Advertisement

Angiopoietin-1 and Angiopoietin-2 Inhibitors: Clinical Development

  • Jessica Gillen
  • Debra Richardson
  • Kathleen MooreEmail author
Evolving Therapies (RM Bukowski, Section Editor)
  • 280 Downloads
Part of the following topical collections:
  1. Topical Collection on Evolving Therapies

Abstract

Purpose of Review

The purpose of this review is to discuss the current understanding of the Tie2-angiopoietin system and its role in tumor growth and metastasis. This review also focuses on preclinical and clinical data published to date that have evaluated Tie2-angiopoietin inhibition.

Recent Findings

Tie2 inhibition has shown significant promise in preclinical models, notable for decreased tumor burden and fewer sites of metastatic disease across various malignancies. However, data from human clinical trials have shown more mixed results. Trebananib, rebastanib, and MEDI3617 are the three Tie2-angiopoietin inhibitors that have been most widely evaluated in phase I and II trials. Further investigation into these therapies is ongoing.

Summary

The Tie2-angiopoietin pathway continues to show promise in preclinical and some clinical trials, including studies on recurrent or metastatic breast and renal cell carcinomas. Further evaluation of these therapies, however, is warranted to better understand their optimal clinical utility.

Keywords

Tie2 inhibition Angiopoietin inhibition Angiogenesis Anti-angiogenic therapy 

Notes

Compliance with Ethical Standards

Conflict of Interest

Jessica Gillen declares that she has no conflict of interest.

Debra Richardson has received compensation from Genentech and Ipsen for participation on advisory boards, and has served on steering committees for and received travel grants from Tesaro and Karyopharm Therapeutics.

