Skip to main content

Advertisement

SpringerLink
Log in

Sunitinib, a multitargeted tyrosine kinase inhibitor, in the management of gastrointestinal stromal tumor

  • Published:
Current Oncology Reports Aims and scope Submit manuscript

Abstract

Due to the remarkable advances in the understanding of the biology of gastrointestinal stromal tumors (GIST), tyrosine kinase inhibition has become the mainstay of therapy for patients with advanced GIST. Sunitinib is a tyrosine kinase inhibitor with a wide range of kinase inhibition, including KIT, platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor (VEGF), and FLT3. Sunitinib has demonstrated benefit in patients with advanced GIST who have progressed on primary therapy with imatinib. The objectives of this review are to discuss the role of sunitinib in the current management of GIST, to review the unique side effect profile of the agent, and to discuss future trends in the use of the drug as the understanding of the mechanism of GIST evolves.

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

Similar content being viewed by others

References and Recommended Reading

  1. Joensuu, H, Fletcher C, Dimitrijevic S, et al.: Management of malignant gastrointestinal stromal tumors. Lancet Oncol 2002, 3:655–664.

    Article  PubMed  CAS  Google Scholar 

  2. Emory TS, Sobin LH, Lukes L, et al.: Prognosis of gastrointestinal smooth muscle (stromal) tumors: dependence on anatomic site. Am J Surg Pathol 1999, 23:82–87.

    Article  PubMed  CAS  Google Scholar 

  3. Miettinen M, Monihan JM, Sarlomo-Rikala M, et al.: Gastrointestinal stromal tumors/smooth muscle tumors (GISTs) primary in the omentum and mesentery: clinicopathologic and immunohistochemical study of 26 cases. Am J Surg Pathol 1999, 23:1109–1118.

    Article  PubMed  CAS  Google Scholar 

  4. Miettinen M, Sarlomo-Rikala M, Lasota J: Gastrointestinal stromal tumors: recent advances in understanding of their biology. Hum Pathol 1999, 30:1213–1220.

    Article  PubMed  CAS  Google Scholar 

  5. Nilsson B, Bumming P, Meis-Kindblom JM, et al.: Gastrointestinal stromal tumors: the incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era—a population-based study in western Sweden. Cancer 2005, 103:821–829.

    Article  PubMed  Google Scholar 

  6. Hirota, S, Isozaki K, Moriyama Y, et al.: Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 1998, 279:577–580.

    Article  PubMed  CAS  Google Scholar 

  7. Heinrich MC, Rubin BP, Longley BJ, Fletcher JA: Biology and genetic aspects of gastrointestinal stromal tumors: KIT activation and cytogenetic alterations. Hum Pathol 2002, 33:484–495.

    Article  PubMed  CAS  Google Scholar 

  8. Heinrich MC, Corless CL, Duensing A, et al.: PDGFRA activating mutations in gastrointestinal stromal tumors. Science 2003, 299:708–710.

    Article  PubMed  CAS  Google Scholar 

  9. Corless CL, Schroeder A, Griffith D, et al.: PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib. J Clin Oncol 2005, 23:5357–5364.

    Article  PubMed  CAS  Google Scholar 

  10. National Comprehensive Cancer Network: Clinical Practice Guidelines in Oncology. Soft Tissue Sarcoma, GIST.v.1.2007. http://www.nccn.org.. Accessed April 2007.

  11. Tuveson DA, Willis NA, Jacks T, et al.: STI571 inactivation of the gastrointestinal stromal tumor c-KIT oncoprotein: biological and clinical implications. Oncogene 2001, 20:5054–5048.

    Article  PubMed  CAS  Google Scholar 

  12. Joensuu H, Roberts PJ, Sarlomo-Rikala M, et al.: Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med 2001, 344:1052–1056.

    Article  PubMed  CAS  Google Scholar 

  13. Demetri GD, von Mehren M, Blanke CD, et al.: Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 2002, 347:472–480.

    Article  PubMed  CAS  Google Scholar 

  14. Rankin C, Von Mehren M, Blanke C, et al.: Dose effect of imatinib in patients with metastatic GIST — Phase III Sarcoma Group Study S0033 [abstract]. J Clin Oncol Proc ASCO 2004 Vol. 22:9005.

    Google Scholar 

  15. Verweij J, Casali PG, Zalcberg J, et al.: Progression-free survival of gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet 2004, 364:1127–1134.

    Article  PubMed  CAS  Google Scholar 

  16. Blanke CD, Demetri GD, Von Mehren M, et al.: Long-term follow-up of a phase II randomized trial in advanced gastrointestinal stromal tumor (GIST) patients (pts) treated with imatinib mesylate [abstract]. J Clin Oncol Proc ASCO 2006, 24:9528

    Google Scholar 

  17. Antonescu CR, Besmer P, Guo T, et al.: Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation. Clin Cancer Res 2005, 11:4182–4190.

    Article  PubMed  CAS  Google Scholar 

  18. Chen LL, Trent JC, Wu EF, et al.: A missense mutation in KIT kinase domain 1 correlates with imatinib resistance in gastrointestinal stromal tumors. Cancer Res 2004, 64:5913–5919.

