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Updated: Jun 12, 2025
Ovarian Cancer Patient-Derived Organoid Models for Pre-Clinical Drug Testing
Published on: September 15, 2023
Developing patient-derived organoids to demonstrate JX24120 inhibits SAMe synthesis in endometrial cancer by
Chunxue Zhang1, Xiaojing Lu1, Ting Ni1
1Department of Gynecologic Oncology, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Shanghai Key Laboratory of Embryo Original Disease, Shanghai 200030, China.
Abstract:
Endometrial cancer (EC) is one of the most common gynecologic malignancies, which lacking effective drugs for intractable conditions or patients unsuitable for surgeries. Recently, the patient-derived organoids (PDOs) are found feasible for cancer research and drug discoveries. Here, we have successfully established a panel of PDOs from EC and conducted drug repurposing screening and mechanism analysis for cancer treatment. We confirmed that the regulatory β subunit of methionine adenosyltransferase (MAT2B) is highly correlated with malignant progression in endometrial cancer. Through drug screening on PDOs, we identify JX24120, chlorpromazine derivative, as a specific inhibitor for MAT2B, which directly binds to MAT2B (Kd = 4.724 μM) and inhibits the viability of EC PDOs and canonical cell lines. Correspondingly, gene editing assessment demonstrates that JX24120 suppresses tumor growth depending on the presence of MAT2B in vivo and in vitro. Mechanistically, JX24120 induces inhibition of S-adenosylmethionine (SAMe) synthesis, leading to suppressed mTORC1 signaling, abnormal energy metabolism and protein synthesis, and eventually apoptosis. Taken together, our study offers a novel approach for drug discovery and efficacy assessment by using the PDOs models. These findings suggest that JX24120 may be a potent MAT2B inhibitor and will hopefully serve as a prospective compound for endometrial cancer therapy.
Insights
Patient-derived organoids reveal JX24120, a MAT2B inhibitor, effectively targets endometrial cancer by disrupting SAMe synthesis and mTORC1 signaling, offering a new therapeutic avenue.
Area of Science:
- Gynecologic Oncology
- Cancer Therapeutics
- Drug Discovery
Background:
- Endometrial cancer (EC) presents challenges due to limited effective treatments for advanced or surgical-ineligible cases.
- Patient-derived organoids (PDOs) offer a promising platform for preclinical cancer research and drug development.
Purpose of the Study:
- To establish and utilize a panel of EC PDOs for drug repurposing and mechanistic studies.
- To identify novel therapeutic targets and compounds for endometrial cancer treatment.
Main Methods:
- Establishment of a diverse panel of endometrial cancer patient-derived organoids (EC PDOs).
- Drug repurposing screening using EC PDOs to identify potential therapeutic agents.
- In vitro and in vivo validation of drug efficacy and mechanism of action, including gene editing assessments.
- Biochemical assays to determine drug-target binding affinity and downstream signaling pathway inhibition.
Main Results:
- The regulatory β subunit of methionine adenosyltransferase (MAT2B) was identified as a key factor in EC malignant progression.
- JX24120, a chlorpromazine derivative, was identified as a specific MAT2B inhibitor with direct binding affinity (Kd = 4.724 μM).
- JX24120 demonstrated significant inhibition of EC PDO and cell line viability, dependent on MAT2B expression, and suppressed tumor growth in vivo.
- Mechanistically, JX24120 inhibits S-adenosylmethionine (SAMe) synthesis, leading to suppressed mTORC1 signaling, altered metabolism, impaired protein synthesis, and apoptosis.
Conclusions:
- EC PDOs provide a valuable model for drug discovery and efficacy evaluation.
- JX24120 is a potent inhibitor of MAT2B, showing promise as a novel therapeutic agent for endometrial cancer.
- Targeting MAT2B via JX24120 offers a potential new strategy for treating endometrial cancer by disrupting critical cellular pathways.
