Abstract：
Phosphatidylinositol 3-kinase (PI3-K) signalling pathway is a crucial path in cancer for cell survival and thus represents an intriguing target for new paediatric anti-cancer drugs. However, the unique clinical toxicities of targeting this pathway (resulting in hyperglycaemia) difficulties combining with chemotherapy, rarity of mutations in childhood tumours and concomitant mutations have resulted in major barriers to clinical translation of these inhibitors in treating both adults and children. Mutations in PIK3CA predict response to PI3-K inhibitors in adult cancers. The same mutations occur in children as in adults, but they are significantly less frequent in paediatrics. In children, high-grade gliomas, especially diffuse midline gliomas (DMG), have the highest incidence of PIK3CA mutations. New mutation-specific PI3-K inhibitors reduce toxicity from on-target PI3-Kα wild-type activity. The mTOR inhibitor everolimus is approved for subependymal giant cell astrocytomas. In paediatric cancers, mTOR inhibitors have been predominantly evaluated by academia, without an overall strategy, in empiric, mutation-agnostic clinical trials with very low response rates to monotherapy. Therefore, future trials of single agent or combination strategies of mTOR inhibitors in childhood cancer should be supported by very strong biological rationale and preclinical data. Further preclinical evaluation of glycogen synthase kinase-3 beta inhibitors is required. Similarly, even where there is an AKT mutation (∼0.1 %), the role of AKT inhibitors in paediatric cancers remains unclear. Patient advocates strongly urged analysing and conserving data from every child participating in a clinical trial. A priority is to evaluate mutation-specific, central nervous system-penetrant PI3-K inhibitors in children with DMG in a rational biological combination. The choice of combination, should be based on the genomic landscape e.g. PTEN loss and resistance mechanisms supported by preclinical data. However, in view of the very rare populations involved, innovative regulatory approaches are needed to generate data for an indication.
摘要：
磷脂酰肌醇3-激酶（PI3-K）信号通路是癌症中细胞存活的关键途径，因此代表了新的儿科抗癌药物的有趣靶标。然而,针对这一途径的独特临床毒性（导致高血糖）与化疗相结合的困难，儿童肿瘤中罕见的突变和伴随的突变已导致这些抑制剂在治疗成人和儿童中的临床翻译的主要障碍。PIK3CA中的突变预测成人癌症中对PI3-K抑制剂的反应。儿童和成人发生相同的突变，但是它们在儿科中的频率明显较低。在儿童中，高级别神经胶质瘤,尤其是弥漫性中线胶质瘤（DMG），PIK3CA突变发生率最高。新的突变特异性PI3-K抑制剂降低了目标PI3-Kα野生型活性的毒性。mTOR抑制剂依维莫司被批准用于室管膜下巨细胞星形细胞瘤。在儿科癌症中，mTOR抑制剂主要由学术界评估，没有总体战略，在经验性的,突变无关的临床试验，对单一疗法的反应率非常低。因此,mTOR抑制剂用于儿童癌症的单药或联合治疗的未来试验应得到非常有力的生物学理论基础和临床前数据的支持.糖原合酶激酶-3β抑制剂的进一步临床前评估是必需的。同样，即使有AKT突变(~0.1%)，AKT抑制剂在儿科癌症中的作用尚不清楚.患者倡导者强烈敦促分析和保存参与临床试验的每个儿童的数据。首要任务是评估特定的突变，中枢神经系统穿透性PI3-K抑制剂在儿童DMG中的合理生物学组合。组合的选择，应基于基因组景观，例如PTEN丢失和临床前数据支持的抗性机制。然而,鉴于涉及的人群非常罕见，需要创新的监管方法来生成适应症的数据。
