TY - JOUR
T1 - A High-throughput Approach to Identify Effective Systemic Agents for the Treatment of Anaplastic Thyroid Carcinoma
AU - Henderson, Ying C.
AU - Mohamed, Abdallah S.R.
AU - Maniakas, Anastasios
AU - Chen, Yunyun
AU - Powell, Reid T.
AU - Peng, Shaohua
AU - Cardenas, Maria
AU - Williams, Michelle D.
AU - Bell, Diana
AU - Zafereo, Mark E.
AU - Wang, Rui Jennifer
AU - Scherer, Steve E.
AU - Wheeler, David A.
AU - Cabanillas, Maria E.
AU - Hofmann, Marie Claude
AU - Johnson, Faye M.
AU - Stephan, Clifford C.
AU - Sandulache, Vlad
AU - Lai, Stephen Y.
N1 - Publisher Copyright:
© 2021 The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
PY - 2021/10/1
Y1 - 2021/10/1
N2 - 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.
AB - 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.
KW - (PDX) model
KW - LBH-589
KW - anaplastic thyroid carcinoma
KW - high-throughput screening
KW - patient-derived xenograft
UR - http://www.scopus.com/inward/record.url?scp=85117228153&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85117228153&partnerID=8YFLogxK
U2 - 10.1210/clinem/dgab424
DO - 10.1210/clinem/dgab424
M3 - Article
C2 - 34120183
AN - SCOPUS:85117228153
SN - 0021-972X
VL - 106
SP - 2962
EP - 2978
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 10
ER -