Mutant ACVR1 Arrests Glial Cell Differentiation to Drive Tumorigenesis in Pediatric Gliomas
Jerome Fortin1, Ruxiao Tian1, Ida Zarrabi1
1Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
Abstract:
Diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors for which there is currently no effective treatment. Some of these tumors combine gain-of-function mutations in ACVR1, PIK3CA, and histone H3-encoding genes. The oncogenic mechanisms of action of ACVR1 mutations are currently unknown. Using mouse models, we demonstrate that Acvr1G328V arrests the differentiation of oligodendroglial lineage cells, and cooperates with Hist1h3bK27M and Pik3caH1047R to generate high-grade diffuse gliomas. Mechanistically, Acvr1G328V upregulates transcription factors which control differentiation and DIPG cell fitness. Furthermore, we characterize E6201 as a dual inhibitor of ACVR1 and MEK1/2, and demonstrate its efficacy toward tumor cells in vivo. Collectively, our results describe an oncogenic mechanism of action for ACVR1 mutations, and suggest therapeutic strategies for DIPGs.
Insights
ACVR1 mutations drive pediatric Diffuse Intrinsic Pontine Gliomas (DIPGs) by halting cell differentiation. A dual ACVR1/MEK inhibitor, E6201, shows promise in treating these aggressive brain tumors.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors.
- Currently, no effective treatments exist for DIPGs.
- ACVR1 mutations are found in some DIPGs, but their oncogenic role is unclear.
Purpose of the Study:
- To elucidate the oncogenic mechanisms of ACVR1 mutations in DIPGs.
- To identify potential therapeutic strategies for DIPGs.
Main Methods:
- Utilized mouse models to study Acvr1G328V mutations.
- Investigated the cooperative effects of Acvr1G328V with Hist1h3bK27M and Pik3caH1047R.
- Characterized E6201 as a dual ACVR1 and MEK1/2 inhibitor.
Main Results:
- Acvr1G328V arrests oligodendroglial differentiation and cooperates with other mutations to form high-grade gliomas.
- Acvr1G328V upregulates transcription factors crucial for DIPG cell fitness.
- E6201 demonstrated efficacy against DIPG cells in vivo.
Conclusions:
- ACVR1 mutations contribute to DIPG development through specific oncogenic mechanisms.
- Targeting ACVR1 and MEK pathways presents a potential therapeutic avenue for DIPGs.
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