Metastatic group 3 medulloblastoma is driven by PRUNE1 targeting NME1-TGF-β-OTX2-SNAIL via PTEN inhibition

Area of Science:

• * Pediatric oncology
• * Molecular biology
• * Cancer genetics

Background:

• * Paediatric medulloblastoma groups 3 and 4 exhibit high metastatic potential and poor survival due to genetic alterations.
• * PRUNE1 is overexpressed in metastatic medulloblastoma group 3, correlating with TGF-β signaling activation, c-MYC amplification, and OTX2 expression.

Purpose of the Study:

• * To elucidate the PRUNE1 signaling pathway activation in metastatic medulloblastoma.
• * To investigate the therapeutic potential of targeting the PRUNE1 pathway with novel small molecules and peptides.

Main Methods:

• * Analysis of PRUNE1 pathway activation, including interactions with NME1, TGF-β, OTX2, SNAIL, and PTEN.
• * Preclinical evaluation of a pyrimido-pyrimidine derivative (AA7.1) and a PRUNE1/NME1 inhibitory peptide in orthotopic xenograft models using D425-Med cells.
• * Whole exome sequencing of metastatic medulloblastoma primary tumors to identify common deleterious gene variants.

Main Results:

• * Detailed the PRUNE1 activation cascade: PRUNE1/NME1 binding, TGF-β activation, OTX2 and SNAIL upregulation, and PTEN inhibition.
• * AA7.1 demonstrated efficacy by enhancing PRUNE1 degradation, inhibiting the pathway, and increasing PTEN expression.
• * Both AA7.1 and the peptide significantly reduced tumor growth and metastatic spread in preclinical models.
• * Identified 23 common homozygous deleterious gene variants in metastatic medulloblastoma.

Conclusions:

• * The PRUNE1/TGF-β/OTX2/PTEN axis is a critical driver of metastasis in medulloblastoma group 3.
• * Targeting this axis with agents like AA7.1 holds promise for developing novel, targeted therapies for metastatic medulloblastoma.
• * Understanding medulloblastoma-driver mutations alongside pathway analysis is crucial for future therapeutic strategies.