Mitchell Hsu

Introduction. Medullary thyroid cancer (MTC) is a malignant growth of C cells, which are calcitonin secreting cells that are derived from neural crest cells.¹ The majority of these tumors and tumor conditions are related to point mutations of RET with RET M918T being the most prominent, leading to autophosphorylation and activation of RET cell growth pathway.^2-4 At lower stages, complete thyroidectomies with cervical lymph node dissections are the main treatment. However, at metastatic stages of the disease, the best FDA-approved treatment for RET MTC’s are tyrosine kinase inhibitors like Cabozantinib and Vandetanib.^5-7  Methods. B16F10 cells were cultured in Transwell plates either with hepatic growth factor (HGF) within the upper well plate or HGF in the lower well plate with increasing amounts of Cabozantinib. After 24 hours, these cultures were stained with calcein-AM. MDA-MB-231 cells were implanted in mice, grown for 14 days with graded doses of Cabozantininb, excised, and stained for hypoxia, apoptosis, proliferation, and vascularization immunofluorescence; these tumors were also weighed every 2 days and recorded.^5,6 Cabozantinib and Vandetanib were dynamically modelled to determine receptor binding sites and binding affinities.⁸ Coadministration of increasing amounts of Cabozantinib and Vandetanib with mito-CP to cause cell apoptosis were measured with western blotting.⁹  Results. These studies showed that Cabozantinib acted as a competitive ATP binding site inhibitor in RET, MET, and VEGFR-2 receptors. As a result, Cabozantinib was shown to inhibit tumor cell proliferation and migration across stained Transwell plates; immunofluorescence of mice tumors showed increases in hypoxia, increases in apoptosis, decreased proliferation biomarkers, and decreased vascularization; cell growth was reduced in mice. Vandetanib has a similar mechanism, but it has a higher affinity for RET, VEGFR-2, and EGFR instead of MET. Both drugs increase the efficacy of mito-CP, a mitochondrial superoxide dismutase mimetic, increasing apoptosis of TT cells as measured by cell lysate with western blotting.^5-9  Conclusion. The results show that both Cabozantinib and Vandetanib have high affinity for RET and other tyrosine receptors that potentiate carcinomas, leading to decreases in proliferation migration, vascularization, and increasing the rate of apoptosis. There may be therapeutic potential in combining these tyrosine kinase inhibitors with other chemotherapeutics like mito-CP to improve apoptotic qualities.

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