We agree that models of pediatric low-grade glioma (pLGG) are currently suboptimal. To address this gap, we developed new patient- derived pLGG cell lines, including the first-ever human neurofibromatosis 1 (NF1) null pilocytic astrocytoma (PA) cell line.¹ We include this line and other short-term pLGG cultures grown under cell reprogramming conditions in our paper. We disagree with the assertion that infiltrative, grade II gliomas make up the bulk of recurrent/refractory pediatric gliomas. In a series of 198 pediatric non-NF1 tumors, grade II tumors comprised only 6/198 cases. Midline location, extent of resection, and underlying biology (BRAF rearrangements or mutation with loss of CDKN2A) were most likely to impact recurrence and need for treatment.² Inhibitors of mitogen-activated protein kinase kinase (MEK) penetrate poorly into normal brain parenchyma; however, in the case of avidly gadolinium contrast-enhancing PA—which comprises the vast majority of pLGGs—trametinib, selumetinib, and binimetinib have demonstrated efficacy in pediatric patients.³ The results are so clear that the current Children’s Oncology Group phase III pLGG clinical trial randomizes to carboplatin/vincristine or selumetinib in first-line therapy (NCT04166409). Experimental and clinical evidence does not support the letterwriters’ assertion that heterogeneously contrast-enhancing atypical teratoid rhabdoid tumor (AT/RT) has a more leaky blood–tumor barrier than avidly contrast-enhancing PA. In our hands, binimetinib and selumetinib suppress the growth of AT/RT cells in vitro and in flank xenografts (Shahab et al, in press) but have no efficacy against AT/RT orthotopic xenografts, similar to results recently described for trametinib.⁴ In contrast, the target of rapamycin complex 1 and 2 (TORC1/2) kinase inhibitor TAK228 inhibits the growth of orthotopic AT/RT xenografts as a single agent.⁵ TAK228 (also known as MLN128, INK128, and sapanisertib) penetrates the brain in animal studies, and is currently being tested to determine drug penetration in human recurrent glioblastoma tumors (NCT02133183). The human BT40 BRAF^V600E pLGG flank model is imperfect. However, the sensitivity of BT40 to MEK inhibitors predicted the success of these agents in pLGG.⁶ The genetically engineered mouse models (GEMMs) of mitogen activated protein kinase-activated glioma have a long latency of tumor formation (in the case of LGG models) making longitudinal treatment studies impractical, or are high-grade glioma models, which have little shared biology with pLGG. GEMMs have an uneven track record of predicting responses in human tumors—notably the GEMM malignant peripheral nerve sheath tumor model demonstrated susceptibility to mammalian target of rapamycin (mTOR) inhibitors and heat shock protein 90 inhibitors, but these findings did not translate into clinical activity in patients.⁷ We found that trametinib/TAK228 therapy targeted the vascularity of BT40 tumors. Abnormal vasculature is a hallmark of PA, and drugs targeting blood vessels, such as bevacizumab, are effective. Patients with gadolinium enhancing pLGG often show remarkable reduction in enhancement after initiation of MEK inhibitor therapy. Our work in BT40 (with validation in human vascular models) mechanistically explains this curious clinical effect of MEK inhibition in patients and shows the combinatorial activity of mTOR and MEK inhibitors. As the statistician George Box wrote, “All models are wrong; some models are useful.” ⁸ While BT40 is an imperfect model, we maintain that its history of predicting response in pLGG patients makes it highly useful.

中文翻译：

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致编辑的信：“所有模型都是错误的；某些模型是有用的”。

我们同意，小儿低度神经胶质瘤（pLGG）的模型目前尚不理想。为了解决这一空白，我们开发了新的源自患者的pLGG细胞系，包括有史以来第一个人类神经纤维瘤病1（NF1）无效的毛细胞星形细胞瘤（PA）细胞系。¹我们在本文中包括该细胞系和在细胞重编程条件下生长的其他短期pLGG培养物。我们不同意这样的说法，浸润性II级神经胶质瘤占复发性/难治性小儿神经胶质瘤的大部分。在一系列198例儿科非NF1肿瘤中，II级肿瘤仅占6/198例。中线位置，切除范围和基础生物学（BRAF重排或CDKN2A缺失突变）最有可能影响复发和治疗需求。²丝裂原活化蛋白激酶激酶（MEK）的抑制剂很难渗透到正常的脑实质中。但是，在包含大量pLGG的狂热的contrast增强对比剂PA的情况下，曲美替尼，selumetinib和binimetinib已在儿科患者中显示出疗效。³结果是如此清晰，以至于当前的儿童肿瘤小组III期pLGG临床试验在第一线治疗（NCT04166409）中将卡铂/长春新碱或selumetinib随机分组。实验和临床证据不支持写信人的论断，即非均匀增强造影剂的非典型类畸形类横纹肌瘤（AT / RT）比强烈增强造影剂的PA具有更大的渗漏血液肿瘤屏障。在我们手中，比尼美替尼和selumetinib在体外和侧面异种移植物中抑制AT / RT细胞的生长（Shahab等，已出版），但对AT / RT原位异种移植物没有效力，类似于最近对曲美替尼描述的结果。⁴相反，雷帕霉素复合物1和2（TORC1 / 2）激酶抑制剂TAK228的靶标则抑制了原位AT / RT异种移植物的单药生长。⁵ TAK228（也称为MLN128，INK128和sapanisertib）在动物研究中已渗透到大脑，目前正在测试以确定在人类复发性胶质母细胞瘤肿瘤中的药物渗透（NCT02133183）。人类BT40 BRAF ^V600E pLGG侧面模型不完美。但是，BT40对MEK抑制剂的敏感性预示了这些药物在pLGG中的成功。⁶丝裂原激活的蛋白激酶激活的神经胶质瘤的基因工程小鼠模型（GEMM）具有长的肿瘤形成潜伏期（对于LGG模型而言），使得纵向治疗研究不切​​实际，或者是高级的神经胶质瘤模型，它们几乎没有共同的生物学特性与pLGG。GEMMs在人类肿瘤中预测反应的追踪记录不均匀-尤其是GEMM恶性周围神经鞘瘤模型显示出对雷帕霉素（mTOR）抑制剂和热休克蛋白90抑制剂对哺乳动物靶标的敏感性，但这些发现并未转化为对耐心。⁷我们发现曲美替尼/ TAK228治疗靶向BT40肿瘤的血管。异常的脉管系统是PA的标志，贝伐单抗等靶向血管的药物有效。initiation增强pLGG的患者通常在MEK抑制剂治疗开始后表现出明显的增强降低。我们在BT40中的工作（在人体血管模型中得到验证）以机械方式解释了患者对MEK抑制的这种奇怪的临床效果，并显示了mTOR和MEK抑制剂的组合活性。正如统计学家乔治·博克斯（George Box）所说：“所有模型都是错误的。一些模型很有用。” ⁸尽管BT40是一个不完善的模型，但我们认为其预测pLGG患者反应的历史使其非常有用。