Kathleen Moore has received research funding for investigator-initiated trials from ImmunoGen, Genentech/Roche, PTC Therapeutics, and Eli Lilly; has received compensation for participation on advisory boards from Clovis, AstraZeneca, Tesaro, ImmunoGen, Genentech/Roche, VBL Therapeutics, Janssen, Aravive, OncoMed, Samumed, and Merck; has received compensation for sales force training from Pfizer; and served as an unbranded speaker for AstraZeneca for DNA damage response.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    Gale NW, Yancopoulos GD. Growth factors acting via endothelial cell-specific receptor tyrosine kinases: VEGFs, angiopoietins, and ephrins in vascular development. Genes Dev. 1999;13(9):1055–66.PubMedCrossRefGoogle Scholar
  2. 2.
    Folkman J. Role of angiogenesis in tumor growth and metastasis. Semin Oncol. 2002;29(6 Suppl 16):15–8.PubMedCrossRefGoogle Scholar
  3. 3.
    Chung AS, Lee J, Ferrara N. Targeting the tumour vasculature: insights from physiological angiogenesis. Nat Rev Cancer. 2010;10(7):505–14.PubMedCrossRefGoogle Scholar
  4. 4.
    Daly C, Eichten A, Castanaro C, Pasnikowski E, Adler A, Lalani AS, et al. Angiopoietin-2 functions as a Tie2 agonist in tumor models, where it limits the effects of VEGF inhibition. Cancer Res. 2013;73(1):108–18.PubMedCrossRefGoogle Scholar
  5. 5.
    Harney AS, Karagiannis GS, Pignatelli J, Smith BD, Kadioglu E, Wise SC, et al. The selective Tie2 inhibitor rebastinib blocks recruitment and function of Tie2(hi) macrophages in breast cancer and pancreatic neuroendocrine tumors. Mol Cancer Ther. 2017;16(11):2486–501.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Saharinen P, Eklund L, Alitalo K. Therapeutic targeting of the angiopoietin-TIE pathway. Nat Rev Drug Discov. 2017;16(9):635–61.PubMedCrossRefGoogle Scholar
  7. 7.
    Augustin HG, Young Koh G, Thurston G, Alitalo K. Control of vascular morphogenesis and homeostasis through the angiopoietin-tie system. Nat Rev Mol Cell Biol. 2009;10(3):165–77.PubMedCrossRefGoogle Scholar
  8. 8.
    Park JH, Park KJ, Kim YS, Sheen SS, Lee KS, Lee HN, et al. Serum angiopoietin-2 as a clinical marker for lung cancer. Chest. 2007;132(1):200–6.PubMedCrossRefGoogle Scholar
  9. 9.
    Huang H, Bhat A, Woodnutt G, Lappe R. Targeting the ANGPT–TIE2 pathway in malignancy. Nat Rev Cancer. 2010;10:575–85.PubMedCrossRefGoogle Scholar
  10. 10.
    Lewis CE, Ferrara N. Multiple effects of angiopoietin-2 blockade on tumors. Cancer Cell. 2011;19(4):431–3.PubMedCrossRefGoogle Scholar
  11. 11.
    Ibberson M, Bron S, Guex N, Faes-van't Hull E, Ifticene-Treboux A, Henry L, et al. TIE-2 and VEGFR kinase activities drive immunosuppressive function of TIE-2-expressing monocytes in human breast tumors. Clin Cancer Res. 2013;19(13):3439–49.PubMedCrossRefGoogle Scholar
  12. 12.
    Harney AS, Arwert EN, Entenberg D, Wang Y, Guo P, Qian BZ, et al. Real-time imaging reveals local, transient vascular permeability, and tumor cell intravasation stimulated by TIE2hi macrophage-derived VEGFA. Cancer Discov. 2015;5(9):932–43.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Ferrara N. VEGF and intraocular neovascularization: from discovery to therapy. Transl Vis Sci Technol. 2016;5(2):10.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Jayson GC, Kerbel R, Ellis LM, Harris AL. Antiangiogenic therapy in oncology: current status and future directions. Lancet. 2016;388(10043):518–29.PubMedCrossRefGoogle Scholar
  15. 15.
    Bergers G, Hanahan D. Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer. 2008;8(8):592–603.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Rigamonti N, Kadioglu E, Keklikoglou I, Wyser Rmili C, Leow CC, de Palma M. Role of angiopoietin-2 in adaptive tumor resistance to VEGF signaling blockade. Cell Rep. 2014;8(3):696–706.PubMedCrossRefGoogle Scholar
  17. 17.
    Vasudev NS, Reynolds AR. Anti-angiogenic therapy for cancer: current progress, unresolved questions and future directions. Angiogenesis. 2014;17(3):471–94.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Mazzieri R, Pucci F, Moi D, Zonari E, Ranghetti A, Berti A, et al. Targeting the ANG2/TIE2 axis inhibits tumor growth and metastasis by impairing angiogenesis and disabling rebounds of proangiogenic myeloid cells. Cancer Cell. 2011;19(4):512–26.PubMedCrossRefGoogle Scholar
  19. 19.
