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Updated: Jan 7, 2026
An Orthotopic Mouse Model of Anaplastic Thyroid Carcinoma
Published on: April 17, 2013
Organoid-based drug screening identifies homoharringtonine as a therapeutic agent for anaplastic thyroid cancer via
Xinyue Zhang1, Zhihui Li2, Jiaye Liu3
1Department of Nuclear Medicine, West China Hospital, Sichuan University, No 37. Guoxue Alley, Chengdu, 610000, China.
Purpose:
Anaplastic thyroid cancer (ATC) is a rare but aggressive malignancy with unmet clinical needs for novel therapeutic agents. Most prior studies have relied on limited ATC cell lines, which fail to recapitulate tumor heterogeneity. This study aimed to discover novel agent for ATC via patient-derived organoid (PDO)-based drug screening and investigate the underlying therapeutic mechanism.
Methods:
Drug screening was performed on ATC organoids using a drug library of stem cell differentiation compounds. RNA-sequencing identified pathway-level mechanisms, while structure-based molecular docking prioritized target proteins.
Results:
Using a library of stem cell differentiation compounds, we identified homoharringtonine (HHT) as a potent inhibitor for ATC growth in vitro and in vivo. Mechanistically, this effect was mediated by lysosomal dysfunction, which blocked autophagosome-lysosome fusion and triggered cytotoxicity. Furthermore, HHT exhibited high affinity for the PI3K p110 subunit, activating the PI3K-AKT-mTOR pathway to phosphorylate transcription factor EB, retaining it in the cytoplasm and thereby inhibiting lysosomal biogenesis.
Conclusion:
Our study demonstrates the utility of cancer organoids in drug discovery and identifies HHT as a promising therapeuticagent for ATC.
Insights
Patient-derived organoids identified homoharringtonine (HHT) as a potent drug for anaplastic thyroid cancer (ATC). HHT inhibits ATC growth by disrupting lysosomal function and activating the PI3K-AKT-mTOR pathway.
Area of Science:
- Oncology
- Drug Discovery
- Molecular Biology
Background:
- Anaplastic thyroid cancer (ATC) is a rare, aggressive malignancy with limited treatment options.
- Existing research often uses limited cell lines, failing to capture tumor heterogeneity.
Purpose of the Study:
- Discover novel therapeutic agents for ATC using patient-derived organoids (PDOs).
- Investigate the mechanism of action for identified therapeutic agents.
Main Methods:
- Drug screening of ATC PDOs with stem cell differentiation compounds.
- RNA-sequencing for pathway-level mechanism identification.
- Structure-based molecular docking to prioritize target proteins.
Main Results:
- Homoharringtonine (HHT) identified as a potent inhibitor of ATC growth in vitro and in vivo.
- HHT induces cytotoxicity via lysosomal dysfunction, blocking autophagosome-lysosome fusion.
- HHT targets the PI3K p110 subunit, activating the PI3K-AKT-mTOR pathway and inhibiting lysosomal biogenesis.
Conclusions:
- This study highlights the effectiveness of PDOs in drug discovery for rare cancers.
- HHT is identified as a promising therapeutic agent for anaplastic thyroid cancer.
