A High-Throughput Approach to Identify Effective Systemic Agents for the Treatment of Anaplastic Thyroid Carcinoma. | Academic Article individual record
abstract

BACKGROUND: Despite the use of aggressive multimodality treatment, most anaplastic thyroid carcinoma (ATC) patients die within a year of diagnosis. Although the combination of BRAF and MEK inhibitors has recently been approved for use in BRAF-mutated ATC, they remain effective in a minority of patients who are likely to develop drug resistance. There remains a critical clinical need for effective systemic agents for ATC with a reasonable toxicity profile to allow for rapid translational development. METHODS & METHODS: Twelve human thyroid cancer cell lines with comprehensive genomic characterization were used in a high-throughput screening (HTS) of 257 compounds to select agents with maximal growth inhibition. Cell proliferation, colony formation, orthotopic thyroid models, and patient-derived xenograft models (PDX) were used to validate the selected agents. RESULTS: Seventeen compounds were effective and docetaxel, LBH-589, and pralatrexate were selected for additional in vitro and in vivo analysis as they have been previously approved by the FDA for other cancers. Significant tumor growth inhibition (TGI) was detected in all tested models treated with LBH-589; pralatrexate demonstrated significant TGI in the orthotopic papillary thyroid carcinoma model and two PDX models; docetaxel demonstrated significant TGI only in the context of mutant TP53. CONCLUSIONS: HTS identified classes of systemic agents which demonstrate preferential effectiveness against aggressive thyroid cancers, particularly those with mutant TP53. Preclinical validation in both orthotopic and PDX models, which are accurate in vivo models mimicking tumor microenvironment, may support initiation of early phase clinical trials in non-BRAF mutated or refractory to BRAF/MEK inhibition ATC.

author list (cited authors)
Henderson, Y. C., Mohamed, A., Maniakas, A., Chen, Y., Powell, R. T., Peng, S., ... Lai, S. Y.
publication date
2021
publisher
keywords
  • Anaplastic Thyroid Carcinoma
  • Lbh-589
  • Patient-derived Xenograft (pdx) Model
  • High-throughput Screening
PubMed Central ID
34120183
identifier
540083SE
Digital Object Identifier (DOI)