Cellular Signaling Pathway Alterations and Potential Targeted Therapies for Medullary Thyroid Carcinoma

Giunti, Serena; Antonelli, Alessandro; Amorosi, Andrea; Santarpia, Libero

doi:10.1155/2013/803171

Cited by 37 publications

(26 citation statements)

References 106 publications

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“…Cabozantinib inhibits the signaling of VEGF/VEGFR2 and HGF/MET pathways, which are involved in MTC pathogenesis [6,8]. It has been demonstrated that anti-angiogenic agents may lead to tumor cell starvation and increase tumor hypoxia, which represents one of the major causes of drug resistance in solid tumors [9].…”

Section: Introductionmentioning

confidence: 99%

2ME2 inhibits the activated hypoxia-inducible pathways by cabozantinib and enhances its efficacy against medullary thyroid carcinoma

et al. 2015

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Cabozantinib is a multi-targeted tyrosine kinase inhibitor targeting vascular endothelial growth factor (VEGF) receptor (VEGFR)-2, MET (c-Met, also called hepatocyte growth factor (HGF) receptor), and other receptor tyrosine kinases. Cabozantinib has recently been approved for treating advanced medullary thyroid carcinoma (MTC), but its long-term benefit remains uncertain and dose-dependent adverse events are very common. The present study has demonstrated that 2-methoxyestradiol (2ME2), an inhibitor of hypoxia-inducible factors (HIFs) and a promising anticancer agent under investigation in clinical trials, strengthens anticancer activities of cabozantinib against MTC cells in vitro and in vivo. The activated hypoxia-inducible pathways, which are mainly regulated by HIF-1, contribute to the resistance of hypoxic MTC cells to cabozantinib. Cabozantinib upregulated HIF-1α expression at translational levels and increased the expression of the downstream factors including VEGF, lactate dehydrogenase A (LDHA), HGF, and MET. 2ME2 corrected the activated pathways by cabozantinib through downregulating HIF-1α expression and inhibiting its nuclear translocation in hypoxic MTC cells. Administration of 2ME2 enhanced the efficacy of cabozantinib in suppressing the growth of MTC cell line xenografts and patient-derived xenografts established in mice. Given that 2ME2 targets insensitive hypoxic cancer cells to cabozantinib and can inhibit the activated pathways by cabozantinib, the present results warrant further investigation of 2ME2, particularly in combination with cabozantinib, for the treatment of MTC.

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Section: Introductionmentioning

confidence: 99%

2ME2 inhibits the activated hypoxia-inducible pathways by cabozantinib and enhances its efficacy against medullary thyroid carcinoma

et al. 2015

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“…But the ectopic thyroid cancer, particularly the ectopic thyroid cancer growing on the skull, is a rare disease, and no reports on related molecular pathways have yet to be found (18). According to the information screen on the self-made tissue microarray and single-specimen paraffin slice verification, and by combining IPPS 6.0 image analysis software (19) and statistical processing (Figures 3 and 4), the results showed that the Akt and mTOR protein expressions in the AktmTOR signaling pathway of skull growing ectopic thyroid cancer were significantly higher than those in the orthotopic and metastatic thyroid cancer (P=0.012, 0.002) and (P=0.002, 0.004).…”

Section: Thyroid Cancer Molecular Signal Pathwaysmentioning

confidence: 99%

Clinical characteristics and molecular pathology of skull ectopic thyroid cancer

Cao

Wang

et al. 2016

Ann. Transl. Med.

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Thyroid cancer is very common, but skull ectopic thyroid cancer has not been reported in 50 years of literatures in foreign countries. There are only four cases of the skull ectopic thyroid cancer reported in more than 30 years of domestic literature including the cases in this report. This paper aims to investigate the clinical characteristics and possible molecular mechanisms of this rare disease. Five keywords of "thyroid gland", "ectopic thyroid", "thyroid cancer", "ectopic thyroid cancer" and "metastatic thyroid cancer" were included and 50 years of literatures in the PubMed-MEDLINE and Wanfang database were reviewed. By combining the test data of 2 cases of surgical patient tissue microarray specimens-molecular immunology pathology, the possible molecular mechanisms were analyzed and molecular regulation network diagram was drawn. The skull ectopic thyroid cancer has not been reported in 50 years of literatures in foreign countries and there are only four cases of the skull ectopic thyroid cancer reported in more than 30 years of domestic literature including the cases in this report. The molecular expressions of skull ectopic thyroid cancer, orthotopic thyroid cancer, and metastatic thyroid cancer were not the same: (I) AKT (P=0.012, 0.002) and mTOR (P=0.002, 0.004) were highly expressed in the skull ectopic thyroid cancer; (II) BRAF (P=0.029, 0.014) and ERK (P=0.002, 0.001) were highly expressed in orthotopic thyroid cancer; (III) MMP-9 (P=0.023, 0.016) was highly expressed in metastatic thyroid cancer. According to the molecular information base, the PI3K is predicted to be a key crossing gene of the above three signaling pathways, which showed no significant differences in these three thyroid cancers (P=0.692, 0.388, 0.227), but PI3K has regulation roles in the three signaling pathways of Akt/mTOR, MAPK, and NF-κB. PI3K gene is an important starting gene of thyroid cancers. After the canceration starts, due to the fact that the local microenvironments of thyroid cancers in different parts are different, the thyroid cancers are regulated by different signaling pathways. The ectopic thyroid cancer was correlated with Akt/mTOR pathway high expression; orthotopic thyroid was related with MAPK/BRAF/ERK signaling pathway high expression; and the metastatic thyroid cancer was related with NFkB/ MMP9 high expression.

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“…Epidermal growth factor receptor has been shown to be overexpressed in some cases of MTC. Tissue microassay studies found that only 20% of cases were strongly reactive for epidermal growth factor receptor and that tumors with the most aggressive RET mutations showed reduced epidermal growth factor receptor expression 10. Fibroblast growth factor receptor 4 has also been reported to be overexpressed in MTC 10…”

Section: Molecular Biology In Mtcmentioning

confidence: 99%

Cabozantinib for progressive metastatic medullary thyroid cancer: a review

Colombo¹,

Wein²

2014

TCRM

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Medullary thyroid cancer is uncommon and patients typically present with advanced disease. Treatment options for patients with progressive, metastatic medullary thyroid cancer had been limited until recently. Tyrosine kinase inhibitors have garnered increasing interest in this subset of patients. The US Food and Drug Administration recently approved cabozantinib, a tyrosine kinase inhibitor, after promising results were shown in a large Phase III clinical trial. This review summarizes the clinical pharmacology, clinical trials, and safety data for cabozantinib and concludes with a discussion of possible future directions for the treatment of medullary thyroid cancer.

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Cellular Signaling Pathway Alterations and Potential Targeted Therapies for Medullary Thyroid Carcinoma

Cited by 37 publications

References 106 publications

2ME2 inhibits the activated hypoxia-inducible pathways by cabozantinib and enhances its efficacy against medullary thyroid carcinoma

2ME2 inhibits the activated hypoxia-inducible pathways by cabozantinib and enhances its efficacy against medullary thyroid carcinoma

Clinical characteristics and molecular pathology of skull ectopic thyroid cancer

Cabozantinib for progressive metastatic medullary thyroid cancer: a review

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