A High-throughput Approach to Identify Effective Systemic Agents for the Treatment of Anaplastic Thyroid Carcinoma.

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.

MATERIAL AND 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 (PDX) models 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 US Food and Drug Administration 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 2 PDX models; and docetaxel demonstrated significant TGI only in the context of mutant TP53.

CONCLUSIONS:

HTS identified classes of systemic agents that 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.

• Authors: Ying C Henderson, Abdallah S R Mohamed, Anastasios Maniakas, Yunyun Chen, Reid T Powell, Shaohua Peng, Maria Cardenas, Michelle D Williams, Diana Bell, Mark E Zafereo, Rui Jennifer Wang, Steve E Scherer, David A Wheeler, Maria E Cabanillas, Marie-Claude Hofmann, Faye M Johnson, Clifford C Stephan, Vlad Sandulache, Stephen Y Lai
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 106 Issue 10 Pg. 2962-2978 (09 27 2021) ISSN: 1945-7197 [Electronic] United States
• PMID: 34120183 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: [email protected].

Chemical References

• Antineoplastic Agents
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins B-raf

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Carcinogenicity Tests
• Cell Line, Tumor
• Disease Models, Animal
• High-Throughput Screening Assays
• Humans
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins B-raf (drug effects)
• Thyroid Carcinoma, Anaplastic (drug therapy)
• Thyroid Neoplasms (drug therapy)
• Tumor Microenvironment (drug effects)