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Pazopanib: A novel multitargeted tyrosine kinase inhibitor

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Abstract

Pazopanib (GW786034) is a second-generation multitargeted tyrosine kinase inhibitor against vascular endothelial growth factor receptor-1,-2, and-3, platelet-derived growth factor receptor-α, platelet-derived growth factor receptor-β, and c-kit. Preclinical evaluation has revealed excellent antiangiogenic and antitumor activity, and synergism was observed in combination with chemotherapeutic drugs. Significant antitumor activity was found in animal models of a variety of tumors, accompanied by desirable pharmacokinetics and oral bioavailability. Phase I clinical trials have revealed manageable toxicities and desirable pharmacokinetics as well as activity in renal cancer and several other tumors. Ongoing trials are further evaluating pazopanib in a variety of malignancies.

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References and Recommended Reading

  1. Ullrich A, Schlessinger J: Signal transduction by receptors with tyrosine kinase activity. Cell 1990, 61:203–212.

    Article  PubMed  CAS  Google Scholar 

  2. Hubbard SR, Till JH: Protein tyrosine kinases: structure and function. Annu Rev Biochem 2000, 69:373–398.

    Article  PubMed  CAS  Google Scholar 

  3. Yancopoulos GD, Davis S, Gale NW, et al.: Vascular-specific growth factors and blood vessel formation. Nature 2000, 407:242–248.

    Article  PubMed  CAS  Google Scholar 

  4. Bilodeau, MT, Fraley ME, Hartman GD: Kinase insert domain-containing receptor kinase inhibitors as antiangiogenic agents. Expert Opin Invest Drugs 2002, 11:737.

    Article  CAS  Google Scholar 

  5. Holmgren L, O’Reilly, MS, Folkman J: Dormancy of micrometastases: Balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nat Med 1995, 1:149–153.

    Article  PubMed  CAS  Google Scholar 

  6. Zetter BR: Angiogenesis and tumor metastasis. Annu Rev Med 1998, 49:407–424.

    Article  PubMed  CAS  Google Scholar 

  7. Lindahl P, Johansson BR, Leveen P, Betsholtz C: Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 1997, 277:242–245.

    Article  PubMed  CAS  Google Scholar 

  8. Demetri GD: Targeting c-Kit mutations in solid tumors: scientific rationale and novel therapeutic options. Semin Oncol 2001, 28:19–26.

    Article  PubMed  CAS  Google Scholar 

  9. Gschwind A, Fischer OM, Ullrich A: The discovery of receptor tyrosine kinases: targets for cancer therapy. Nat Rev 2004, 4:361–370.

    CAS  Google Scholar 

  10. Dancey J, Sausville EA: Issues and progress with protein kinase inhibitors for cancer treatment. Nat Rev Drug Discov 2003, 2:296–313.

    Article  PubMed  CAS  Google Scholar 

  11. Renhowe PA: Inhibitors of growth factor receptor kinase-dependent signaling pathways in anticancer chemotherapy—cinical progress. Curr Opin Drug Discov Dev 2002, 5:214–224.

    CAS  Google Scholar 

  12. Adams J, Huang P, Patrick DA: Strategy for the design of multiplex inhibitors for kinase-mediated signaling in angiogenesis. Curr Opin Chem Biol 2002, 6:486–492.

    Article  PubMed  CAS  Google Scholar 

  13. Arteaga CL: Molecular therapeutics: Is one promiscuous drug against multiple targets better than combinations of molecule-specific drugs? Clin Cancer Res 2003, 9:1231–1232.

    PubMed  CAS  Google Scholar 

  14. Mandel DB, Laird AD, Xin X, et al.: In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmarcokinetic/pharmacodynamic relationship. Clin Cancer Res 2003, 9:327–337.

    Google Scholar 

  15. Wilhelm SM, Carter C, Tang L, et al.: BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 2004, 64:7099–7109.

    Article  PubMed  CAS  Google Scholar 

  16. Motzer RJ, Hutson TE, Tomczak P, et al.: Phase III randomized trial of sunitinib malate (SU11248) versus interferon-alfa as first-line systemic therapy for patients with metastatic renal cell carcinoma [abstract]. Proc ASCO 2006, 24(Suppl 2):LBA3.

    Google Scholar 

  17. Escudier B, Szczylik C, Eisen T, et al.: Randomized phase III trial of the Raf kinase and VEGFR inhibitor sorafenib (BAY 43-9006) in patients with advanced renal cell carcinoma. Eur J Cancer 2005, 3(Suppl):226 (abstract 794).

    Google Scholar 

  18. Kumar R, Harrington LE, Hopper TM, et al.: Correlation of anti-tumor and anti-angiogenic activity of VEGFR inhibitors with inhibition of VEGFR2 phosphorylation in mice. J Clin Oncol 2005, 23(16S):9537.

    Google Scholar 

  19. Cheung M, Boloor A, Hinkle KW, et al.: Discovery of indazolylpyrimidines as potent inhibitors of VEGFR2 tyrosine kinase [abstract]. Proc Am Assoc Cancer Res 2003, 44:9.

    Google Scholar 

  20. Podar K, Simoncini M, Le Gouill S, et al.: Effects of the indazolylpyrimidine GW786034 on angiogenesis and MM cell growth: therapeutic implications. Blood (ASH Annual Meeting Abstracts) 2004, 104:2452.

    Google Scholar 

  21. Podar K, Tonon, G, Abtahi D, et al.: In vitro and in vivo activity of the VEGF receptor inhibitor PAZOPANIB (GW786034) in Multiple myeloma: therapeutic implications [abstract]. Proc Amer Assoc Cancer Res 2006, 47:5658.

    Google Scholar 

  22. Suttle AB, Hurwitz H, Dowlati A, et al.: Pharmacokinetics (PK) and tolerability of GW786034, a VEGFR tyrosine kinase inhibitor, after daily oral administration to patients with solid tumors [abstract]. J Clin Oncol Proc ASCO 2004, 22(14S):3054.

    Google Scholar 

  23. Hurwitz H, Dowlati A, Savage S, et al.: Safety, tolerability and pharmacokinetics of oral administration of GW786034 in pts with solid tumors. J Clin Oncol 2005, 23(16S):3012.

    Google Scholar 

  24. Hutson TE, Bukowski RM: A phase II study of GW786034 using a randomized discontinuation design in patients with locally recurrent or metastatic clear-cell renal cell carcinoma. Clin Genitourin Cancer 2006, 4:296–298.

    Article  PubMed  CAS  Google Scholar 

  25. Rini BI, Small EJ: Biology and clinical development of vascular endothelial growth factor-targeted therapy in renal cell carcinoma. J Clin Oncol 2005, 23:1028–1043.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Texas Oncology, P.A., Baylor Sammons Cancer Center, 3535 Worth Street, Dallas, TX, 75246, USA

    Guru Sonpavde MD & Thomas E. Hutson DO, PharmD

Authors
  1. Guru Sonpavde MD
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  2. Thomas E. Hutson DO, PharmD
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Correspondence to Thomas E. Hutson DO, PharmD.

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Sonpavde, G., Hutson, T.E. Pazopanib: A novel multitargeted tyrosine kinase inhibitor. Curr Oncol Rep 9, 115–119 (2007). https://doi.org/10.1007/s11912-007-0007-2

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  • DOI: https://doi.org/10.1007/s11912-007-0007-2

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