Department of Cell and Molecular Biology, QIMR Berghofer Medical Research Institute, Brisbane, 4006, Australia.
Faculty of Medicine, the University of Queensland, Brisbane, 4006, Australia.
Acta Neuropathol Commun. 2019 Jul 30;7(1):123. doi: 10.1186/s40478-019-0773-8.
BACKGROUND: Medulloblastoma (MB) is the most common malignant brain tumour in children but also rarely occur in adults. Sonic Hedgehog (SHH) driven MB is associated with aberrant activation of the SHH signalling pathway. SMO inhibitors, sonidegib and vismodegib, have been used as selective antagonist of the hedgehog pathway that acts by binding to SMO, and inhibits activation of the downstream hedgehog target genes. Several clinical trials investigating SMO inhibitors for the treatment of relapsed MB patients have been published. METHODS: We conducted a systemic review and meta-analysis among these Phase I and II clinical trials. The pooled effect of SMO inhibitors in relapsed MB were analysed using Reviewer Manager 5.3 software. The clinical efficacy of SMO inhibitors on SHH subtype of MB were measured by the objective response rate. The risk difference was obtained by comparing the ORR between SHH and non-SHH subtypes of MB. RESULTS: The five studies all had clear criteria for patient recruitment, adequate follow-up time for endpoint assessment and clear definition of tumour responses. MB patients had good compliance in the trials. The pooled objective response rate (ORR) of SMO inhibitor was 37% and 0 against SHH-driven and other MBs. The pooled ORR of sonidegib was 55% among MB and 0 among MB subgroup. Vismodegib also had no efficacy on non-SHH subtype of MB. The sonidegib against SHH-driven MB produced the ORR 1.87-fold higher than that of vismodegib (95%CI 1.23, 6.69). Among paediatric patients, the efficacy of sonidegib was 3.67-fold higher than vismodegib (p < 0.05). A total of 320 cases received SMO inhibitor therapy and 36 cases reported grade 3/4 dose-limiting toxicity (DLT). The rate of grade 3/4 DLT was similar between patients receiving vismodegib and sonidegib (11.6% vs. 11.2%). CONCLUSION: Sonidegib and vismodegib were well tolerated and demonstrated anti-tumour activity in SHH-driven paediatric and adult MB by effectively inhibiting Hh signalling. These results support the ongoing clinical trials using SMO inhibitors in combination with conventional chemotherapies for the treatment of relapsed MB.
背景：成神经管细胞瘤（MB）是儿童中最常见的恶性脑肿瘤，但也很少发生在成人中。由 Sonic Hedgehog（SHH）驱动的 MB 与 SHH 信号通路的异常激活有关。SMO 抑制剂，如 sonidegib 和 vismodegib，已被用作 Hedgehog 通路的选择性拮抗剂，通过与 SMO 结合并抑制 Hedgehog 下游靶基因的激活来发挥作用。已经发表了几项关于 SMO 抑制剂治疗复发性 MB 患者的临床试验。
方法：我们对这些 I 期和 II 期临床试验进行了系统评价和荟萃分析。使用 Reviewer Manager 5.3 软件分析 SMO 抑制剂在复发性 MB 中的汇总效果。通过客观缓解率来衡量 SMO 抑制剂对 SHH 亚型 MB 的临床疗效。通过比较 SHH 和非 SHH 亚型 MB 的 ORR 来获得风险差异。
结果：五项研究均对患者招募有明确的标准，终点评估有足够的随访时间，肿瘤反应的定义明确。试验中 MB 患者的依从性良好。SMO 抑制剂的总客观缓解率（ORR）为 37%，对 SHH 驱动和其他 MB 为 0。sonidegib 在 MB 中的总 ORR 为 55%，在 MB 亚组中为 0。vismodegib 对非 SHH 亚型 MB 也无效。sonidegib 对 SHH 驱动的 MB 产生的 ORR 比 vismodegib 高 1.87 倍（95%CI 1.23,6.69）。在儿科患者中，sonidegib 的疗效比 vismodegib 高 3.67 倍（p<0.05）。共有 320 例患者接受了 SMO 抑制剂治疗，36 例报告了 3/4 级剂量限制毒性（DLT）。接受 vismodegib 和 sonidegib 的患者 3/4 级 DLT 发生率相似（11.6%比 11.2%）。
结论：sonidegib 和 vismodegib 耐受性良好，通过有效抑制 Hh 信号，在 SHH 驱动的儿科和成人 MB 中显示出抗肿瘤活性。这些结果支持正在进行的临床试验，使用 SMO 抑制剂联合常规化疗治疗复发性 MB。
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