Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal.
Research Institute for Medicines (iMed), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal.
Int J Mol Sci. 2022 May 11;23(10):5351. doi: 10.3390/ijms23105351.
One of the biggest challenges in neuro-oncology is understanding the complexity of central nervous system tumors, such as gliomas, in order to develop suitable therapeutics. Conventional therapies in malignant gliomas reconcile surgery and radiotherapy with the use of chemotherapeutic options such as temozolomide, chloroethyl nitrosoureas and the combination therapy of procarbazine, lomustine and vincristine. With the unraveling of deregulated cancer cell signaling pathways, targeted therapies have been developed. The most affected signaling pathways in glioma cells involve tyrosine kinase receptors and their downstream pathways, such as the phosphatidylinositol 3-kinases (PI3K/AKT/mTOR) and mitogen-activated protein kinase pathways (MAPK). MAPK pathway inhibitors include farnesyl transferase inhibitors, Ras kinase inhibitors and mitogen-activated protein extracellular regulated kinase (MEK) inhibitors, while PI3K/AKT/mTOR pathway inhibitors are divided into pan-inhibitors, PI3K/mTOR dual inhibitors and AKT inhibitors. The relevance of the immune system in carcinogenesis has led to the development of immunotherapy, through vaccination, blocking of immune checkpoints, oncolytic viruses, and adoptive immunotherapy using chimeric antigen receptor T cells. In this article we provide a comprehensive review of the signaling pathways underlying malignant transformation, the therapies currently used in the treatment of malignant gliomas and further explore therapies under development, including several ongoing clinical trials.
神经肿瘤学面临的最大挑战之一是理解中枢神经系统肿瘤（如神经胶质瘤）的复杂性，以便开发出合适的治疗方法。恶性神经胶质瘤的常规治疗方法是将手术、放疗与化疗选择（如替莫唑胺、氯乙基硝脲类药物以及丙卡巴肼、洛莫司汀和长春新碱的联合治疗）相结合。随着失调的癌细胞信号通路的阐明，靶向治疗已经得到了发展。在神经胶质瘤细胞中受影响最严重的信号通路涉及酪氨酸激酶受体及其下游通路，如磷脂酰肌醇 3-激酶（PI3K/AKT/mTOR）和丝裂原激活蛋白激酶通路（MAPK）。MAPK 通路抑制剂包括法呢基转移酶抑制剂、Ras 激酶抑制剂和丝裂原激活蛋白细胞外调节激酶（MEK）抑制剂，而 PI3K/AKT/mTOR 通路抑制剂分为泛抑制剂、PI3K/mTOR 双重抑制剂和 AKT 抑制剂。免疫系统在致癌作用中的相关性导致了免疫疗法的发展，包括疫苗接种、免疫检查点阻断、溶瘤病毒和嵌合抗原受体 T 细胞的过继免疫疗法。在本文中，我们全面回顾了恶性转化的信号通路、目前用于治疗恶性神经胶质瘤的治疗方法，并进一步探讨了正在开发的治疗方法，包括几项正在进行的临床试验。
