Drug Repurposing as a Novel Treatment Approach for Medullary Thyroid Carcinoma
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PublisherThe University of Arizona.
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EmbargoRelease after 05/26/2023
AbstractMedullary thyroid carcinoma (MTC) is the most aggressive form of thyroid carcinoma with a high rate of metastasis. The gain-of-function mutation in the RET proto-oncogene has been identified as the primary cause of the development of MTC, which is a part of multiple endocrine neoplasia type 2 (MEN2) syndrome. The dominant-activating mutation in the RET proto-oncogene promotes the phosphorylation of RET receptor in a ligand independent manner. This leads to constitutive activation of downstream signaling pathways that are involved in cell growth, survival, and proliferation. Owing to their potential role in the tumor development, RET has been regarded as an exceptional molecular target for MTC treatment. Therefore, targeting RET activation with drug-like small molecules offers a potential treatment strategy for patients with MTC. Our approach included screening for potential hits utilizing a cell-based bioluminescence reporter system in which the luciferase gene expression is driven by the RET promoter. In this study, we provide three chemical drugs which effectively suppressed RET activity and can be repurposed to treat or control MTC. Each of the drugs included in this research represents a unique pathway and inhibitory mechanism, and each was successfully reduced MTC tumor growth, metastasis, invasion and survival. We believe these drugs are promising candidates for preclinical and clinical studies as mono-therapy and/or for use in combination with other agents to manage MTC.
Degree ProgramGraduate College
Pharmacology & Toxicology