Advertisement

Current Oncology Reports

, Volume 8, Issue 4, pp 291–296 | Cite as

Targeted therapy for dermatofibrosarcoma protuberans

  • Thomas A. Abrams
  • Scott M. Schuetze
Article

Abstract

Dermatofibrosarcoma protuberans (DFSP) is a rare, cutaneous tumor characterized by aggressive local invasion. Local recurrence after excision is common, especially when negative margins are not achieved. DFSP frequently exhibits translocation of chromosomes 17 and 22, t(17;22). This rearrangement fuses the collagen type Ià1 (COL1A1) gene to the platelet-derived growth factor B-chain (PDGFB) gene. The resultant chimeric gene causes unregulated expression of platelet-derived growth factor leading to abnormal activation of the platelet-derived growth factor receptor (PDGFR) â tyrosine kinase through an autocrine loop. This is believed to be the critical event in DFSP tumorigenesis. Imatinib mesylate is a potent inhibitor of several protein tyrosine kinases, including the PDGFRs. Clinical evidence suggests that imatinib mesylate is a safe and effective treatment in DFSP, especially in cases of recurrent or metastatic disease. Three phase II, multicenter clinical trials are open to further investigate the role of imatinib mesylate in DFSP.

Keywords

Imatinib Protein Tyrosine Kinase Imatinib Mesylate Negative Margin Wide Local Excision 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References and Recommended Reading

