Wang Yuekun, Long Piaopiao, Wang Yu, Ma Wenbin
Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Front Oncol. 2020 Nov 30;10:593578. doi: 10.3389/fonc.2020.593578. eCollection 2020.
Glioblastoma multiforme (GBM) is the most common primary central nervous (CNS) system malignancy with a poor prognosis. The standard treatment for GBM is neurosurgical resection, followed by radiochemotherapy and adjuvant temozolomide chemotherapy. Predictive biomarkers, such as methylation of the promoter region of the O6-methylguanine DNA methyltransferase (MGMT) gene, can successfully distinguish subgroups with different prognosis after temozolomide chemotherapy. Based on multiomics studies, epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), BRAF V600E mutation, neurotrophic tyrosine receptor kinase (NTRK) fusions and other potential therapy targets have been found.
We have reviewed the preclinical and clinical evidence for NTRK fusions and TRK inhibitors therapy in cancers with NTRK fusions in pan-cancer and gliomas.
Several NTRK1/2/3 fusions have been reported in GBM and preclinical studies have proven that NTRK fusions are potential driver mutations in some high-grade gliomas. Tropomyosin receptor kinase (TRK) inhibitors have shown efficacy as targeted therapies for extracranial tumors with NTRK fusions in recent clinical trials, with potential CNS tolerability and activity. However, whether NTRK gene fusions can affect survival status, the efficacy and resistance of TRK inhibitors in GBMs are lacking high-level evidences.
For GBM patients, NTRK fusions and TRK inhibitors are potential target therapy strategy but remain biological mechanism and clinical significance unclarified. More clinical data and future clinical trials are needed to provide more evidence that supports targeted therapy for GBM with NTRK fusions.
多形性胶质母细胞瘤（GBM）是最常见的原发性中枢神经系统（CNS）恶性肿瘤，预后较差。GBM的标准治疗方法是神经外科手术切除，随后进行放化疗和辅助替莫唑胺化疗。预测性生物标志物，如O6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）基因启动子区域的甲基化，可成功区分替莫唑胺化疗后预后不同的亚组。基于多组学研究，已发现表皮生长因子受体（EGFR）、血管内皮生长因子（VEGF）、BRAF V600E突变、神经营养性酪氨酸受体激酶（NTRK）融合等潜在治疗靶点。
我们回顾了NTRK融合及TRK抑制剂在泛癌和胶质瘤中NTRK融合癌症治疗的临床前和临床证据。
在GBM中已报道了几种NTRK1/2/3融合，临床前研究已证明NTRK融合是一些高级别胶质瘤中的潜在驱动突变。原肌球蛋白受体激酶（TRK）抑制剂在最近的临床试验中已显示出对具有NTRK融合的颅外肿瘤的靶向治疗效果，具有潜在的中枢神经系统耐受性和活性。然而，NTRK基因融合是否会影响生存状态，TRK抑制剂在GBM中的疗效和耐药性缺乏高水平证据。
对于GBM患者，NTRK融合和TRK抑制剂是潜在的靶向治疗策略，但生物学机制和临床意义仍不明确。需要更多的临床数据和未来的临床试验来提供更多证据支持针对GBM中NTRK融合的靶向治疗。
