Abstract
Pediatric brain tumors are the most common solid tumors in children and are also a leading culprit of cancer-related fatalities in children. Pediatric brain tumors remain hard to treat. In this study, we demonstrated that medulloblastoma, pediatric glioblastoma, and atypical teratoid rhabdoid tumors express significant levels of acid ceramidase, where levels are highest in the radioresistant tumors, suggesting that acid ceramidase may confer radioresistance. More importantly, we also showed that acid ceramidase inhibitors are highly effective at targeting these pediatric brain tumors with low IC50 values (4.6–50 μM). This data suggests acid ceramidase as a novel drug target for adjuvant pediatric brain tumor therapies. Of these acid ceramidase inhibitors, carmofur has seen clinical use in Japan since 1981 for colorectal cancers and is a promising drug to undergo further animal studies and subsequently a clinical trial as a treatment for pediatric patients with brain tumors.
Highlights
Malignant brain tumors are the most frequent solid tumors in the pediatric population; they constitute 20% to 30% of all pediatric cancers and represent the predominant cause of cancer-related deaths in childhood [1]
We demonstrated that medulloblastoma, pediatric glioblastoma, and atypical teratoid rhabdoid tumors express significant levels of acid ceramidase, where levels are highest in the radioresistant tumors, suggesting that acid ceramidase may confer radioresistance
We showed that acid ceramidase inhibitors are highly effective at targeting these pediatric brain tumors with low half maximal inhibitory concentration (IC50) values (4.6–50 μM)
Summary
Malignant brain tumors are the most frequent solid tumors in the pediatric population; they constitute 20% to 30% of all pediatric cancers and represent the predominant cause of cancer-related deaths in childhood [1]. We focus on three malignant brain tumors – atypical rhabdoid/teratoid tumor (ATRT), glioblastoma, and medulloblastoma. No guidelines exist for optimal treatment and different multimodal protocols are presently being studied to improve outcomes [2]. Most institutions employ surgery and adjuvant radiotherapy, but the role of chemotherapy remains investigational [3, 4]. Medulloblastoma has been the most studied with the best overall survival. The standard treatment is chemotherapy (adjuvant lomustine, vincristine, cyclophosphamide, and cisplatin) after reduceddose radiotherapy concomitantly with vincristine [1, 5,6,7]. Given the longer life expectancy, a key concern is the development of long-term toxicity associated with current treatment protocols [6, 8, 9]
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