  1. 1.
    Laskin WB: Dermatofibrosarcoma protuberans. CA Cancer J Clin 1992, 42:116–125. A comprehensive review for clinicians interested in learning about DFSP.PubMedGoogle Scholar
  2. 2.
    Bowne WB, Antonescu CR, Leung DHY, et al.: Dermato-fibrosarcoma protuberans: a clinicopathologic analysis of patients treated and followed at a single institution. Cancer 2000, 88:2711–2720.PubMedCrossRefGoogle Scholar
  3. 3.
    Pedeutour F, Coindre JM, Sozzi G, et al.: Supernumerary ring chromosomes containing chromosome 17 sequences: a specific feature of Dermatofibrosarcoma protuberans? Cancer Genet Cytogenet 1994, 76:1–9. A historically significant article, one of the first to propose an association between specific cytogenetic abnormalities and DFSP.PubMedCrossRefGoogle Scholar
  4. 4.
    Pedeutour F, Simon MP, Minoletti F, et al.: Ring 22 chromosomes in Dermatofibrosarcoma protuberans are low-level amplifiers of chromosome 17 and 22 sequences. Cancer Res 1995, 55:2400–2403.PubMedGoogle Scholar
  5. 5.
    Naeem R, Lux ML, Huang SF, et al.: Ring chromosomes in Dermatofibrosarcoma protuberans are composed of interspersed sequences from chromosomes 17 and 22. Am J Pathol 1995, 147:1553–1558.PubMedGoogle Scholar
  6. 6.
    Pedeutour F, Simon MP, Minoletti F, et al.: Translocation, t(17;22)(q22;q13), in dermatofibrosarcome protuberans: a new tumor-associated chromosome rearrangement. Cytogenet Cell Genet 1996, 72:171–174.PubMedGoogle Scholar
  7. 7.
    Simon MP, Pedeutour F, Sirvent N, et al.: Deregulation of the platelet-derived growth factor B-chain gene via fusion with collagen gene COL1A1 in Dermatofibrosarcoma protuberans and giant-cell fibroblastoma. Nat Genet 1997, 15:95–98.PubMedCrossRefGoogle Scholar
  8. 8.
    Shimizu A, O’Brien KP, Sjöblom T, et al.: The dermato-fibrosarcoma protuberans-associated collagen type Ialpha1/platelet-derived growth factor (PDGF) B-chain fusion gene generates a transforming protein that is processed to functional PDGF-BB. Cancer Res 1999, 59:3719–3723.PubMedGoogle Scholar
  9. 9.
    Simon MP, Navarro M, Roux D, Pouysségur J: Structural and functional analysis of a chimeric protein COL1A1-PDGFB generated by the translocation t(17;22)(q22;q13.1) in Dermatofibrosarcoma protuberans (DP). Oncogene 2001, 20:2965–2975. This elegant experiment shows that the protein in DFSP generated by t(17;22) is identical in structure and function to that which is produced from the ring chromosome.PubMedCrossRefGoogle Scholar
  10. 10.
    Sirvent N, Maire G, Pedeutour F: Genetics of dermatofibrosarcoma protuberans family of tumors: from ring chromosomes to tyrosine kinase inhibitor treatment. Genes Chromosomes Cancer 2003, 37:1–19. A very good review of DFSP molecular genetics and recommended reading for anyone interested in targeted therapy for the disease.PubMedCrossRefGoogle Scholar
  11. 11.
    Sjöblom T, O’Brien KP, Shimizu A, et al.: Growth inhibition of Dermatofibrosarcoma protuberans tumors by the platelet-derived growth factor antagonist STI157 through induction of apoptosis. Cancer Res 2001, 61:5778–5783.PubMedGoogle Scholar
  12. 12.
    Greco A, Roccato E, Miranda C, et al.: Growth-inhibitory effect of STI157 on cells transformed by the COL1A1/ PDGFB rearrangement. Int J Cancer 2001, 92:354–360.PubMedCrossRefGoogle Scholar
  13. 13.
    Buchdunger E, O’Reilly T, Wood J, et al.: Pharmacology of imatinib (STI157). Eur J Cancer 2002, 38(Suppl 5):S28-S36.PubMedCrossRefGoogle Scholar
  14. 14.
    Maki RG, Awan RA, Dixon RH, et al.: Differential sensitivity to imatinib of 2 patients with metastatic sarcoma arising from Dermatofibrosarcoma protuberans. Int J Cancer 2002, 100:623–626.PubMedCrossRefGoogle Scholar
  15. 15.
    Rubin BP, Schuetze SM, Eary JF, et al.: Molecular targeting of platelet-derived growth factor B by imatinib mesylate in a patient with metastatic Dermatofibrosarcoma protuberans. J Clin Oncol 2002, 20:3586–3591.PubMedCrossRefGoogle Scholar
  16. 16.
    Mizutani K, Tamada Y, Hara K, et al.: Imatinib mesylate inhibits the growth of metastatic lung lesions in a patient with Dermatofibrosarcoma protuberans [letter]. Br J Dermatol 2004, 151:235–236.PubMedCrossRefGoogle Scholar
  17. 17.
    Price VE, Fletcher JA, Zielenska M, et al.: Imatinib mesylate: an attractive alternative in young children with large, surgically challenging Dermatofibrosarcoma protuberans. Pediatr Blood Cancer 2005, 44:511–515.PubMedCrossRefGoogle Scholar
  18. 18.
    Labropoulos SV, Fletcher JA, Oliveira AM, et al.: Sustained complete remission of metastatic Dermatofibrosarcoma protuberans with imatinib mesylate. Anticancer Drugs 2005, 16:461–466.PubMedCrossRefGoogle Scholar
