Skip to main content

Advertisement

SpringerLink
Log in

The novel kinase inhibitor ponatinib is an effective anti-angiogenic agent against neuroblastoma

  • PRECLINICAL STUDIES
  • Published:
Investigational New Drugs Aims and scope Submit manuscript

Summary

Background High-risk neuroblastoma has poor outcomes with high rates of relapse despite aggressive treatment, and novel therapies are needed to improve these outcomes. Ponatinib is a multi-tyrosine kinase inhibitor that targets many pathways implicated in neuroblastoma pathogenesis. We hypothesized that ponatinib would be effective against neuroblastoma in preclinical models. Methods We evaluated the effects of ponatinib on survival and migration of human neuroblastoma cells in vitro. Using orthotopic xenograft mouse models of human neuroblastoma, we analyzed tumors treated with ponatinib for growth, gross and histologic appearance, and vascularity. Results Ponatinib treatment of neuroblastoma cells resulted in decreased cell viability and migration in vitro. In mice with orthotopic xenograft neuroblastoma tumors, treatment with ponatinib resulted in decreased growth and vascularity. Conclusions Ponatinib reduces neuroblastoma cell viability in vitro and reduces tumor growth and vascularity in vivo. The antitumor effects of ponatinib suggest its potential as a novel therapeutic agent for neuroblastoma, and further preclinical testing is warranted.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Pinto NR, Applebaum MA, Volchenboum SL, Matthay KK, London WB, Ambros PF, Nakagawara A, Berthold F, Schleiermacher G, Park JR, Valteau-Couanet D, Pearson AD, Cohn SL (2015) Advances in risk classification and treatment strategies for neuroblastoma. J Clin Oncol 33(27):3008–3017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Maris JM (2010) Recent advances in neuroblastoma. N Engl J Med 362(23):2202–2211

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. London WB, Castel V, Monclair T, Ambros PF, Pearson AD, Cohn SL, Berthold F, Nakagawara A, Ladenstein RL, Iehara T, Matthay KK (2011) Clinical and biologic features predictive of survival after relapse of neuroblastoma: a report from the International neuroblastoma risk group project. J Clin Oncol 29(24):3286–3292

    Article  PubMed  PubMed Central  Google Scholar 

  4. O’Hare T, Shakespeare WC, Zhu X, Eide CA, Rivera VM, Wang F, Adrian LT, Zhou T, Huang WS, Xu Q, Metcalf CA, Tyner JW, Loriaux MM, Corbin AS, Wardwell S, Ning Y, Keats JA, Wang Y, Sundaramoorthi R, Thomas M, Zhou D, Snodgrass J, Commodore L, Sawyer TK, Dalgarno DC, Deininger MW, Druker BJ, Clackson T (2009) AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell 16(5):401–412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Gozgit JM, Wong MJ, Moran L, Wardwell S, Mohemmad QK, Narasimhan NI, Shakespeare WC, Wang F, Clackson T, Rivera VM (2012) Ponatinib (AP24534), a multitargeted pan-FGFR inhibitor with activity in multiple FGFR-amplified or mutated cancer models. Mol Cancer Ther 11(3):690–699

    Article  CAS  PubMed  Google Scholar 

  6. De Falco V, Buonocore P, Muthu M, Torregrossa L, Basolo F, Billaud M, Gozgit JM, Carlomagno F, Santoro M (2013) Ponatinib (AP24534) is a novel potent inhibitor of oncogenic RET mutants associated with thyroid cancer. J Clin Endocrinol Metab 98(5):E811–E819

    Article  PubMed  Google Scholar 

  7. Mologni L, Redaelli S, Morandi A, Plaza-Menacho I, Gambacorti-Passerini C (2013) Ponatinib is a potent inhibitor of wild-type and drug-resistant gatekeeper mutant RET kinase. Mol Cell Endocrinol 377(1–2):1–6

    Article  CAS  PubMed  Google Scholar 

  8. Sadovnik I, Lierman E, Peter B, Herrmann H, Suppan V, Stefanzl G, Haas O, Lion T, Pickl W, Cools J, Vandenberghe P, Valent P (2014) Identification of Ponatinib as a potent inhibitor of growth, migration, and activation of neoplastic eosinophils carrying FIP1L1-PDGFRA. Exp Hematol 42(4):282–293.e4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Garner AP, Gozgit JM, Anjum R, Vodala S, Schrock A, Zhou T, Serrano C, Eilers G, Zhu M, Ketzer J, Wardwell S, Ning Y, Song Y, Kohlmann A, Wang F, Clackson T, Heinrich MC, Fletcher JA, Bauer S, Rivera VM (2014) Ponatinib inhibits polyclonal drug-resistant KIT oncoproteins and shows therapeutic potential in heavily pretreated gastrointestinal stromal tumor (GIST) patients. Clin Cancer Res 20(22):5745–5755