    Park JS, Kim IK, Han S, Park I, Kim C, Bae J, et al. Normalization of tumor vessels by Tie2 activation and Ang2 inhibition enhances drug delivery and produces a favorable tumor microenvironment. Cancer Cell. 2016;30(6):953–67.PubMedCrossRefGoogle Scholar
  20. 20.
    Piao Y, Park SY, Henry V, Smith BD, Tiao N, Flynn DL, et al. Novel MET/TIE2/VEGFR2 inhibitor altiratinib inhibits tumor growth and invasiveness in bevacizumab-resistant glioblastoma mouse models. Neuro-Oncology. 2016;18(9):1230–41.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Zhou C, Clamp A, Backen A, Berzuini C, Renehan A, Banks RE, et al. Systematic analysis of circulating soluble angiogenesis-associated proteins in ICON7 identifies Tie2 as a biomarker of vascular progression on bevacizumab. Br J Cancer. 2016;115(2):228–35.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Backen A, Renehan AG, Clamp AR, Berzuini C, Zhou C, Oza A, et al. The combination of circulating Ang1 and Tie2 levels predicts progression-free survival advantage in bevacizumab-treated patients with ovarian cancer. Clin Cancer Res. 2014;20(17):4549–58.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Tuppurainen L, Sallinen H, Karvonen A, Valkonen E, Laakso H, Liimatainen T, et al. Combined gene therapy using AdsVEGFR2 and AdsTie2 with chemotherapy reduces the growth of human ovarian cancer and formation of ascites in mice. Int J Gynecol Cancer. 2017;27(5):879–86.PubMedCrossRefGoogle Scholar
  24. 24.
    Vergote I, Oaknin A, Baurain JF, Ananda S, Wong S, Su X, et al. A phase 1b, open-label study of trebananib in combination with paclitaxel and carboplatin in patients with ovarian cancer receiving interval or primary debulking surgery. Eur J Cancer. 2014;50(14):2408–16.PubMedCrossRefGoogle Scholar
  25. 25.
    Monk BJ, Poveda A, Vergote I, Raspagliesi F, Fujiwara K, Bae DS, et al. Anti-angiopoietin therapy with trebananib for recurrent ovarian cancer (TRINOVA-1): a randomised, multicentre, double-blind, placebo-controlled phase 3 trial. Lancet Oncol. 2014;15(8):799–808.PubMedCrossRefGoogle Scholar
  26. 26.
    Vergote I, Schilder RJ, Pippitt CH Jr, Wong S, Gordon AN, Scudder S, et al. A phase 1b study of trebananib in combination with pegylated liposomal doxorubicin or topotecan in women with recurrent platinum-resistant or partially platinum-sensitive ovarian cancer. Gynecol Oncol. 2014;135(1):25–33.PubMedCrossRefGoogle Scholar
  27. 27.
    Doi T, Ohtsu A, Fuse N, Yoshino T, Tahara M, Shibayama K, et al. Phase 1 study of trebananib (AMG 386), an angiogenesis targeting angiopoietin-1/2 antagonist, in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol. 2013;71(1):227–35.PubMedCrossRefGoogle Scholar
  28. 28.
    Karlan BY, Oza AM, Richardson GE, Provencher DM, Hansen VL, Buck M, et al. Randomized, double-blind, placebo-controlled phase II study of AMG 386 combined with weekly paclitaxel in patients with recurrent ovarian cancer. J Clin Oncol. 2012;30(4):362–71.PubMedCrossRefGoogle Scholar
  29. 29.
    • Monk BJ, Minion LE, Coleman RL. Anti-angiogenic agents in ovarian cancer: past, present, and future. Ann Oncol. 2016;27(Suppl 1):i33–9 This article reviewed the current state of anti-angiogenic therapies as used in ovarian cancers and helped clarify the role of anti-VEGF and anti-angiopoietin therapy specifically. PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    • Monk BJ, et al. Final results of a phase 3 study of trebananib plus weekly paclitaxel in recurrent ovarian cancer (TRINOVA-1): long-term survival, impact of ascites, and progression-free survival-2. Gynecol Oncol. 2016;143(1):27–34 This was the first phase 3 trial of a Tie2/angiopoietin-2 inhibitor in ovarian cancer. It specifically evaluated both progression-free and overall survival in women with recurrent disease. PubMedCrossRefGoogle Scholar
  31. 31.
    Marth C, Vergote I, Scambia G, Oberaigner W, Clamp A, Berger R, et al. ENGOT-ov-6/TRINOVA-2: randomised, double-blind, phase 3 study of pegylated liposomal doxorubicin plus trebananib or placebo in women with recurrent partially platinum-sensitive or resistant ovarian cancer. Eur J Cancer. 2017;70:111–21.PubMedCrossRefGoogle Scholar
  32. 32.
    Marchetti C, Gasparri ML, Ruscito I, Palaia I, Perniola G, Carrone A, et al. Advances in anti-angiogenic agents for ovarian cancer treatment: the role of trebananib (AMG 386). Crit Rev Oncol Hematol. 2015;94(3):302–10.PubMedCrossRefGoogle Scholar
