Ubiquitin proteasome-mediated protein degradation has been implicated in posttranslational oncogenesis in medulloblastoma. Current research is evaluating the clinical implications of proteasome inhibition as a therapeutic target. In medulloblastoma cell lines, proteasome inhibitors induce apoptosis and inhibit cell proliferation via multiple pathways involving activation of caspase pathways, NFκB (nuclear factor kappalightchain-enhancer of activated B cells) pathway inhibition, reduced AKT/mTOR pathway activity, and proapoptotic protein expression. Second-generation proteasome inhibitors demonstrate blood-brain barrier penetration while maintaining antitumor effect. This review summarizes the ubiquitin-proteasome system in the pathogenesis of medulloblastoma and the potential clinical implications.
Background Ewing sarcoma (EWS) is a rare type of pediatric bone and soft tissue tumor that accounts for approximately 1% of all pediatric malignancies. It most commonly occurs in the long bones or axial skeleton, and rarely includes extraosseous sites or intracranial involvement. Reports of primary intracranial EWS are minimal. Pediatric intracranial EWS is even more rare with less than 15 cases reported. Case Description We describe the case of primary intracranial EWS in a 12 month old male. The patient’s initial MRI showed a large heterogeneous supratentorial cystic and solid mass centered in the right parietal region measuring 9.1cm x10.3cm x 7.6cm. No distant metastases were detected. The patient underwent surgical resection and pathology was consistent with a small round blue cell tumor. Further pathological evaluation revealed presence of EWSR1-FLI1 fusion and was negative for CD99, GFAP, synaptophysin, Olig2, desmin, and CAM5.2. Stains for INI1 and BRG1 were retained. The patient was treated with adjuvant chemotherapy and focal proton beam radiation (as per AEWS0031). Conclusion Primary intracranial Ewing Sarcoma is a rare pediatric brain tumor and, to our knowledge, this would be the youngest reported case to date. This case demonstrates the successful application of a sarcoma-based regimen to a primary intracranial EWS tumor with no evidence of residual tumor on MRI at 8 months into treatment. Future studies should be directed at understanding the biology of these rare tumors and optimizing treatment approaches.
BACKGROUND: Brain tumors are the second most common type of pediatric cancer and the leading cause of all cancer-related deaths in children. Medulloblastoma (MB) is the most common type of malignant pediatric brain tumor and has a five-year overall survival ranging from 40-75%, depending on the patient’s age and other prognostic features. There are various anti-cancer therapies against medulloblastoma, but the treatment of recurrent and refractory disease remains a challenge. As a result, the need for new and novel therapies remain a top priority. One area of interest in CNS tumors are targets within mitochondria. Magmas overexpression has been reported in multiple types of metabolically active tissue and cancer cells, including prostate cancer, pituitary adenoma, and glioma. Some new data suggest that specific subgroups of medulloblastoma may also overexpress Magmas. This ongoing study aims to examine whether Magmas inhibition by compound “BT9” could be beneficial in the treatment of medulloblastoma. METHODS: We continue to study the ability of a Magmas inhibitor (BT#9) as a therapeutic agent in stable medulloblastoma cell lines and patient-derived primary cultures by performing MTT assays, tunnel assays, flow cytometry, migration assays, and invasion assays. RESULTS: Similar to the adult GBM studies, Magmas inhibition by BT#9 had significant cytotoxic effects, causing both decreased cell proliferation, increased apoptosis, and blocked cell migration in medulloblastoma cell lines DAOY, D283, and D425. IC50s determined for each during different time points demonstrated an average range 2-5μM compared to the average range seen in adult glioblastoma cell cultures which could range up to 10 μM. These findings suggest that the inhibition of Magmas could potentially optimize clinical outcomes in recurrent/refractory medulloblastoma and warrants further investigation. Our future studies will include the determination of IC50s for primary cell cultures and in vitro testing with patient-derived xenograft models.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.