Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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Heinrich, M.C. et al.

Heinrich, McArthur, Demetri, Joensuu, Bono, Herrmann, Hirte, Cresta, Koslin, Corless, Dirnhofer, van Oosterom, Nikolova, Dimitrijevic, Fletcher,

Clinical and molecular studies of the effect of imatinib on advanced aggressive fibromatosis (desmoid tumor).

PURPOSE: To determine the clinical efficacy of imatinib in patients with advanced aggressive fibromatosis (AF) and to identify the molecular basis of response/nonresponse to this agent. PATIENTS AND METHODS: Nineteen patients with AF were treated with imatinib (800 mg/d) as part of a phase II clinical study. Tumor specimens were analyzed for mutations of KIT, PDGFRA, PDGFRB, and CTNNB1 (beta-catenin). Tumor expression of total and activated KIT, PDGFRA, and PDGFRB were assessed using immunohistochemistry and immunoblotting techniques. We also measured plasma levels of PDGF-AA and PDGF-BB in patients and normal patient controls. RESULTS: Three of 19 patients (15.7%) had a partial response to treatment, with four additional patients having stable disease that lasted more than 1 year (overall 1 year tumor control rate of 36.8%). No mutations of KIT, PDGFRA, or PDGFRB were found. Sixteen of 19 patients (84%) had mutations involving the WNT pathway (APC or CTNNB1). However, there was no correlation between WNT pathway mutations and clinical response to imatinib. AF tumors expressed minimal to null levels of KIT and PDGFRA but expressed levels of PDGFRB that are comparable with normal fibroblasts. However, PDGFRB phosphorylation was not detected, suggesting that PDGFRB is only weakly activated. AF patients had elevated levels of PDGF-AA and PDGF-BB compared with normal patient controls. Notably, the plasma level of PDGF-BB was inversely correlated with time to treatment failure. CONCLUSION: Imatinib is an active agent in the treatment of advanced AF. Imatinib response in AF patients may be mediated by inhibition of PDGFRB kinase activity.[1]

References

Clinical and molecular studies of the effect of imatinib on advanced aggressive fibromatosis (desmoid tumor). Heinrich, M.C., McArthur, G.A., Demetri, G.D., Joensuu, H., Bono, P., Herrmann, R., Hirte, H., Cresta, S., Koslin, D.B., Corless, C.L., Dirnhofer, S., van Oosterom, A.T., Nikolova, Z., Dimitrijevic, S., Fletcher, J.A. J. Clin. Oncol. (2006) [Pubmed]

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