  33. 33.
    • Moore KN, et al. A phase II trial of trebananib (AMG 386; IND#111071), a selective angiopoietin 1/2 neutralizing peptibody, in patients with persistent/recurrent carcinoma of the endometrium: an NRG/Gynecologic Oncology Group trial. Gynecol Oncol. 2015;138(3):513–8 This study determined that further investigation into trebananib in women with recurrent or persistent endometrial cancer was not warranted. PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Abou-Alfa GK, Blanc JF, Miles S, Ganten T, Trojan J, Cebon J, et al. Phase II study of first-line trebananib plus sorafenib in patients with advanced hepatocellular carcinoma. Oncologist. 2017;22(7):780–e65.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Peeters M, Strickland AH, Lichinitser M, Suresh AVS, Manikhas G, Shapiro J, et al. A randomised, double-blind, placebo-controlled phase 2 study of trebananib (AMG 386) in combination with FOLFIRI in patients with previously treated metastatic colorectal carcinoma. Br J Cancer. 2013;108(3):503–11.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Eatock MM, Tebbutt NC, Bampton CL, Strickland AH, Valladares-Ayerbes M, Swieboda-Sadlej A, et al. Phase II randomized, double-blind, placebo-controlled study of AMG 386 (trebananib) in combination with cisplatin and capecitabine in patients with metastatic gastro-oesophageal cancer. Ann Oncol. 2013;24(3):710–8.PubMedCrossRefGoogle Scholar
  37. 37.
    • Dieras V, et al. Trebananib (AMG 386) plus weekly paclitaxel with or without bevacizumab as first-line therapy for HER2-negative locally recurrent or metastatic breast cancer: a phase 2 randomized study. Breast. 2015;24(3):182–90 This article is one of the primary studies evaluating trebananib in the frontline setting for breast cancer. No significant improvements were noted in PFS at the given dosese, but noted rationale for investigation of increased doses. PubMedCrossRefGoogle Scholar
  38. 38.
    Kaufman PA, Wildiers H, Freyer G, Kemeny M, Gonçalves A, Jerusalem G, et al. Phase 1b study of trebananib plus paclitaxel and trastuzumab in patients with HER2-positive locally recurrent or metastatic breast cancer. Clin Breast Cancer. 2018.Google Scholar
  39. 39.
    Hong DS, et al. A phase I, open-label study of trebananib combined with sorafenib or sunitinib in patients with advanced renal cell carcinoma. Clin Genitourin Cancer. 2014;12(3):167–177.e2.PubMedCrossRefGoogle Scholar
  40. 40.
    Atkins MB, Gravis G, Drosik K, Demkow T, Tomczak P, Wong SS, et al. Trebananib (AMG 386) in combination with sunitinib in patients with metastatic renal cell cancer: an open-label, multicenter, phase II study. J Clin Oncol. 2015;33(30):3431–8.PubMedCrossRefGoogle Scholar
  41. 41.
    Cortes J, Talpaz M, Smith HP, Snyder DS, Khoury J, Bhalla KN, et al. Phase 1 dose-finding study of rebastinib (DCC-2036) in patients with relapsed chronic myeloid leukemia and acute myeloid leukemia. Haematologica. 2017;102(3):519–28.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Jesus Del Santo Anampa Mesias MHO, Xue X, Condeelis J, Sparano JA. Phase Ib study of rebastinib plus antitubulin therapy with paclitaxel or eribulin in patients with metastatic breast cancer (MBC). Chicago: American Association of Cancer Research Annual Meeting; 2018.Google Scholar
  43. 43.
    Leow CC, Coffman K, Inigo I, Breen S, Czapiga M, Soukharev S, et al. MEDI3617, a human anti-angiopoietin 2 monoclonal antibody, inhibits angiogenesis and tumor growth in human tumor xenograft models. Int J Oncol. 2012;40(5):1321–30.PubMedGoogle Scholar
  44. 44.
    Molnar N, Siemann DW. Inhibition of endothelial/smooth muscle cell contact loss by the investigational angiopoietin-2 antibody MEDI3617. Microvasc Res. 2012;83(3):290–7.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Hyman DM, Rizvi N, Natale R, Armstrong DK, Birrer M, Recht L, et al. Phase I study of MEDI3617, a selective angiopoietin-2 inhibitor alone and combined with carboplatin/paclitaxel, paclitaxel, or bevacizumab for advanced solid tumors. Clin Cancer Res. 2018;24(12):2749–57.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Jessica Gillen
    • 1
  • Debra Richardson
    • 1
  • Kathleen Moore
    • 1
    Email author
  1. 1.The University of Oklahoma Stephenson Cancer CenterOklahoma CityUSA

Personalised recommendations