Advisor(s)
Sadanandan Velu
Committee Member(s)
Anna Sorace
Hui-Ting Lee
Pengfei Wang
Renata Jaskula-Sztul
School
College of Arts and Sciences
Document Type
Dissertation
Department (new version)
Chemistry
Date of Award
1-7-2025
Abstract
Medullary thyroid carcinoma (MTC), a rare neuroendocrine tumor, presents considerable clinical challenges due to its tendency to metastasize to organs such as the liver, bones, and brain, resulting in poor patient outcomes. Voltage-gated sodium channels (VGSCs) have emerged as potential therapeutic targets in various malignancies due to their crucial role in promoting cancer cell progression, migration, invasion, and metastasis. This dissertation investigates the specific contributions of the VGSC NaV1.7 subtype in MTC, evaluating its potential as a therapeutic target and elucidating its mechanistic involvement in MTC. Initially, we assessed VGSC subtypes expression in MTC cells. The screening revealed an overexpression of NaV1.7 in metastatic MTC cell line, MZ-CRC-1 relative to primary MTC cell line, TT and normal thyroid cell lines. Immunohistochemical analysis of MTC patient tissues compared to normal thyroid tissues further supported these findings, identifying NaV1.7 as a promising biomarker for MTC progression and a potential therapeutic target. Subsequently, a small-molecule NaV1.7 inhibitor, SV188, was identified and characterized. SV188 exhibited potent inhibition of sodium currents and significantly reduced migration, and invasion of MTC cells in vitro. Moreover, SV188 prevented liver metastasis in a metastatic MTC mouse model, underscoring its potential as a novel anti-metastatic therapeutic agent for MTC. We extended this investigation by designing, synthesizing, and evaluating 17 analogs of SV188 through ligand-based and structure-activity relationship (SAR) studies. The structure modifications at the phenyl rings and head group enhanced sodium current blockade while reducing toxicity. Notably, one analog, IIB7, which is less toxic toward MZ-CRC-1 (CC50 > 100 μM) achieved a 71% reduction in MTC cell invasion, marking an improvement in the reduction of MTC metastasis. Finally, the mechanistic role of NaV1.7 in MTC metastasis was investigated. Knockdown of NaV1.7 in MZ-CRC-1 cells using RNA interference (RNAi) led to significant reductions in cell migration, invasion, and the mRNA expression of 15 genes associated with metastasis. These findings suggest that NaV1.7 is a critical regulator of metastasis-related pathways in MZ-CRC-1 cells. In summary, this dissertation elucidates the critical involvement of NaV1.7 in MTC metastasis and presents innovative NaV1.7 inhibitors as potential therapeutic strategies to attenuate metastatic progression of MTC.
ProQuest ID
Recommended Citation
Pukkanasut, Piyasuda, "Voltage-Gated Sodium Channel Nav1.7 Subtype: A Promising Therapeutic Target For Metastatic Medullary Thyroid Cancer" (2025). All ETDs from UAB. 7304.
https://digitalcommons.library.uab.edu/etd-collection/7304
