Thesis
Efficacy of next-generation BRAF inhibitors in differentiated thyroid carcinomas
Master of Science (M.S.), Drexel University
Aug 2020
DOI:
https://doi.org/10.17918/00000522
Abstract
The serine-threonine kinase BRAF is mutated in 50% of papillary thyroid carcinoma (PTC), the most common form of thyroid cancer. The vast majority of BRAF mutations is at position 600 where valine is substituted to glutamic acid or lysine (BRAFV600E/K). This oncogenic mutation stimulates MAPK pathway activation, driving tumour growth and suppressing apoptotic signalling. Patients suffering with PTC often undergo surgical resection coupled with adjuvant radioiodine ablation and lifelong thyroid hormone replacement therapy. In most cases this is curative; however, since most PTC patients diagnosed are under the age of 65, adverse effects associated with prolonged therapy is concerning. Transient radioiodine treatment may cause bone marrow suppression, gonadal damage, and even secondary cancers. Furthermore, hormone replacement therapy increases the risk of developing atrial fibrillation and osteoporosis. Recent studies using mutant-selective BRAF inhibitors (BRAFi), like vemurafenib and dabrafenib, as neoadjuvant agents for advanced melanoma have been very encouraging; however, these treatments have poor efficacy against mutant BRAF thyroid carcinomas. Here we assess the usefulness of the next-generation BRAFi, PLX8394, against human PTC cell lines. PLX8394 differs from its predecessors as it disrupts RAF-level dimerization while inhibiting BRAF kinase activity; these properties make it an intriguing neoadjuvant therapy candidate for PTC. Among a panel of next-generation BRAFi, we demonstrated MAPK signal suppression by PLX8394 but found heterogeneity in reduction of cell growth and S-phase entry. Our results suggest next-generation BRAFi can be a valuable component of an effective treatment against PTC.
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Details
- Title
- Efficacy of next-generation BRAF inhibitors in differentiated thyroid carcinomas
- Creators
- Jacob Chinshiang Yo
- Contributors
- Edward J. Hartsough (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Master of Science (M.S.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- vii, 54 pages
- Resource Type
- Thesis
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; College of Medicine; Drexel University
- Other Identifier
- 991015327414504721