Abstract
Simple SummaryPhytocannabinoids Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) have been demonstrated to exhibit anti-cancer activity in preclinical models of brain cancer leading to new clinical trials for adults with glioblastoma. We describe here the first report that has investigated a role for THC and CBD in pediatric brain cancer. Cannabinoids had cytotoxic activity against medulloblastoma and ependymoma cells in vitro, functioning in part through the inhibition of cell cycle progression and the induction of autophagy. Despite these effects in vitro, when tested in orthotopic mouse models of medulloblastoma or ependymoma, no impact on animal survival was observed. Furthermore, cannabinoids neither enhanced nor impaired conventional chemotherapy in a medulloblastoma mouse model. These data show that while THC and CBD do have some effects on medulloblastoma and ependymoma cells, are well tolerated, and have minimal adverse effects, they do not appear to elicit any survival benefit in preclinical models of pediatric brain cancer.Children with medulloblastoma and ependymoma are treated with a multidisciplinary approach that incorporates surgery, radiotherapy, and chemotherapy; however, overall survival rates for patients with high-risk disease remain unsatisfactory. Data indicate that plant-derived cannabinoids are effective against adult glioblastoma; however, preclinical evidence supporting their use in pediatric brain cancers is lacking. Here we investigated the potential role for Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) in medulloblastoma and ependymoma. Dose-dependent cytotoxicity of medulloblastoma and ependymoma cells was induced by THC and CBD in vitro, and a synergistic reduction in viability was observed when both drugs were combined. Mechanistically, cannabinoids induced cell cycle arrest, in part by the production of reactive oxygen species, autophagy, and apoptosis; however, this did not translate to increased survival in orthotopic transplant models despite being well tolerated. We also tested the combination of cannabinoids with the medulloblastoma drug cyclophosphamide, and despite some in vitro synergism, no survival advantage was observed in vivo. Consequently, clinical benefit from the use of cannabinoids in the treatment of high-grade medulloblastoma and ependymoma is expected to be limited. This study emphasizes the importance of preclinical models in validating therapeutic agent efficacy prior to clinical trials, ensuring that enrolled patients are afforded the most promising therapies available.
Highlights
Pediatric medulloblastoma and ependymoma represent the first and third most common childhood brain malignancies, respectively [1]
These include the binding of the potential role for ∆9tetrahydrocannabinol (THC) to CB1R and CB2R, in addition to THC and CBD binding to a range of other cellular proteins including adenosine receptor, transient receptor potential (TRP) channels, peroxisome proliferator-activated receptors (PPARs), and other G-protein coupled receptors including GPR55 and GPR18 [33,34,35]
We aimed to determine if cannabinoids might be effective treatments against medulloblastoma and ependymoma and report here the first study that investigates THC and CBD for the treatment of pediatric brain cancers
Summary
Pediatric medulloblastoma and ependymoma represent the first and third most common childhood brain malignancies, respectively [1]. Current up-front treatment for medulloblastoma involves maximal safe surgical resection, followed by craniospinal irradiation and a combination of chemotherapeutic agents such as tubulin inhibitors and DNA alkylators [2]. The poorest survival rates are associated with MYC-amplified Group 3 or TP53-mutated SHH disease, highlighting the urgency for the development of novel therapies to improve survival rates for these medulloblastoma subtypes. No chemotherapeutic regimen has proven clinically beneficial in the treatment of pediatric ependymoma to date, results from ACNS0831 suggest that some patients may benefit from maintenance chemotherapy [9]. Complicating the current lack of safe and efficacious therapies, ependymal malignancies with similar histological grades exhibit genetic heterogeneity, leading to a diverse range of patient outcomes despite identical treatment strategies [10]. On the basis of transcriptomics and DNA methylation patterns, ependymoma has been delineated into multiple subgroups, of which posterior fossa A ependymoma (EPN_PFA) and C11orf fusion-positive ependymoma (formerly EPN_RELA, and recently renamed due to the identification of other fusion partners for C11orf95) predominate in children [11,12]
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