  19. 19.
    McArthur GA, Demetri GD, van Oosterom A, et al.: Molecular and clinical analysis of locally advanced Dermatofibrosarcoma protuberans treated with imatinib: Imatinib Target Exploration Consortium Study B2225. J Clin Oncol 2005, 23:866–873. A landmark article, representing the first substantial collection of patients with advanced DFSP to be treated with imatinib. High rates of response were demonstrated.PubMedCrossRefGoogle Scholar
  20. 20.
    Suit H, Spiro I, Mankin HJ, et al.: Radiation in management of patients with Dermatofibrosarcoma protuberans. J Clin Oncol 1996, 14:2365–2369.PubMedGoogle Scholar
  21. 21.
    Shmookler BM, Enzinger FM, Weiss SW: Giant cell fibroblastoma: a juvenile form of Dermatofibrosarcoma protuberans. Cancer 1989, 64:2154–2161.PubMedCrossRefGoogle Scholar
  22. 22.
    Terrier-Lacombe M-J, Guillou L, Maire G, et al.: Dermato-fibrosarcoma protuberans, giant cell fibroblastoma, and hybrid lesions in children: clinicopathologic comparative analysis of 28 cases with molecular data. Am J Surg Pathol 2003, 27:27–39.PubMedCrossRefGoogle Scholar
  23. 23.
    Rutgers EJT, Kroon BBR, Albus-Lutter CE, Gortzak E: Dermatofibrosarcoma protuberans: treatment and prognosis. Eur J Surg Oncol 1992, 18:241–248.PubMedGoogle Scholar
  24. 24.
    Gloster HMJr: Dermatofibrosarcoma protuberans. J Am Acad Dermatol 1996, 35:355–375.PubMedCrossRefGoogle Scholar
  25. 25.
    Billings SD, Folpe AL. Cutaneous and subcutaneous fibrohistiocytic tumors of intermediate malignancy. Am J Dermatopathol 2004, 26:141–155.PubMedCrossRefGoogle Scholar
  26. 26.
    Mentzel T, Beham A, Katenkamp D, et al.: Fibrosarcomatous ("high-grade") Dermatofibrosarcoma protuberans: clinicopathologic and immunohistochemical study of a series of 41 cases with emphasis on prognostic signifi-cance. Am J Surg Pathol 1998, 22:576–587.PubMedCrossRefGoogle Scholar
  27. 27.
    Taylor HB, Helwig EB. Dermatofibrosarcoma protuberans: a study of 115 cases. Cancer 1962, 15:717–725.PubMedCrossRefGoogle Scholar
  28. 28.
    Fiore M, Miceli R, Mussi C, et al.: Dermatofibrosarcoma protuberans treated at a single institution: a surgical disease with a high cure rate. J Clin Oncol 2005, 23:7669–7675.PubMedCrossRefGoogle Scholar
  29. 29.
    DuBay D, Cimmino V, Lowe L, et al.: Low recurrence rate after surgery for Dermatofibrosarcoma protuberans. Cancer 2004, 100:1008–1016.PubMedCrossRefGoogle Scholar
  30. 30.
    Chung CK, Jacobs IA, Salti GI. Outcomes of surgery for Dermatofibrosarcoma protuberans. Eur J Surg Oncol 2004, 30:341–345.CrossRefGoogle Scholar
  31. 31.
    Khatri VP, Galante JM, Bold RJ, et al.: Dermatofibrosarcoma protuberans: reappraisal of wide local excision and impact of inadequate initial treatment. Ann Surg Oncol 2003, 10:1118–1122.PubMedCrossRefGoogle Scholar
  32. 32.
    Snow SN, Gordon EM, Larson PO, et al.: Dermatofibrosarcoma protuberans: a report on 29 patients treated by Mohs micrographic surgery with long-term follow-up and review of the literature. Cancer 2004, 101:28–38.PubMedCrossRefGoogle Scholar
  33. 33.
    Goldblum JR, Reith JD, Weiss SW. Sarcomas arising in Dermatofibrosarcoma protuberans. Am J Surg Pathol 2000, 24:1125–1130.PubMedCrossRefGoogle Scholar
  34. 34.
    Dagan R, Morris CG, Zlotecki RA, et al.: Radiotherapy in the treatment of Dermatofibrosarcoma protuberans. Am J Clin Oncol 2005, 28:537–539.PubMedCrossRefGoogle Scholar
  35. 35.
    Sun LM, Wang CJ, Huang C-C, et al.: Dermatofibrosarcoma protuberans: treatment results of 35 cases. Radiother Oncol 2000, 57:175–181.PubMedCrossRefGoogle Scholar
  36. 36.
    Mendoza CB, Gerwig WH, Watne AL: Dermatofibrosarcoma protuberans with metastases treated with methotrexate. Am J Surg 1970, 120:119–121.PubMedCrossRefGoogle Scholar
  37. 37.
    Cools J, DeAngelo DJ, Gotlieb J, et al.: A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med 2003, 348:1201–1214.PubMedCrossRefGoogle Scholar
  38. 38.
    Imatinib mesylate in treating patients with locally recurrent or metastatic Dermatofibrosarcoma protuberans (DFSP) or transformed fibrosarcomatous DFSP. Accessible at http://www.clinicaltrials.gov/ct/show/NCT00084630Google Scholar
  39. 39.
    Imatinib mesylate in treating patients with locally advanced or metastatic Dermatofibrosarcoma protuberans or giant cell fibroblastoma. Accessible at http://www. clinicaltrials.gov/ct/show/NCT00085475Google Scholar

Copyright information

© Current Science Inc 2006

Authors and Affiliations

  1. 1.Division of Hematology/Oncology, Department of MedicineUniversity of Michigan Comprehensive Cancer CenterAnn ArborUSA

Personalised recommendations