College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Ministry of National Guard-Health Affairs, Riyadh 11426, Saudi Arabia.
King Abdullah International Medical Research Center, Department of Cellular Therapy and Cancer Research, King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), Ministry of National Guard-Health Affairs, Riyadh 11426, Saudi Arabia.
Int J Mol Sci. 2021 Dec 31;23(1):464. doi: 10.3390/ijms23010464.
Medulloblastoma is a common fatal pediatric brain tumor. More treatment options are required to prolong survival and decrease disability. mTOR proteins play an essential role in the disease pathogenesis, and are an essential target for therapy. Three generations of mTOR inhibitors have been developed and are clinically used for immunosuppression and chemotherapy for multiple cancers. Only a few mTOR inhibitors have been investigated for the treatment of medulloblastoma and other pediatric tumors. The first-generation mTOR, sirolimus, temsirolimus, and everolimus, went through phase I clinical trials. The second-generation mTOR, AZD8055 and sapanisertib, suppressed medulloblastoma cell growth; however, limited studies have investigated possible resistance pathways. No clinical trials have been found to treat medulloblastoma using third-generation mTOR inhibitors. This systematic review highlights the mechanisms of resistance of mTOR inhibitors in medulloblastoma and includes IDO1, T cells, Mnk2, and eIF4E, as they prolong malignant cell survival. The findings promote the importance of combination therapy in medulloblastoma due to its highly resistant nature.
髓母细胞瘤是一种常见的致命性小儿脑肿瘤。需要更多的治疗选择来延长生存期并减少残疾。mTOR 蛋白在疾病发病机制中起着至关重要的作用，是治疗的重要靶点。已经开发了三代 mTOR 抑制剂，临床上用于多种癌症的免疫抑制和化疗。只有少数 mTOR 抑制剂被用于治疗髓母细胞瘤和其他小儿肿瘤。第一代 mTOR 雷帕霉素、替西罗莫司和依维莫司已经进行了 I 期临床试验。第二代 mTOR，AZD8055 和 sapanisertib，抑制髓母细胞瘤细胞生长；然而，对可能的耐药途径的研究有限。没有发现使用第三代 mTOR 抑制剂治疗髓母细胞瘤的临床试验。本系统综述强调了 mTOR 抑制剂在髓母细胞瘤中的耐药机制，包括 IDO1、T 细胞、Mnk2 和 eIF4E，因为它们延长了恶性细胞的存活时间。这些发现由于髓母细胞瘤的高度耐药性，促进了联合治疗的重要性。
