1. A High-throughput Approach to Identify Effective Systemic Agents for the Treatment of Anaplastic Thyroid Carcinoma
- Author
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Shaohua Peng, Abdallah S.R. Mohamed, Yunyun Chen, Michelle D. Williams, Diana Bell, Ying C. Henderson, Maria E. Cabanillas, Clifford Stephan, Maria F. Cardenas, Anastasios Maniakas, Steve Scherer, Faye M. Johnson, Rui Jennifer Wang, David A. Wheeler, Vlad C. Sandulache, Stephen Y. Lai, Reid T. Powell, Marie Claude Hofmann, and Mark Zafereo
- Subjects
Proto-Oncogene Proteins B-raf ,0301 basic medicine ,medicine.medical_specialty ,endocrine system diseases ,Carcinogenicity Tests ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Antineoplastic Agents ,Context (language use) ,Thyroid Carcinoma, Anaplastic ,Biochemistry ,Thyroid carcinoma ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,In vivo ,Cell Line, Tumor ,Internal medicine ,Tumor Microenvironment ,Animals ,Humans ,Medicine ,Thyroid Neoplasms ,Protein Kinase Inhibitors ,Clinical Research Article ,Tumor microenvironment ,business.industry ,Biochemistry (medical) ,Thyroid ,Pralatrexate ,High-Throughput Screening Assays ,Clinical trial ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,Docetaxel ,030220 oncology & carcinogenesis ,Cancer research ,business ,medicine.drug - Abstract
BackgroundDespite 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 MethodsTwelve 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.ResultsSeventeen 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.ConclusionsHTS 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.
- Published
- 2021