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Published on: March 30, 2019
An organoid-based drug screening identified a menin-MLL inhibitor for endometrial cancer through regulating the HIF
Jingyao Chen1, Lei Zhao1, Hongling Peng2
1Department of Thoracic Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
Abstract:
Tumor organoids recapitulate pathological properties and would serve as an excellent ex vivo model for drug discovery. Here, we performed an unbiased drug screening on drivers-defined tumor organoids from mouse endometrial cancer, the most prevalent gynecological malignancy in human, with a small molecule library targeting epigenetic factors. Among them, menin-MLL inhibitors MI-136 and MI-463 scored. The therapeutic capacity of MI-136 was further validated in tumor organoids in vitro and an orthotopic model in vivo. CRISPR/cas9-mediated mutations of major components of the menin-MLL complex, Men1, Kmt2a and Ash2l, inhibited the growth of tumor organoids, suggesting that the complex was the target of MI-136. Transcriptome analysis showed that the hypoxia-inducible factor (HIF) pathway was the most significantly downregulated pathway by MI-136 treatment. Consistently, Men1, Kmt2a, and Ash2l knockout also repressed the expressions of the HIF target genes. Loss of Hif1a or Hif1b partially phenocopied the inhibition of the menin-MLL complex by MI-136 or mutations in term of tumor organoid growth. Further, we found that MEN1 was upregulated in human endometrial cancers, which were tightly correlated with the expression levels of HIF1A, and associated with poor prognosis. Importantly, MI-136 also significantly inhibited the growth of endometrial cancer organoids derived from patients. Thus, our study identified MI-136 as a potential inhibitor for endometrial cancer through regulating the HIF pathway, a novel molecular mechanism distinguished from those in AML and prostate cancer.
Insights
Menin-MLL inhibitors like MI-136 show promise for treating endometrial cancer. This epigenetic therapy targets the hypoxia-inducible factor (HIF) pathway, offering a novel therapeutic strategy for this prevalent gynecological malignancy.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Endometrial cancer is the most common gynecological malignancy.
- Tumor organoids offer a valuable ex vivo model for studying cancer pathology and drug discovery.
- Epigenetic factors play a crucial role in cancer development and progression.
Purpose of the Study:
- To identify novel therapeutic targets and drugs for endometrial cancer using an unbiased drug screening approach.
- To investigate the therapeutic potential of menin-MLL inhibitors in endometrial cancer models.
- To elucidate the molecular mechanism underlying the anti-cancer effects of MI-136.
Main Methods:
- Unbiased drug screening of a small molecule library targeting epigenetic factors on mouse endometrial cancer organoids.
- In vitro and in vivo validation of MI-136 efficacy using tumor organoids and orthotopic models.
- CRISPR/cas9-mediated gene knockout of menin-MLL complex components (Men1, Kmt2a, Ash2l).
- Transcriptome analysis to identify molecular pathways affected by MI-136 treatment.
- Analysis of MEN1 and HIF1A expression in human endometrial cancer tissues.
Main Results:
- Menin-MLL inhibitors MI-136 and MI-463 demonstrated significant anti-cancer activity.
- MI-136 effectively inhibited tumor growth in vitro and in vivo.
- Disruption of the menin-MLL complex (Men1, Kmt2a, Ash2l) inhibited tumor organoid growth.
- MI-136 treatment and menin-MLL complex disruption led to significant downregulation of the hypoxia-inducible factor (HIF) pathway.
- Loss of Hif1a or Hif1b partially mimicked the effects of menin-MLL complex inhibition.
- MEN1 upregulation in human endometrial cancers correlated with HIF1A expression and poor prognosis.
- MI-136 inhibited patient-derived endometrial cancer organoids.
Conclusions:
- MI-136 is a potent inhibitor of endometrial cancer growth, acting through the regulation of the HIF pathway.
- The menin-MLL complex and the HIF pathway represent novel therapeutic targets for endometrial cancer.
- MI-136 demonstrates potential as a targeted therapy for endometrial cancer, with a distinct mechanism of action compared to its use in AML and prostate cancer.
