Utilizing Three-Dimensional Culture Methods to Improve High-Throughput Drug Screening in Anaplastic Thyroid Carcinoma

SIMPLE SUMMARY: There are currently few treatment options for individuals diagnosed with anaplastic thyroid carcinoma (ATC). Using four distinct ATC cell lines, we screened over 1500 anti-cancer agents and FDA-approved drugs. The initial screen and secondary confirmation testing identified 40 agents of interest for further evaluation. Validation was performed using three-dimensional anaplastic thyroid carcinoma cell cultures (spheroids) in order to more closely recapitulate in vivo drug response. Our approach has enabled identification of three exceptionally potent compounds, bortezomib, cabazitaxel, and YM155, and enhanced in vivo translatability to inform future clinical trials. ABSTRACT: Anaplastic thyroid carcinoma (ATC) is the most aggressive endocrine neoplasm, with a median survival of just four to six months post-diagnosis. Even with surgical and chemotherapeutic interventions, the five-year survival rate is less than 5%. Although combination dabrafenib/trametinib therapy was recently approved for treatment of the ~25% of ATCs harboring BRAFV600E mutations, there are no approved, effective treatments for BRAF-wildtype disease. Herein, we perform a screen of 1525 drugs and evaluate therapeutic candidates using monolayer cell lines and four corresponding spheroid models of anaplastic thyroid carcinoma. We utilize three-dimensional culture methods, as they have been shown to more accurately recapitulate tumor responses in vivo. These three-dimensional cultures include four distinct ATC spheroid lines representing unique morphology and mutational drivers to provide drug prioritization that will be more readily translatable to the clinic. Using this screen, we identify three exceptionally potent compounds (bortezomib, cabazitaxel, and YM155) that have established safety profiles and could potentially be moved into clinical trial for the treatment of anaplastic thyroid carcinoma, a disease with few treatment options.