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ahmad S, Johnson GL, Scott JE (2015) Identification of ponatinib and other known kinase inhibitors with potent MEKK2 inhibitory activity. Biochem Biophys Res Commun 463(4):888–893

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Li SQ, Cheuk AT, Shern JF, Song YK, Hurd L, Liao H, Wei JS, Khan J (2013) Targeting wild-type and mutationally activated FGFR4 in rhabdomyosarcoma with the inhibitor ponatinib (AP24534). PLoS One 8(10):e76551

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Gozgit JM, Squillace RM, Wongchenko MJ, Miller D, Wardwell S, Mohemmad Q, Narasimhan NI, Wang F, Clackson T, Rivera VM (2013) Combined targeting of FGFR2 and mTOR by ponatinib and ridaforolimus results in synergistic antitumor activity in FGFR2 mutant endometrial cancer models. Cancer Chemother Pharmacol 71(5):1315–1323

    Article  CAS  PubMed  Google Scholar 

  13. Wynes MW, Hinz TK, Gao D, Martini M, Marek LA, Ware KE, Edwards MG, Böhm D, Perner S, Helfrich BA, Dziadziuszko R, Jassem J, Wojtylak S, Sejda A, Gozgit JM, Bunn PA, Camidge DR, Tan AC, Hirsch FR, Heasley LE (2014) FGFR1 mRNA and protein expression, not gene copy number, predict FGFR TKI sensitivity across all lung cancer histologies. Clin Cancer Res 20(12):3299–3309

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Zhang J, Zhou Q, Gao G, Wang Y, Fang Z, Li G, Yu M, Kong L, Xing Y, Gao X (2014) The effects of ponatinib, a multi-targeted tyrosine kinase inhibitor, against human U87 malignant glioblastoma cells. Onco Targets Ther 7:2013–2019

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Langer I, Vertongen P, Perret J, Fontaine J, Atassi G, Robberecht P (2000) Expression of vascular endothelial growth factor (VEGF) and VEGF receptors in human neuroblastomas. Med Pediatr Oncol 34(6):386–393

    Article  CAS  PubMed  Google Scholar 

  16. Meister B, Grünebach F, Bautz F, Brugger W, Fink FM, Kanz L, Möhle R (1999) Expression of vascular endothelial growth factor (VEGF) and its receptors in human neuroblastoma. Eur J Cancer 35(3):445–449

    Article  CAS  PubMed  Google Scholar 

  17. Fakhari M, Pullirsch D, Paya K, Abraham D, Hofbauer R, Aharinejad S (2002) Upregulation of vascular endothelial growth factor receptors is associated with advanced neuroblastoma. J Pediatr Surg 37(4):582–587

    Article  CAS  PubMed  Google Scholar 

  18. Nakamura T, Ishizaka Y, Nagao M, Hara M, Ishikawa T (1994) Expression of the ret proto-oncogene product in human normal and neoplastic tissues of neural crest origin. J Pathol 172(3):255–260

    Article  CAS  PubMed  Google Scholar 

  19. Beaudry P, Nilsson M, Rioth M, Prox D, Poon D, Xu L, Zweidler-Mckay P, Ryan A, Folkman J, Ryeom S, Heymach J (2008) Potent antitumor effects of ZD6474 on neuroblastoma via dual targeting of tumor cells and tumor endothelium. Mol Cancer Ther 7(2):418–424

    Article  CAS  PubMed  Google Scholar 

  20. Zage PE, Zeng L, Palla S, Fang W, Nilsson MB, Heymach JV, Zweidler-McKay PA (2010) A novel therapeutic combination for neuroblastoma: the vascular endothelial growth factor receptor/epidermal growth factor receptor/rearranged during transfection inhibitor vandetanib with 13-cis-retinoic acid. Cancer 116(10):2465–2475

    CAS  PubMed  Google Scholar 

  21. Calero R, Morchon E, Johnsen JI, Serrano R (2014) Sunitinib suppress neuroblastoma growth through degradation of MYCN and inhibition of angiogenesis. PLoS One 9(4):e95628

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Scorsone K, Zhang L, Woodfield SE, Hicks J, Zage PE (2014) The novel kinase inhibitor EMD1214063 is effective against neuroblastoma. Invest New Drugs 32(5):815–824

  23. Zhang L, Scorsone K, Woodfield SE, Zage PE (2015) Sensitivity of neuroblastoma to the novel kinase inhibitor cabozantinib is mediated by ERK inhibition. Cancer Chemother Pharmacol 76(5):977–987

    Article  CAS  PubMed  Google Scholar 

  24. Ribatti D, Alessandri G, Baronio M, Raffaghello L, Cosimo E, Marimpietri D, Montaldo PG, De Falco G, Caruso A, Vacca A, Ponzoni M (2001) Inhibition of neuroblastoma-induced angiogenesis by fenretinide. Int J Cancer 94(3):314–321

