Modeling germline mutations in pineoblastoma uncovers lysosome disruption-based therapy

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.