CLM3, a multitarget tyrosine kinase inhibitor with antiangiogenic properties, is active against primary anaplastic thyroid cancer in vitro and in vivo

Alessandro Antonelli, Guido Bocci, Poupak Fallahi, Concettina La Motta, Silvia Martina Ferrari, Caterina Mancusi, Anna Fioravanti, Teresa Di Desidero, Stefania Sartini, Alessandro Corti, Simona Piaggi, Gabriele Materazzi, Claudio Spinelli, Gabriella Fontanini, Romano Danesi, Federico Da Settimo, Paolo Miccoli
Journal of Clinical Endocrinology and Metabolism 2014, 99 (4): E572-81

CONTEXT AND OBJECTIVE: We have studied the antitumor activity of a pyrazolo[3,4-d]pyrimidine compound (CLM3) proposed for a multiple signal transduction inhibition [including the RET tyrosine kinase, epidermal growth factor receptor, and vascular endothelial growth factor (VEGF) receptor and with antiangiogenic activity] in primary anaplastic thyroid cancer (ATC) cells, in the human cell line 8305C (undifferentiated thyroid cancer), and in an ATC-cell line (AF).

DESIGN AND MAIN OUTCOME MEASURES: CLM3 was tested in primary ATC cells at the concentrations of 5, 10, 30, and 50 μM; in 8305C cells, in AF cells, at 1, 5, 10, 30, 50, or 100 μM; and in AF cells in CD nu/nu mice.

RESULTS: CLM3 significantly inhibited the proliferation of 8305C and AF cells, also inducing apoptosis. A significant reduction of proliferation with CLM3 in ATC cells (P < .01, ANOVA) was shown. CLM3 increased the percentage of apoptotic ATC cells dose dependently (P < .001, ANOVA) and inhibited migration (P < .01) and invasion (P < .001). The AF cell line was injected sc in CD nu/nu mice, and tumor masses became detectable 15 days later. CLM3 (50 mg/kg per die) significantly inhibited tumor growth (starting 16 d after the beginning of treatment). CLM3 significantly decreased the VEGF-A expression and microvessel density in AF tumor tissues. Furthermore, CLM3 inhibited epidermal growth factor receptor, AKT, and ERK1/2 phosphorylation and down-regulated cyclin D1 in 8305C and AF cells.

CONCLUSIONS: The antitumor and antiangiogenic activity of a pyrazolo[3,4-d]pyrimidine compound (CLM3) is very promising in anaplastic thyroid cancer, opening the way to a future clinical evaluation.

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