Leveraging Medulloblastoma Clonal Dynamics to Overcome Treatment Resistance

Area of Science:

• Oncology
• Pediatric Neuro-oncology
• Molecular Biology

Background:

• Group 3 medulloblastoma is an aggressive pediatric brain tumor with poor outcomes.
• B cell-specific Moloney murine leukemia virus insertion site 1 (BMI1) inhibitors show efficacy but are insufficient alone.
• Previous studies established BMI1 inhibition as a therapeutic strategy for medulloblastoma.

Purpose of the Study:

• To investigate the in vivo clonal dynamics of group 3 medulloblastoma under BMI1 inhibition.
• To identify novel therapeutic vulnerabilities in treatment-refractory medulloblastoma.
• To explore synergistic combinations with BMI1 inhibitor PTC596.

Main Methods:

• Preclinical validation of BMI1 inhibitor PTC596.
• DNA barcoding to profile in vivo clonal dynamics.
• Phosphoproteomic profiling and genome-wide CRISPR screening to identify vulnerabilities.
• Targeting of identified pathways like PI3K.

Main Results:

• Demonstrated treatment-refractory clones in group 3 medulloblastoma.
• Identified context-specific regulators of mTOR, AKT, and PLK1 pathways.
• Synergistic targeting of the PI3K pathway with enzastaurin alongside BMI1 inhibition was most effective.

Conclusions:

• BMI1 inhibition combined with PI3K pathway targeting offers a promising strategy.
• This approach may improve remission durability and survival for patients with refractory medulloblastoma.
• Foundation laid for clinical validation of synergistic inhibitors.