Rubin BP, Schuetze SM, Eary JF, Norwood TH, Mirza S, Conrad EU et al.Molecular targeting of platelet-derived growth factor B by imatinib mesylate in a patient with metastatic dermatofibrosarcoma protuberans. J Clin Oncol 20:3586-3591
Dermatofibrosarcoma protuberans is caused by activation of the platelet-derived growth factor B (PDGFB) receptor, a transmembrane tyrosine kinase. We investigated the response of dermatofibrosarcoma protuberans to the tyrosine kinase inhibitor imatinib mesylate.
A patient with unresectable, metastatic dermatofibrosarcoma protuberans received imatinib mesylate (400 mg bid). Response to therapy was assessed by [18F]fluorodeoxyglucose (FDG) positron emission tomography, magnetic resonance imaging, and histopathologic and immunohistochemical evaluation.
The patient was treated for 4 months with imatinib mesylate. The hypermetabolic uptake of FDG fell to background levels within 2 weeks of treatment, and the tumor volume shrank by over 75% during the 4 months of therapy, allowing for resection of the mass. There was no residual viable tumor in the resected specimen, indicating a complete histologic response to treatment with imatinib mesylate.
Imatinib mesylate is highly active in dermatofibrosarcoma protuberans. The dramatic response seen in this patient demonstrates that inhibition of PDGFB receptor tyrosine kinase activity can significantly impact viability of at least one type of solid tumor.
"Briefly, exclusion criteria include a) studies which did not use Imatinib b) duplicate studies c) studies which discussed molecular characteristics only d) critiques of other case reports e) described patients whose primary diagnosis was not DFSP. A total of 36 articles were included in the systematic review
[16,18-20,23-54]. Response to Imatinib was defined as complete clinical or pathologic response, partial response or stable disease. "
[Show abstract][Hide abstract] ABSTRACT: Dermatofibrosarcoma Protuberans (DFSP) is a rare skin tumor, characterized by frequent local recurrence but is seldom metastatic. It is histologically characterized by storiform arrangement of spindle cells. Cytogenetically, most tumors are characterized by translocation 17:22 leading to overexpression of tyrosine kinase PDGFB which can be targeted with tyrosine kinase inhibitor, Imatinib. We describe the first case of unresectable pancreatic metastases from DFSP treated with neoadjuvant Imatinib and subsequently R0 metastectomy. Additionally, a comprehensive systematic review of DFSP pancreatic metastases and the current published data on the use of Imatinib in DFSP is summarized.
"Preclinical studies of DFSP showed that the constitutive activation of the PDGFRB tyrosine kinase domain resulting from t(17;22)(q22;q13) translocation together with COL1A1-PDGFB gene rearrangement was essential for DFSP pathogenesis , suggesting that DFSP could be targeted by imatinib. Subsequently, a number of case reports and a recent pooled analysis of 2 phase II trials (SWOG-S0345 and EORTC 62027) have also reported promising efficacy of imatinib for advanced and metastatic DFSP , , , . "
[Show abstract][Hide abstract] ABSTRACT: Dermatofibrosarcoma protuberans (DFSP) is a very rare soft tissue sarcoma. DFSP often reveals a specific chromosome translocation, t(17;22)(q22;q13), which results in the fusion of collagen 1 alpha 1 (COL1A1) gene and platelet-derived growth factor-B (PDGFB) gene. The COL1A1-PDGFB fusion protein activates the PDGFB receptor and resultant constitutive activation of PDGFR receptor is essential in the pathogenesis of DFSP. Thus, blocking PDGFR receptor activation with imatinib has shown promising activity in the treatment of advanced and metastatic DFSP. Despite the success with targeted agents in cancers, acquired drug resistance eventually occurs. Here, we tried to identify potential drug resistance mechanisms against imatinib in a 46-year old female with DFSP who initially responded well to imatinib but suffered rapid disease progression. We performed whole-genome sequencing of both pre-treatment and post-treatment tumor tissue to identify the mutational events associated with imatinib resistance. No significant copy number alterations, insertion, and deletions were identified during imatinib treatment. Of note, we identified newly emerged 8 non-synonymous somatic mutations of the genes (ACAP2, CARD10, KIAA0556, PAAQR7, PPP1R39, SAFB2, STARD9, and ZFYVE9) in the imatinib-resistant tumor tissue. This study revealed diverse possible candidate mechanisms by which imatinib resistance to PDGFRB inhibition may arise in DFSP, and highlights the usefulness of whole-genome sequencing in identifying drug resistance mechanisms and in pursuing genome-directed, personalized anti-cancer therapy.
PLoS ONE 07/2013; 8(7):e69752. DOI:10.1371/journal.pone.0069752 · 3.23 Impact Factor
"Imatinib mesylate is a tyrosine kinase receptor inhibitor formerly known as STI-571 or Gleevec; this small molecule, derived from 2-phenylaminopyrimidine, binds to the ATPbinding site, thus inhibiting the tyrosine kinase activity of the PDGFR (both í µí»¼ and í µí»½) and the downstream signals, including the Ras-MAPK-ERK cell proliferation pathway   . Imatinib has been largely studied in human solid tumours, where it has been shown to induce cell growth arrest     . Furthermore, imatinib selectively inhibits the Bcr- Abl tyrosine kinase in chronic myeloid leukemia and c-kit in several human cancers, resulting in either apoptosis or inhibition of proliferation [30, 31, 38–42]. "
[Show abstract][Hide abstract] ABSTRACT: Equine sarcoids are skin tumours of fibroblastic origin affecting equids worldwide. Bovine papillomavirus type-1 (BPV-1) and, less commonly, type-2 are recognized as etiological factors of sarcoids. The transforming activity of BPV is related to the functions of its major oncoprotein E5 which binds to the platelet-derived growth factor β receptor (PDGF β R) causing its phosphorylation and activation. In this study, we demonstrate, by coimmunoprecipitation and immunoblotting, that in equine sarcoid derived cell lines PDGF β R is phosphorylated and binds downstream molecules related to Ras-mitogen-activated protein kinase-ERK pathway thus resulting in Ras activation. Imatinib mesylate is a tyrosine kinase receptors inhibitor which selectively inhibits the activation of PDGF β R in the treatment of several human and animal cancers. Here we show that imatinib inhibits receptor phosphorylation, and cell viability assays demonstrate that this drug decreases sarcoid fibroblasts viability in a dose-dependent manner. This study contributes to a better understanding of the molecular mechanisms involved in the pathology of sarcoids and paves the way to a new therapeutic approach for the treatment of this common equine skin neoplasm.
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