MRI-based machine learning designed with sequential decision steps reliably differentiated four unique medulloblastoma molecular subgroups. Background Radiogenomics of pediatric medulloblastoma (MB) offers an opportunity for MB risk stratification, which may aid therapeutic decision making, family counseling, and selection of patient g...

Of the 4 medulloblastoma subgroups, Group 3 is the most aggressive but the importance of angiogenesis is unknown. This study sought to determine the role of angiogenesis and identify clinically relevant biomarkers of tumor vascularity and survival in Group 3 medulloblastoma. VEGFA mRNA expression and survival from several patient cohorts were analyzed. Group 3 xenografts were implanted intracranially in nude rats. Dynamic susceptibility weighted (DSC) MRI and susceptibility weighted imaging (SWI) were obtained. DSC MRI was used to calculate relative cerebral blood volume (rCBV) and flow (rCBF). Tumor vessel density and rat vascular endothelial growth factor alpha (VEGFA) expression were determined. Patient VEGFA mRNA levels were significantly elevated in Group 3 compared with the other subgroups (P < 0.001) and associated with survival. Xenografts D283, D341, and D425 were identified as Group 3 by RNA hierarchical clustering and MYC amplification. The D283 group had the lowest rCBV and rCBF, followed by D341 and D425 (P < 0.05). These values corresponded to histological vessel density (P < 0.05), rat VEGFA expression (P < 0.05), and survival (P = 0.002). Gene set enrichment analysis identified 5 putative genes with expression profiles corresponding with these findings: RNH1, SCG2, VEGFA, AGGF1, and PROK2. SWI identified 3 xenograft-independent categories of intratumoral vascular architecture with distinct survival (P = 0.004): organized, diffuse microvascular, and heterogeneous. Angiogenesis plays an important role in Group 3 medulloblastoma pathogenesis and survival. DSC MRI and SWI are clinically relevant biomarkers for tumor vascularity and overall survival and can be used to direct the use of antivascular therapies for patients with Group 3 medulloblastoma.

Poliovirus oncolytic immunotherapy is a putatively novel approach to treat pediatric brain tumors. This work sought to determine expression of the poliovirus receptor (PVR), CD155, in low-grade and malignant pediatric brain tumors and its ability to infect, propagate, and inhibit cell proliferation. CD155 expression in pleomorphic xanthoastrocytoma (PXA), medulloblastoma, atypical teratoid rhabdoid tumor, primitive neuroectodermal tumor, and anaplastic ependymoma specimens was assessed. The ability of the polio: rhinovirus recombinant, PVSRIPO, to infect PXA (645 [BRAF V600E mutation], 2363) and medulloblastoma (D283, D341) cells were determined by viral propagation measurement and cell proliferation. PVR mRNA expression was evaluated in 763 medulloblastoma and 1231 normal brain samples. CD155 was expressed in all 12 patient specimens and in PXA and medulloblastoma cell lines. One-step growth curves at a multiplicity of infection of 10 demonstrated productive infection and peak plaque formation units at 5–10 hours. PVSRIPO infection significantly decreased cellular proliferation in 2363, 645, and D341 cell lines at 48 hours (p < 0.05) and resulted in cell death. PVR expression was highest in medulloblastoma subtypes Group 3γ, WNTα, and WNTβ (p < 0.001). This proof-of-concept in vitro study demonstrates that PVSRIPO is capable of infecting, propagating, prohibiting cell proliferation, and killing PXA and Group 3 medulloblastoma.

Medulloblastoma is a heterogeneous disease with at least four distinct molecular subgroups: wingless (WNT), sonic hedgehog (SHH), Group 3, and Group 4. Recently there has been considerable progress defining the molecular drivers and prognostic factors of each subgroup. However, this information has only rarely been used to stratify risk or impact treatment. The purpose of this work is to provide an update on current clinical trials that provide molecularly stratified treatment paradigms. A search was conducted on ClinicalTrials.gov using the following search terms: “medulloblastoma and subgroup”, “medulloblastoma and SHH”, “medulloblastoma and WNT”, and “medulloblastoma and Non-WNT/Non-SHH”. This search resulted in nine distinct clinical trials, five for newly diagnosed medulloblastoma and four for recurrent medulloblastoma. Four trials for newly diagnosed medulloblastoma had a component of craniospinal irradiation reduction for patients with WNT medulloblastoma. Molecularly stratified trials for recurrent medulloblastoma largely focus on SHH. As these trials are ongoing, there are limited data available. A trial in which newly-diagnosed WNT patients received modest chemotherapy without radiation has been closed to accrual due to several early failures. Phase II trials evaluating vismodegib for SHH medulloblastoma in children and adults have been disappointing. In conclusion, although there is an expanding array of clinical trials which incorporate molecular data in prescribing treatment for newly-diagnosed and recurrent medulloblastoma, treatments for these diseases are fairly uniform, with craniospinal radiation dose being the main variable. As the drivers of the distinct subgroups and their associated prognoses are better elucidated, future clinical trials and novel targeted agents are needed to improve outcomes and reduce toxicity where feasible.