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Ref Type Journal Article
PMID (24423321)
Authors Antonelli A, Bocci G, Fallahi P, La Motta C, Ferrari SM, Mancusi C, Fioravanti A, Di Desidero T, Sartini S, Corti A, Piaggi S, Materazzi G, Spinelli C, Fontanini G, Danesi R, Da Settimo F, Miccoli P
Title CLM3, a multitarget tyrosine kinase inhibitor with antiangiogenic properties, is active against primary anaplastic thyroid cancer in vitro and in vivo.
Journal The Journal of clinical endocrinology and metabolism
Vol 99
Issue 4
Date 2014 Apr
URL
Abstract Text 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).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.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.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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
CLM3 CLM3 3 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
CLM3 EGFR Inhibitor (Pan) 46 RET Inhibitor 39 VEGFR2 Inhibitor 35 CLM3 is an small molecule multi-kinase inhibitor with activity against several kinases including Ret, Vegfr2, and Egfr, which potentially leads to decreased tumor cell growth (PMID: 21459081, PMID: 24423321).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF wild-type thyroid gland cancer sensitive CLM3 Preclinical Actionable In a preclinical study, CLM3 inhibited growth, Egfr signaling, and CCND1 expression, in BRAF wild-type thyroid cancer cells in culture (PMID: 24423321). 24423321
Unknown unknown thyroid gland cancer not applicable CLM3 Preclinical - Cell line xenograft Actionable In a preclinical study, CLM3 induced apoptosis and inhibited EGFR phosphorylation and cell proliferation in human anaplastic thyroid cancer cell lines in culture and inhibited tumor growth in xenograft models (PMID: 24423321). 24423321
BRAF V600E thyroid gland cancer sensitive CLM3 Preclinical Actionable In a preclinical study, CLM3 inhibited growth, Egfr signaling, and CCND1 expression in thyroid cancer cells harboring BRAF V600E in culture (PMID: 24423321). 24423321