Subgroup-Enriched Pathways and Kinase Signatures in Medulloblastoma Patient-Derived Xenografts

Medulloblastoma (MB) is the most common malignant pediatric
brain
tumor. MB is classified into four primary molecular subgroups: wingless
(WNT), sonic hedgehog (SHH), Group 3 (G3), and Group 4 (G4), and further
genomic and proteomic subtypes have been reported. Subgroup heterogeneity
and few actionable mutations have hindered the development of targeted
therapies, especially for G3 MB, which has a particularly poor prognosis.
To identify novel therapeutic targets for MB, we performed mass spectrometry-based
deep expression proteomics and phosphoproteomics in 20 orthotopic
patient-derived xenograft (PDX) models of MB comprising SHH, G3, and
G4 subgroups. We found that the proteomic profiles of MB PDX tumors
are closely aligned with those of primary human MB tumors illustrating
the utility of PDX models. SHH PDXs were enriched for NFκB and
p38 MAPK signaling, while G3 PDXs were characterized by MYC activity.
Additionally, we found a significant association between actinomycin
D sensitivity and increased abundance of MYC and MYC target genes.
Our results highlight several candidate pathways that may serve as
targets for new MB therapies. Mass spectrometry data are available
via ProteomeXchange with identifier PXD035070.