    Article  CAS  PubMed  Google Scholar 

  25. Wassberg E, Påhlman S, Westlin JE, Christofferson R (1997) The angiogenesis inhibitor TNP-470 reduces the growth rate of human neuroblastoma in nude rats. Pediatr Res 41(3):327–333

    Article  CAS  PubMed  Google Scholar 

  26. Katzenstein HM, Rademaker AW, Senger C, Salwen HR, Nguyen NN, Thorner PS, Litsas L, Cohn SL (1999) Effectiveness of the angiogenesis inhibitor TNP-470 in reducing the growth of human neuroblastoma in nude mice inversely correlates with tumor burden. Clin Cancer Res 5(12):4273–4278

    CAS  PubMed  Google Scholar 

  27. Katzenstein HM, Salwen HR, Nguyen NN, Meitar D, Cohn SL (2001) Antiangiogenic therapy inhibits human neuroblastoma growth. Med Pediatr Oncol 36(1):190–193

    Article  CAS  PubMed  Google Scholar 

  28. Marimpietri D, Nico B, Vacca A, Mangieri D, Catarsi P, Ponzoni M, Ribatti D (2005) Synergistic inhibition of human neuroblastoma-related angiogenesis by vinblastine and rapamycin. Oncogene 24(45):6785–6795

    Article  CAS  PubMed  Google Scholar 

  29. Brignole C, Marimpietri D, Pastorino F, Nico B, Di Paolo D, Cioni M, Piccardi F, Cilli M, Pezzolo A, Corrias MV, Pistoia V, Ribatti D, Pagnan G, Ponzoni M (2006) Effect of bortezomib on human neuroblastoma cell growth, apoptosis, and angiogenesis. J Natl Cancer Inst 98(16):1142–1157

    Article  CAS  PubMed  Google Scholar 

  30. Kim ES, Soffer SZ, Huang J, McCrudden KW, Yokoi A, Manley CA, Middlesworth W, Kandel JJ, Yamashiro DJ (2002) Distinct response of experimental neuroblastoma to combination antiangiogenic strategies. J Pediatr Surg 37(3):518–522

    Article  PubMed  Google Scholar 

  31. Matthay KK, Reynolds CP, Seeger RC, Shimada H, Adkins ES, Haas-Kogan D, Gerbing RB, London WB, Villablanca JG (2009) Long-term results for children with high-risk neuroblastoma treated on a randomized trial of myeloablative therapy followed by 13-cis-retinoic acid: a children’s oncology group study. J Clin Oncol 27(7):1007–1013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Cortes JE, Kantarjian H, Shah NP, Bixby D, Mauro MJ, Flinn I, O’Hare T, Hu S, Narashimhan NI, Rivera VM, Clackson T, Turner CD, Haluska FG, Druker BJ, Deininger MWN, Talpaz M (2012) Ponatinib in refractory Philadelphia chromosome-positive leukemias. New Engl J Med 367:20075–20088

    Article  CAS  Google Scholar 

  33. Miller GD, Bruno BJ, Lim CS (2014) Resistant mutations in CML and Ph(+)ALL - role of ponatinib. Biologics 8:243–254

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Section of Hematology-Oncology, Department of Pediatrics, Texas Children’s Cancer Center, Baylor College of Medicine, Houston, TX, USA

    Sarah B. Whittle, Linna Zhang, Sarah E. Woodfield, Michael Du & Valeria Smith

  2. Department of Pathology, Baylor College of Medicine, Houston, TX, USA

    Kalyani Patel

  3. Division of Pediatric Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, USA

    Sarah E. Woodfield

  4. Department of Pediatrics, Division of Hematology-Oncology, University of California San Diego School of Medicine, Moores Cancer Center, Room 5311, 3855 Health Sciences Drive, MC 0815, La Jolla, CA, 92093-0815, USA

    Peter E. Zage

  5. Peckham Center for Cancer and Blood Disorders, Rady Children’s Hospital, San Diego, CA, USA

    Peter E. Zage

Authors
  1. Sarah B. Whittle
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kalyani Patel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Linna Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sarah E. Woodfield
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Michael Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Valeria Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Peter E. Zage
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peter E. Zage.

Ethics declarations

Conflict of interest

This study was supported by Ariad Pharmaceuticals. Inc. to PEZ in the form of study drug. All other authors declare that they have no conflict of interest.

Funding

The work was supported by the Section of Pediatric Hematology-Oncology at the Texas Children’s Cancer Center and Baylor College of Medicine in Houston, TX.

Ethical approval

This study does not contain any studies with human participants performed by any of the authors. All applicable international, national, and institutional guidelines for the care and use of animals were followed.

Electronic supplementary material

ESM 1

(PPTX 56 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Whittle, S.B., Patel, K., Zhang, L. et al. The novel kinase inhibitor ponatinib is an effective anti-angiogenic agent against neuroblastoma. Invest New Drugs 34, 685–692 (2016). https://doi.org/10.1007/s10637-016-0387-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10637-016-0387-y

Keywords

Search

Navigation