in the treatment of primary and recurrent ovarian cancer patients after multiple phase III randomized controlled trials have proven its clinical benefit. Based on these positive results, more anti-angiogenic molecules using different mechanisms of action have been developed and are currently under investigation. Among these molecules, the tyrosine kinases inhibitors are probably the most promising ones. Cediranib is a tyrosine kinase inhibitor targeting VEGF receptors that has been tested in various trials with promising results. The aim of this manuscript is to review the current role of cediranib in the treatment of ovarian cancer and to present an overview of the ongoing clinical trials in this setting.

Keywords

Ovarian cancer Cediranib Tyrosine kinase inhibitors Anti-angiogenesis Target therapy 

Notes

Compliance with ethical standards

Conflicts of interest

None

References

  1. 1.
    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65:5–29.CrossRefPubMedGoogle Scholar
  2. 2.
    Heintz AP, Odicino F, Maisonneuve P, et al. Carcinoma of the ovary. FIGO 26th annual report on the results of treatment in gynecological cancer. Int J Gynaecol Obstet. 2006;95(1):S161–92.CrossRefPubMedGoogle Scholar
  3. 3.
    Folkman J, Merler E, Abernathy C, et al. Isolation of a tumor factor responsible for angiogenesis. J Exp Med. 1971;133:275–88.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Perren TJ, Swart AM, Pfisterer J, et al. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med. 2011;365:2484–96.CrossRefPubMedGoogle Scholar
  5. 5.
    Burger RA, Brady MF, Bookman MA, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med. 2011;365:2473–83.CrossRefPubMedGoogle Scholar
  6. 6.
    Matulonis UA, Berlin S, Ivy P, et al. Cediranib, an oral inhibitor of vascular endothelial growth factor receptor kinases, is an active drug in recurrent epithelial ovarian, fallopian tube, and peritoneal cancer. J Clin Oncol. 2009;27:5601–6.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Moore M, Hirte HW, Siu L, et al. Phase I study to determine the safety and pharmacokinetics of the novel Raf kinase and VEGFR inhibitor BAY 43-9006, administered for 28 days on/7 days off in patients with advanced, refractory solid tumors. Ann Oncol. 2005;16:1688–94.CrossRefPubMedGoogle Scholar
  8. 8.
    Friedlander M, Hancock KC, Rischin D, et al. A phase II, open-label study evaluating pazopanib in patients with recurrent ovarian cancer. Gynecol Oncol. 2010;119:32–7.CrossRefPubMedGoogle Scholar
  9. 9.
    Ide ABGN, Warren SL. Vascularization of the Brown-Pearce rabbit epithelioma transplant as seen in the transparent ear chamber. Am J Roentgenol. 1939;42:891–9.Google Scholar
  10. 10.
    Plouet J, Moukadiri H. Specific binding of vasculotropin to bovine brain capillary endothelial cells. Biochimie. 1990;72:51–5.CrossRefPubMedGoogle Scholar
  11. 11.
    Leone Roberti Maggiore U, Bellati F, Ruscito I, et al. Monoclonal antibodies therapies for ovarian cancer. Expert Opin Biol Ther. 2013;13:739–64.CrossRefPubMedGoogle Scholar
  12. 12.
    Bellati F, Napoletano C, Gasparri ML, et al. Monoclonal antibodies in gynecological cancer: a critical point of view. Clin Dev Immunol. 2011;2011:890758.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Bellati F, Napoletano C, Gasparri ML, et al. Current knowledge and open issues regarding bevacizumab in gynaecological neoplasms. Crit Rev Oncol Hematol. 2012;83:35–46.CrossRefPubMedGoogle Scholar
  14. 14.
    Marchetti C, Gasparri ML, Ruscito I, et al. Advances in anti-angiogenic agents for ovarian cancer treatment: the role of trebananib (AMG 386). Crit Rev Oncol Hematol. 2015;94:302–10.CrossRefPubMedGoogle Scholar
  15. 15.
    Wedge SR, Kendrew J, Hennequin LF, et al. AZD2171: a highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer. Cancer Res. 2005;65:4389–400.CrossRefPubMedGoogle Scholar
  16. 16.
    Heckman CA, Holopainen T, Wirzenius M, et al. The tyrosine kinase inhibitor cediranib blocks ligand-induced vascular endothelial growth factor receptor-3 activity and lymphangiogenesis. Cancer Res. 2008;68:4754–62.CrossRefPubMedGoogle Scholar
