Ying C Henderson1, Abdallah S R Mohamed1,2,3, Anastasios Maniakas1,4, Yunyun Chen1, Reid T Powell5, Shaohua Peng6, Maria Cardenas7, Michelle D Williams8, Diana Bell8, Mark E Zafereo1, Rui Jennifer Wang1, Steve E Scherer7, David A Wheeler7,9, Maria E Cabanillas10, Marie-Claude Hofmann10, Faye M Johnson3,6, Clifford C Stephan5, Vlad Sandulache11, Stephen Y Lai1,2,12. 1. Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 2. Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 3. MD Anderson Cancer Center UT Health Graduate School of Biomedical Sciences, Houston, TX, USA. 4. Université de Montréal, Hôpital Maisonneuve-Rosemont, Montreal, QB, Canada. 5. IBT High Throughput Screening Core, Texas A&M Health Science Center, Houston, TX, USA. 6. Department of Thoracic, Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 7. Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA. 8. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 9. Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA. 10. Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 11. Department of Otolaryngology-Head and Neck Surgery, Baylor College of Medicine, Houston, TX, USA. 12. Department of Cellular and Molecular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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.
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.
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