DataSheet_1_BRAF Signaling Inhibition in Glioblastoma: Which Clinical Perspectives?.docx

IDH-wild type (wt) glioblastoma (GB) accounts for approximately 90% of all GB and has a poor outcome. Surgery and adjuvant therapy with temozolomide and radiotherapy is the main therapeutic approach. Unfortunately, after relapse and progression, which occurs in most cases, there are very limited therapeutic options available. BRAF which plays a role in the oncogenesis of several malignant tumors, is also involved in a small proportion of IDH-wt GB. Previous successes with anti-B-Raf targeted therapy in tumors with V600E BRAF mutation like melanoma, combined with the poor prognosis and paucity of therapeutic options for GB patients is leading to a growing interest in the potential efficacy of this approach. This review is thus focused on dissecting the state of the art and future perspectives on BRAF pathway inhibition in IDH-wt GB. Overall, clinical efficacy is mostly described within case reports and umbrella trials, with promising but still insufficient results to draw more definitive conclusions. Further studies are needed to better define the molecular and phenotypic features that predict for a favorable response to treatment. In addition, limitations of B-Raf-inhibitors, in monotherapy or in combination with other therapeutic partners, to penetrate the blood-brain barrier and the development of acquired resistance mechanisms responsible for tumor progression need to be addressed.

异柠檬酸脱氢酶野生型（IDH-wt）胶质母细胞瘤（GB）约占所有胶质母细胞瘤的90%，且预后极差。手术联合替莫唑胺辅助化疗与放射治疗是其主要治疗手段。遗憾的是，多数患者会出现复发与病情进展，此时可选择的治疗方案极为有限。BRAF在多种恶性肿瘤的癌变过程中发挥重要作用，在小比例IDH-wt胶质母细胞瘤中同样存在其介导的致癌通路。此前，针对BRAF V600E突变型肿瘤（如黑色素瘤）的抗BRAF靶向治疗已取得成功，加之胶质母细胞瘤患者预后不佳且治疗选择匮乏，使得学界对该疗法在胶质母细胞瘤中的潜在疗效愈发关注。因此，本综述旨在剖析IDH-wt胶质母细胞瘤中BRAF通路抑制疗法的研究现状与未来展望。总体而言，该疗法的临床疗效多来自个案报告与伞式临床试验，虽显示出一定潜力，但结果仍不足以得出确定性结论。仍需开展进一步研究，以明确可预测患者对治疗产生良好应答的分子与表型特征。此外，还需解决BRAF抑制剂单药或联合其他治疗方案时，难以穿透血脑屏障，以及肿瘤进展相关获得性耐药机制产生等问题。