  17. 17.
    Gomez-Rivera F, Santillan-Gomez AA, Younes MN, et al. The tyrosine kinase inhibitor, AZD2171, inhibits vascular endothelial growth factor receptor signaling and growth of anaplastic thyroid cancer in an orthotopic nude mouse model. Clin Cancer Res. 2007;13:4519–27.CrossRefPubMedGoogle Scholar
  18. 18.
    Decio A, Cesca M, Bizzaro F, et al. Cediranib combined with chemotherapy reduces tumor dissemination and prolongs the survival of mice bearing patient-derived ovarian cancer xenografts with different responsiveness to cisplatin. Clin Exp Metastasis. 2015;32:647–58.CrossRefPubMedGoogle Scholar
  19. 19.
    Drevs J, Siegert P, Medinger M, et al. Phase I clinical study of AZD2171, an oral vascular endothelial growth factor signaling inhibitor, in patients with advanced solid tumors. J Clin Oncol. 2007;25:3045–54.CrossRefPubMedGoogle Scholar
  20. 20.
    Trarbach T, Schultheis B, Gauler TC, et al. Phase I open-label study of cediranib, an oral inhibitor of VEGF signalling, in combination with the oral Src inhibitor saracatinib in patients with advanced solid tumours. Investig New Drugs. 2012;30:1962–71.CrossRefGoogle Scholar
  21. 21.
    Musella A, Marchetti C, Gasparri ML, et al. PARP inhibition: a promising therapeutic target in ovarian cancer. Cell Mol Biol (Noisy-le-Grand). 2015;61:44–61.Google Scholar
  22. 22.
    Marchetti C, Imperiale L, Gasparri ML, et al. Olaparib, PARP1 inhibitor in ovarian cancer. Expert Opin Investig Drugs. 2012;21:1575–84.CrossRefPubMedGoogle Scholar
  23. 23.
    Liu JF, Tolaney SM, Birrer M, et al. A phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer. Eur J Cancer. 2013;49:2972–8.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Liu JF, Barry WT, Birrer M, et al. Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study. Lancet Oncol. 2014;15:1207–14.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Robinson ES, Matulonis UA, Ivy P, et al. Rapid development of hypertension and proteinuria with cediranib, an oral vascular endothelial growth factor receptor inhibitor. Clin J Am Soc Nephrol. 2010;5:477–83.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Mulder SF, Boers-Sonderen MJ, van der Heijden HF, et al. A phase II study of cediranib as palliative treatment in patients with symptomatic malignant ascites or pleural effusion. Target Oncol. 2014;9:331–8.CrossRefPubMedGoogle Scholar
  27. 27.
    Hirte H, Lheureux S, Fleming GF, et al. A phase 2 study of cediranib in recurrent or persistent ovarian, peritoneal or fallopian tube cancer: a trial of the Princess Margaret, Chicago and California Phase II Consortia. Gynecol Oncol. 2015;138:55–61.CrossRefPubMedGoogle Scholar
  28. 28.
    Raja FA, Griffin CL, Qian W, et al. Initial toxicity assessment of ICON6: a randomised trial of cediranib plus chemotherapy in platinum-sensitive relapsed ovarian cancer. Br J Cancer. 2011;105:884–9.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Ledermann JA, Perren TJ, Raja FA, et al. Randomised double-blind phase III trial of cediranib (AZD 2171) in relapsed platinum sensitive ovarian cancer: results of the ICON6 trial. Eur J Cancer, 2013; 49:abstrLBA10.Google Scholar
  30. 30.
    Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9:669–76.CrossRefPubMedGoogle Scholar
  31. 31.
    Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science. 2005;307:58–62.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Ilary Ruscito
    • 1
  • Maria Luisa Gasparri
    • 1
    • 2
  • Claudia Marchetti
    • 1
  • Caterina De Medici
    • 1
  • Carlotta Bracchi
    • 1
  • Innocenza Palaia
    • 1
  • Sara Imboden
    • 2
  • Michael D. Mueller
    • 2
  • Andrea Papadia
    • 2
  • Ludovico Muzii
    • 1
  • Pierluigi Benedetti Panici
    • 1
  1. 1.Department of Gynecology, Obstetrics and Urology“Sapienza” University of RomeRomeItaly
  2. 2.Department of Obstetrics and Gynecology, University Hospital of BerneUniversity of BerneBerneSwitzerland

Personalised recommendations