Targeted therapy for dermatofibrosarcoma protuberans

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 Ialpha1 (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) beta 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.

Current treatment options in dermatofibrosarcoma protuberans

“…After 4 months of treatment with 400 mg Imatinib twice daily, the tumor mass shrank by over 75% and the histological examination after subsequent tumor resection showed a complete histologic response without evidence of neoplastic cells. Since then, a few studies demonstrating the chance of achieving partial and complete remissions in metastatic patients have been published (Mizutani et al 2004;Labropoulos et al 2005;Price et al 2005;Abrams and Schuetze 2006;Kasper et al 2006;McArthur 2006;Mehrany et al 2006;Savoia et al 2006;McArthur 2007;Ugurel 2007).…”

Neoadjuvant Imatinib Therapy for Dermatofibrosarcoma Protuberans

“…When imatinib binds at the receptor site, kinase activity downregulates, resulting in growth inhibition and increased apoptosis. [10][11][12][13][14][15][16][17] Imatinib has been used successfully to treat unresectable and metastatic lesions as well as locally advanced primary and recurrent DFSP. 1,6,18,19 This study adds to a growing body of literature showing that the use of imatinib can reduce the tumor burden of DFSP.…”

Sonography of dermatofibrosarcoma protuberans of the groin

“…The tumor has a propensity for local recurrence, especially if negative margins are not achieved by excision. 8,9 DFSP metastasizes hematogenously, but distant metastases are extremely rare and generally occur late after repeated local recurrences. 4 The tumor rarely results in death.…”

“…9 Abnormal activation of a PDGF receptor's beta tyrosine kinase is believed to be a critical event in DFSP's pathogenesis. The recent development of inhibitors of signal transduction by the PDGF B-chain pathway may modify the surgical strategy, which currently relies on wide local excision with margins of 3 cm to prevent local recurrence and tends to be too mutilating.…”