    Article  PubMed  CAS  Google Scholar 

  19. Corless CL, Fletcher JA, Heinrich MC. Biology of gastrointestinal stromal tumors. J Clin Oncol 2004, 22:3813–3825.

    Article  PubMed  CAS  Google Scholar 

  20. Osusky KL, Hallahan DE, Fu A, et al.: The receptor tyrosine kinase inhibitor SU11248 impedes endothelial cell migration, tubule formation and blood vessel formation in vivo on existing tumor vessels. Angiogenesis 2004, 7:225–233.

    Article  PubMed  CAS  Google Scholar 

  21. Abrams TJ, Lee LB, Murray LJ, et al.: SU11248 inhibits KIT and platelet-derived growth factor receptor beta in preclinical models of human small cell kung cancer. Mol Cancer Ther 2003, 2:471–478.

    PubMed  CAS  Google Scholar 

  22. Mendel 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 pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res 2003, 9:327–337.

    PubMed  CAS  Google Scholar 

  23. Murray LJ, Abrams TJ, Long KR, et al.: Su11248 inhibits tumor growth and CSF-1R-dependent osteolysis in an experimental breast cancer bone metastasis model. Clin Exp Metastasis 2003, 20:757–766.

    Article  PubMed  CAS  Google Scholar 

  24. O’Farrell AM, Abrams TJ, Yuen HA, et al.: SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood 2003, 101:3597–3605.

    Article  PubMed  CAS  Google Scholar 

  25. Schueneman AJ, Himmelfarb E, Geng L, et al.: SU11248 maintenance therapy prevents tumor regrowth after fractionated irradiation of murine tumor models. Cancer Res 2003, 63:4009–4016.

    PubMed  CAS  Google Scholar 

  26. Faivre S, Delbaldo C, Vera K, et al.: Safety, pharmacokinetic and anti-tumor activity of SU11248, a novel oral tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol 2006, 24:25–35.

    Article  PubMed  CAS  Google Scholar 

  27. Demetri GD, Desai JA, Fletcher JA, et al.: SU11248, a multi-targeted tyrosine kinase inhibitor, can overcome imatinib (IM) resistance caused by diverse genomic mechanisms in patients (pts) with metastatic gastrointestinal stromal tumor (GIST) [abstract]. J Clin Oncol Proc ASCO 2004, 22(Suppl):3001.

    Google Scholar 

  28. Heinrich MC, Maki RG, Corless CL, et al.: Sunitnib (SU) response in imatinib-resistant (IM-R) GIST correlates with KIT and PDGFRA mutation status [abstract]. J Clin Oncol Proc 2006, 24:9502.

    Google Scholar 

  29. Demetri GD, van Oosterom AT, Garrett CR, et al.: Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 2006, 368:1329–1338.

    Article  PubMed  CAS  Google Scholar 

  30. Robert C, Soria JC, Spatz A, et al.: Cutaneous side-effects of kinase inhibitors and blocking antibodies. Lancet Oncol 2005 6:491–500.

    Article  PubMed  CAS  Google Scholar 

  31. Moss KG, Toner GC, Cherrington JM, et al.: Hair depigmentation is a biological readout for pharmacological inhibition of KIT in mice and humans. J Pharmacol Exp Ther 2003, 307:476–480.

    Article  PubMed  CAS  Google Scholar 

  32. Desai J, Yassa L, Marqusee E, et al.: Hypothyroidism after sunitinib treatment for patients with gastrointestinal stromal tumors. Ann Intern Med 2006, 145:660–664.

    PubMed  Google Scholar 

  33. Rini BI, Tamaskar I, Shaheen P, et al.: Hypothyroidism in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst 2007, 99:81–83.

    Article  PubMed  CAS  Google Scholar 

  34. van den Abbeele T, Melenevsky AY, de Vries D, et al.: Imaging kinase target inhibition with SU11248 by FDG-PET in patients (pts) with imatinib-resistant gastrointestinal stromal tumors (I-R GIST) [abstract]. J Clin Oncol Proc ASCO 2005, 23:9006.

    Google Scholar 

  35. George S, Blay JY, Casali PG, et al.: Continuous daily dosing of sunitinib in patients with advanced gastrointestinal stromal tumor (GIST) [abstract]. To be presented at the Connective Tissue Oncology Society. Venice, Italy; November 2007:648.

    Google Scholar 

  36. Heinrich MC, Shoemaker JS, Corless CL, et al.: Correlation of target kinase genotype with clinical activity of imatinib mesylate (IM) in patients with metastatic GI stromal tumors (GISTs) expressing KIT (KIT+) [abstract]. J Clin Oncol Proc ASCO 2005, 23:7.

    Google Scholar 

  37. Debiec-Rychter M, Sciot R, Le Cesne A, et al.: KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. Eur J Cancer. 2006, 42:1093–1103.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, 44 Binney Street, D1210, Boston, MA, 02115, USA

    Suzanne George MD

Authors
  1. Suzanne George MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Suzanne George MD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

George, S. Sunitinib, a multitargeted tyrosine kinase inhibitor, in the management of gastrointestinal stromal tumor. Curr Oncol Rep 9, 323–327 (2007). https://doi.org/10.1007/s11912-007-0040-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11912-007-0040-1

Keywords

Search

Navigation