Noch Evan K, Ramakrishna Rohan, Magge Rajiv
Department of Neurology, Weill Cornell Medical College, New York, New York, USA.
Department of Neurological Surgery, Weill Cornell Medical College, New York, New York, USA.
World Neurosurg. 2018 Aug;116:505-517. doi: 10.1016/j.wneu.2018.04.022.
Glioblastoma is one of the most lethal human cancers, with poor survival despite surgery, radiation treatment, and chemotherapy. Advances in the treatment of this type of brain tumor are limited because of several resistance mechanisms. Such mechanisms involve limited drug entry into the central nervous system compartment by the blood-brain barrier and by actions of the normal brain to counteract tumor-targeting medications. In addition, the vast heterogeneity in glioblastoma contributes to significant therapeutic resistance by preventing adequate control of the entire tumor mass by a single drug and by facilitating escape mechanisms from targeted agents. The stem cell-like characteristics of glioblastoma promote resistance to chemotherapy, radiation, and immunotherapy through upregulation of efflux transporters, promotion of glioblastoma stem cell proliferation in neurogenic zones, and immune suppression, respectively. Metabolic cascades in glioblastoma prevent effective treatments through the optimization of glucose use, the use of alternative nutrient precursors for energy production, and the induction of hypoxia to enhance tumor growth. In the era of precision medicine, an assortment of molecular techniques is being developed to target an individual's unique tumor, with the hope that this personalized strategy will bypass therapeutic resistance. Although each resistance mechanism presents an array of challenges to effective treatment of glioblastoma, as the field recognizes and addresses these difficulties, future treatments may have more efficacy and promise for patients with glioblastoma.
胶质母细胞瘤是最致命的人类癌症之一，尽管进行了手术、放射治疗和化疗，患者的生存率仍很低。由于多种耐药机制，这种类型的脑肿瘤治疗进展有限。这些机制包括血脑屏障限制药物进入中枢神经系统，以及正常脑组织对肿瘤靶向药物的抵抗作用。此外，胶质母细胞瘤的巨大异质性导致显著的治疗耐药性，这是因为单一药物无法充分控制整个肿瘤块，并且肿瘤具有逃避靶向药物作用的机制。胶质母细胞瘤的干细胞样特征分别通过上调外排转运蛋白、促进胶质母细胞瘤干细胞在神经发生区增殖以及免疫抑制，从而促进对化疗、放疗和免疫治疗的耐药性。胶质母细胞瘤中的代谢级联反应通过优化葡萄糖利用、利用替代营养前体进行能量产生以及诱导缺氧以促进肿瘤生长，从而阻碍有效治疗。在精准医学时代，正在开发各种分子技术来针对个体独特的肿瘤，希望这种个性化策略能够绕过治疗耐药性。尽管每种耐药机制都给胶质母细胞瘤的有效治疗带来了一系列挑战，但随着该领域认识到并解决这些困难，未来的治疗可能对胶质母细胞瘤患者更有效且更有前景。
