Henderson YC, Mohamed ASR, Maniakas A, et al. - Given the critical clinical necessity for effective systemic agents for anaplastic thyroid carcinoma (ATC) with a reasonable toxicity profile to facilitate rapid translational development, researchers herein used 12 human thyroid cancer cell lines with comprehensive genomic characterization in a high-throughput screening (HTS) of 257 compounds to select agents with maximal growth inhibition. The selected agents were validated using cell proliferation, colony formation, orthotopic thyroid models, and patient-derived xenograft models (PDX). They identified 17 compounds as effective and selected docetaxel, LBH-589, and pralatrexate for additional in vitro and in vivo analysis given their prior approval by the FDA for other cancers. Classes of systemic agents, identified via HTS, demonstrated preferential effectiveness against aggressive thyroid cancers, especially those with mutant TP53. Preclinical validation in both orthotopic and PDX models, which are accurate in vivo models mimicking tumor microenvironment, may yield support for initiation of early phase clinical trials in non-BRAF mutated or refractory to BRAF/MEK inhibition ATC.