Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain [1][2][3][4] . Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage [5][6][7][8] . By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL 9,10 . However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage 3,4 . Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTX and OTX2. CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental

The extensive heterogeneity both between and within the medulloblastoma subgroups underscores a critical need for variant-specific biomarkers and therapeutic strategies. We previously identified a role for the CD271/p75 neurotrophin receptor (p75NTR) in regulating stem/progenitor cells in the SHH medulloblastoma subgroup. Here, we demonstrate the utility of CD271 as a novel diagnostic and prognostic marker for SHH medulloblastoma using IHC analysis and transcriptome data across 763 primary tumors. RNA sequencing of CD271 and CD271 cells revealed molecularly distinct, coexisting cellular subsets, both and MAPK/ERK signaling was upregulated in the CD271 population, and inhibiting this pathway reduced endogenous CD271 levels, stem/progenitor cell proliferation, and cell survival as well as cell migration Treatment with the MEK inhibitor selumetinib extended survival and reduced CD271 levels, whereas, treatment with vismodegib, a well-known smoothened (SMO) inhibitor currently in clinical trials for the treatment of recurrent SHH medulloblastoma, had no significant effect in our models. Our study demonstrates the clinical utility of CD271 as both a diagnostic and prognostic tool for SHH medulloblastoma tumors and reveals a novel role for MEK inhibitors in targeting CD271 SHH medulloblastoma cells. This study identifies CD271 as a specific and novel biomarker of SHH-type medulloblastoma and that targeting CD271 cells through MEK inhibition represents a novel therapeutic strategy for the treatment of SHH medulloblastoma. .

Medulloblastoma (MB) is the most common primary malignant pediatric brain cancer. We recently identified novel roles for the MEK/MAPK pathway in regulating human Sonic Hedgehog (SHH) MB tumorigenesis. The MEK inhibitor, selumetinib, decreased SHH MB growth while extending survival in mouse models. However, the treated mice ultimately succumbed to disease progression. Here, we perform RNA sequencing on selumetinib-treated orthotopic xenografts to identify molecular pathways that compensate for MEK inhibition specifically in vivo. Notably, the JAK/STAT3 pathway exhibits increased activation in selumetinib-treated tumors. The combination of selumetinib and the JAK/STAT3 pathway inhibitor, pacritinib, further reduces growth in two xenograft models and also enhances survival. Multiplex spatial profiling of proteins in drug-treated xenografts reveals shifted molecular dependencies and compensatory changes following combination drug treatment. Our study warrants further investigation into MEK and JAK/STAT3 inhibition as a novel combinatory therapeutic strategy for SHH MB.

No abstract

s iv40NEURO-ONCOLOGY • JUNE 2017 Cytosine (NAC), the fragmented mitochondrial morphology was rescued to their fused morphology. NADPH Oxidase 4 (NOX4) is a known producer of ROS in cells. When we treated CGNPs with apocynin, an NADPH oxidase inhibitor, a significant reduction in proliferation was observed. NOX4 was also found to localise in the peri-vascular niche in SmoA1 tumors. This could have possible implications for a role of ROS in promoting the proliferation of tumor re-populating cells post irradiation. Our goal is to determine if manipulating ROS-mediated mitochondrial dynamics can restore the metabolic profile of tumor cells to that of non-transformed, non-proliferating cells. This would suggest a potential novel treatment paradigm for medulloblastoma that may reduce the requirement for high dose radiation.