Apart from oncogenic signaling activation by loss of NF1, also somatic alterations, most prominently mutations or fusions involving BRAF, have been described in pediatric high-grade gliomas [
17]. More recently, fusions of other signaling molecules, such as NTRK1/2/3, ALK, MET, or ROS1, have been discovered by large-scale high-throughput screens [
18‐
20]. Importantly, as alterations in these oncogenes are also found in adult cancer types, inhibitors targeting these receptors have already undergone clinical development involving the pediatric population [
21]. Preclinical analyses of our group and others demonstrate good effects of these inhibitors against fusion-positive cancer cells corroborating first results within ongoing clinical trials as well as selected case reports [
19,
20,
22].
Currently available inhibitors include crizotinib, larotrectinib and entrectinib, which are approved by European Medicines Agency (EMA) and US Food and Drug Administration (FDA), as well as the second-generation inhibitors selitrectinib and repotrectinib, which are in clinical development [
21]. It has to be considered that these inhibitors show different specificity for the aforementioned therapy targets and are only approved within certain indications, in particular in the pediatric population (Table
1).
Table 1
Targeted inhibitors for oncogenic gene fusions in pediatric brain tumors (adapted from [
17])
Crizotinib | ALK, MET, NTRK1/2/3 (minimal), ROS1 | ALK/ROS1 altered (lung cancer) |
Larotrectinib | NTRK1/2/3 | NTRK fusion-positive tumors (any age) |
Entrectinib | ALK, NTRK1/2/3, ROS1 | NTRK fusion-positive tumors (> 12 years), ROS1 altered (lung cancer) |
Selitrectinib | NTRK1/2/3 (including most mutations) | – |
Repotrectinib | ALK, ROS1, NTRK1/2/3 (including most mutations) | – |
Only a minor proportion of high-grade gliomas harbor these specific gene fusions, underlying that comprehensive molecular profiling of pediatric brain tumors at an early timepoint is required in order to facilitate detection of these therapeutic targets. With respect to brain tumors, penetration of the blood–brain barrier is also of particular interest. In general, penetration of crizotinib to the central nervous system is considered to be poor, but still efficacy in pediatric brain tumors has been described [
19]. For the newer compounds larotrectinib and entrectinib both have demonstrated effects against pediatric brain tumors in a clinical setting [
20,
22]. These novel compounds are generally well tolerated, only a minority of patients require dose modifications or discontinuation of treatment [
21]. With respect to blood–brain barrier penetration, first analyses point towards a more favorable profile of entrectinib, as animal studies have demonstrated higher penetration of tumor tissue [
23]. In addition, it was recently shown that entrectinib also efficiently enters the cerebrospinal fluid [
22]. Still, it has to be considered that safety profiles in the pediatric population, and in young children in particular, are currently more established for larotrectinib, which is also reflected by the approval independent of age. Response to these inhibitors is usually quick and frequently also for a prolonged period of time [
21,
22]. Still, various resistance mechanisms have been described in the adult population, including resistance mutations, and second-generation inhibitors are already being developed. Less is known about resistance mechanisms in pediatric brain tumors, but we have recently described NF2 mutation and activation insulin receptor (INSR) signaling as potential resistance mechanisms [
23]. The main ongoing pediatric trials with targeted drugs are listed in Table
2.
Table 2
Main ongoing pediatric trials with targeted drugs
Selumetinib | Low-Grade Glioma (LGG) | NCT04166409 |
Selumetinib | Recurrent or Progressive Low-Grade Glioma (LGG) | NCT04576117 |
Mirdametinib | Low-Grade Glioma (LGG) | NCT04923126 |
Trametinib, Everolimus | Recurrent Low-Grade Glioma (LGG) | NCT04485559 |
Trametinib | Pediatric Glioma or Plexiform Neurofibroma and Activation of the MAPK/ERK Pathway | NCT03363217 |
Trametinib, Dabrafenib | Recurrent or Progressive Glioma in Children and Young Adults | NCT04201457 |
Larotrectinib | Untreated TRK Fusion Solid Tumors and TRK Fusion Relapsed Acute Leukemia | NCT03834961 |
Larotrectinib | High-Grade Glioma With NTRK Fusion | NCT04655404 |
Larotrectinib | Tumors with NTRK-fusion in Children | NCT02637687 |
Entrectinib | Locally Advanced or Metastatic Solid or Primary CNS Tumors | NCT02650401 |
Selitrectinib | Solid Tumors Harboring NTRK Fusion | NCT03215511 |
Repotrectinib | Pediatric and Young Adult Subjects Harboring ALK, ROS1, OR NTRK1‑3 Alterations | NCT04094610 |