Modeling germline mutations in pineoblastoma uncovers lysosome disruption-based therapy
Philip E D Chung1,2, Deena M A Gendoo3, Ronak Ghanbari-Azarnier1,2
1Toronto General Research Institute, University Health Network, 67 College Street, Toronto, ON, M5G 2M1, Canada.
Abstract:
Pineoblastoma is a rare pediatric cancer induced by germline mutations in the tumor suppressors RB1 or DICER1. Presence of leptomeningeal metastases is indicative of poor prognosis. Here we report that inactivation of Rb plus p53 via a WAP-Cre transgene, commonly used to target the mammary gland during pregnancy, induces metastatic pineoblastoma resembling the human disease with 100% penetrance. A stabilizing mutation rather than deletion of p53 accelerates metastatic dissemination. Deletion of Dicer1 plus p53 via WAP-Cre also predisposes to pineoblastoma, albeit with lower penetrance. In silico analysis predicts tricyclic antidepressants such as nortriptyline as potential therapeutics for both pineoblastoma models. Nortriptyline disrupts the lysosome, leading to accumulation of non-functional autophagosome, cathepsin B release and pineoblastoma cell death. Nortriptyline further synergizes with the antineoplastic drug gemcitabine to effectively suppress pineoblastoma in our preclinical models, offering new modality for this lethal childhood malignancy.
Insights
Researchers developed mouse models of metastatic pineoblastoma by inactivating Rb and p53 tumor suppressors. The drug nortriptyline showed promise in treating this rare pediatric cancer, especially when combined with gemcitabine.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Pineoblastoma is a rare pediatric cancer often linked to germline mutations in RB1 or DICER1.
- Leptomeningeal metastases are associated with a poor prognosis in pineoblastoma patients.
Purpose of the Study:
- To establish preclinical models of metastatic pineoblastoma.
- To identify potential therapeutic strategies for pineoblastoma.
Main Methods:
- Inactivation of Rb and p53 tumor suppressors using a WAP-Cre transgene in mice.
- In silico analysis to predict potential drug candidates.
- Evaluation of nortriptyline and gemcitabine in preclinical pineoblastoma models.
Main Results:
- Inactivation of Rb plus p53 induced metastatic pineoblastoma with 100% penetrance.
- A stabilizing p53 mutation accelerated metastatic spread compared to p53 deletion.
- Deletion of Dicer1 plus p53 also led to pineoblastoma, but with lower penetrance.
- In silico analysis identified nortriptyline as a potential therapeutic.
- Nortriptyline demonstrated efficacy by disrupting lysosomes and inducing pineoblastoma cell death.
- Nortriptyline synergized with gemcitabine to suppress pineoblastoma in preclinical models.
Conclusions:
- The developed mouse models accurately recapitulate human metastatic pineoblastoma.
- Nortriptyline shows therapeutic potential for pineoblastoma, acting via lysosomal disruption.
- Combination therapy with nortriptyline and gemcitabine offers a promising new treatment strategy for this lethal childhood malignancy.
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