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Abstract
PURPOSE:
New strategies to restore sodium iodide symporter (NIS) expression and function in radioiodine therapy-refractive anaplastic thyroid cancers (ATCs) are urgently required. Recently, we reported the regulatory role of estrogen-related receptor gamma (ERRγ) in ATC cell NIS function. Herein, we identified DN200434 as a highly potent (functional IC50 = 0.006 μM), selective, and orally available ERRγ inverse agonist for NIS enhancement in ATC.

EXPERIMENTAL DESIGN:
We sought to identify better ERRγ-targeting ligands and explored the crystal structure of ERRγ in complex with DN200434. After treating ATC cells with DN200434, the change in iodide-handling gene expression as well as radioiodine avidity was examined. ATC tumor-bearing mice were orally administered with DN200434, followed by 124I-positron emission tomography/computed tomography (PET/CT). For radioiodine therapy, ATC tumor-bearing mice treated with DN200434 were administered 131I (beta ray-emitting therapeutic radioiodine) and then bioluminescent imaging was performed to monitor the therapeutic effects. Histological analysis was performed to evaluate ERRγ expression status in normal tissue and ATC tissue, respectively.

RESULTS:
DN200434-ERRγ complex crystallographic studies revealed that DN200434 binds to key ERRγ binding pocket residues through four-way interactions. DN200434 effectively upregulated iodide-handling genes and restored radioiodine avidity in ATC tumor lesions, as confirmed by 124I-PET/CT. DN200434 enhanced ATC tumor radioiodine therapy susceptibility, markedly inhibiting tumor growth. Histological findings of patients with ATC showed higher ERRγ expression in tumors than in normal tissue, supporting ERRγ as a therapeutic target for ATC.

CONCLUSIONS:
DN200434 shows potential clinical applicability for diagnosis and treatment of ATC or other poorly differentiated thyroid cancers.

Author information

Singh TD1, Song J2, Kim J3, Chin J4, Ji HD5, Lee JE3, Lee SB3, Yoon H3, Yu JH3, Kim SK6, Yoon GS7, Hwang H8, Lee HW9, Oh JM10, Lee SW11, Lee J11, Choi HS12, Na SY13, Choi WI14, Park YJ15, Song YS16, Kim YA17, Lee IK18, Cho SJ4, Jeon YH19.
1
All India Institute of Medical Sciences.
2
Structural analysis, Daegu-Gyeongbuk Medical Innovation Foundation.
3
Daegu-Gyeongbuk Medical Innovation Foundation.
4
New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation.
5
Kyungpook National University Hospital.
6
Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation.
7
Pathology, Kyungpook National University School of Medicine.
8
New drug development center, Daegu-Gyeongbuk Medical Innovation Foundation.
9
Department of Nuclear Medicine, School of Medicine, Kyungpook National University Hospital.
10
Department of Nuclear Medicine, Kyungpook National University School of Medicine and Hospital.
11
Department of Nuclear Medicine, School of Medicine, Kyungpook National University.
12
School of Biological Sciences and Technology, Chonnam National University.
13
School of Biological Sciences and Technology, Chonnam National University, National Creative Research Initiatives Center for Nuclear Receptor Signals.
14
Biochemistry and Molecular Biology, Yonsei University College of Medicine.
15
Internal Medicine, Seoul National University College of Medicine.
16
Internal Medicine, Seoul National University Hospital.
17
Departments of Pathology, Seoul National University Boramae Medical Center.
18
Department of Internal Medicine, Kyungpook National University School of Medicine.
19
Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation jeon9014@gmail.com.