New York University Langone Medical Center, New York, New York, USA.
Curr Opin Neurol. 2024 Dec 1;37(6):702-707. doi: 10.1097/WCO.0000000000001319. Epub 2024 Sep 26.
Current biological findings provide new insights into the genetics driving growth of low-grade gliomas in pediatric patients. This has provided new targets for novel therapies. The purpose of this paper is to review novel therapies for pediatric low-grade gliomas that have been published in the past 24 months.
Low-grade gliomas are often driven by mitogen activated protein kinase (MAPK) alterations either with BRAF V600E point mutations or BRAF fusions. Current advances have also highlighted novel fusions of fibroblast growth factor receptor (FGFR), myeloblastosis family of transcription factors (MYB), meningioma 1 tumor suppressor (MN1), neurotrophic receptor kinase family of receptors (NTRK), Kristen RAS (Rat Sarcoma Virus) oncogene homolog in mammals (KRAS), Receptor tyrosine kinase ROS proto oncogene 1 (ROS1), protein kinase C alpha (PRKCA), and platelet derive growth factor receptor (PDGFR) amplification. Novel therapies have been employed and are showing encouraging results in pediatric low-grade gliomas. Current trials are underway with newer generation pan RAF inhibitors and mitogen activated protein kinase - kinase (MEK) inhibitors. Other early phase clinical trials have provided safety data in pediatric patients targeting FGFR fusion, NTRK fusion, PDGFR amplification and ROS1 mutations.
Historical treatment options in pediatric low-grade gliomas have utilized surgery, radiation therapy and conventional chemotherapy. Recently greater insight into their biology has found that alterations in MAPK driven pathways are often the hallmark of tumorigenesis. Targeting these novel pathways has led to tumor control and shrinkage without the use of conventional chemotherapy. Caution should be taken however, since these treatment options are still novel, and we do not fully appreciate the long-term effects. Nonetheless a new era of targeted medicine is here.
目前的生物学发现为儿科低级别胶质瘤的遗传驱动因素提供了新的见解。这为新疗法提供了新的靶点。本文旨在综述过去 24 个月发表的治疗儿科低级别胶质瘤的新疗法。
低级别胶质瘤通常由丝裂原活化蛋白激酶（MAPK）改变驱动，包括 BRAF V600E 点突变或 BRAF 融合。目前的进展还强调了成纤维细胞生长因子受体（FGFR）、髓母细胞瘤转录因子家族（MYB）、脑膜瘤 1 肿瘤抑制因子（MN1）、神经营养受体激酶家族受体（NTRK）、哺乳动物 Kirsten RAS（大鼠肉瘤病毒）致癌基因同源物（KRAS）、受体酪氨酸激酶 ROS 原癌基因 1（ROS1）、蛋白激酶 Cα（PRKCA）和血小板衍生生长因子受体（PDGFR）扩增的新融合。新型疗法已被应用，并在儿科低级别胶质瘤中显示出可喜的结果。目前正在进行使用新一代泛 RAF 抑制剂和丝裂原活化蛋白激酶激酶（MEK）抑制剂的试验。其他早期临床阶段试验为针对 FGFR 融合、NTRK 融合、PDGFR 扩增和 ROS1 突变的儿科患者提供了安全性数据。
儿科低级别胶质瘤的历史治疗选择包括手术、放疗和常规化疗。最近，对其生物学的更深入了解发现，MAPK 驱动途径的改变通常是肿瘤发生的标志。针对这些新途径的治疗导致了肿瘤控制和缩小，而无需使用常规化疗。然而，需要谨慎，因为这些治疗选择仍然是新的，我们不完全了解其长期影响。尽管如此，靶向药物治疗的新时代已经到来。
