Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
The Journal of clinical endocrinology and metabolism	99	4	2014 Apr	E572-81	J Clin Endocrinol Metab

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	2	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
CLM3			EGFR Inhibitor (Pan) 62 RET Inhibitor 53 VEGFR2 Inhibitor 37	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, PMID: 32055496).

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 V600E	thyroid 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
BRAF wild-type	thyroid 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