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Tumors of the central nervous system (CNS) are the most common pediatric tumor type and the leading cause of cancer-related death in children and adolescents. In recent decades, multiple molecular approaches have been applied to decipher the biological nature of these aggressive cancers, leading to more precise tumor classification and precision medicine approaches. Nevertheless, treatment of these tumors remains challenging due to the sensitive location, young age of patients, and resistance to current therapeutic strategies. Recently, several targeted therapy targets have been approved by the US Food and Drug Administration and European Medicines Agency for the treatment of pediatric brain tumors or are being investigated within clinical trials. Furthermore, the improved sensitivity of methods to detect small amounts of DNA or RNA in liquid biopsy samples provides a novel source for an almost limitless, less invasive, and longitudinal monitoring opportunity. Take home message: Targeted therapies have added novel therapeutic options to combat pediatric CNS tumors and liquid biopsy is promising to aid in guiding precision oncology approaches. However, single-agent therapy is rarely curative, necessitating further efforts to investigate improved therapeutic regimens including these novel therapies.
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Although cancer is generally rare in children and adolescents it is the second most common cause of death among the population aged 1–14 and central nervous system (CNS) tumors account for the majority of cancer-related deaths [1]. Despite the improvement in prognosis in the last decades [2], location, histology, and molecular background are the main predictors of long-term morbidity and survival. Patients diagnosed with histologically similar tumors can have an excellent prognosis if gross-total resection is possible, while they can suffer from multiple comorbidities or even succumb to the disease if resection is not possible. Similar differences apply to certain molecular features that have been shown to determine prognosis, such as the H3K27M alteration in diffuse midline glioma [3]; MYC-amplification in group 3 medulloblastoma [4, 5], and 1q gain and 6p loss in posterior fossa ependymoma [6]. In addition, novel tumor types are continuously being described necessitating clear guidance and future trials to determine the best standard of care [7]. Therefore, molecular profiling of pediatric CNS tumors is a standard of care in many countries allowing not only for better prediction of clinical outcome, but also for risk-adapted treatment strategies and the introduction of novel targeted therapies.
In this short review, we will discuss the approved and emerging targeted therapeutics for pediatric CNS tumors and potential future applications of novel diagnostic methods, such as liquid biopsies.
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Approved and emerging targeted therapeutics
Among pediatric CNS tumors, pediatric low-grade gliomas (pLGG) are the most common tumor type. Their biology and prognosis differ significantly from tumors occurring in adult patients, with a 20-year overall survival rate of 87% [8]. To evaluate the molecular background of these tumors, numerous systematic molecular studies have been performed, revealing a pathologic activation of the RAS/MAP kinase signaling pathway in the vast majority of cases [9‐11]. Following these analyses, it is now known that the majority of pLGGs harbor a KIAA1549::BRAF fusion (35–60%), followed by a BRAF p.V600E point-mutation (10–15%) and alterations in the FGFR signaling pathway. It has been also shown that tumors with BRAF p.V600E mutations may be associated with a worse prognosis when treated with standard chemotherapy [10, 12]. These results translate directly into clinical treatment, since inhibitors of the RAS/MAP kinase pathway are available and have been approved for multiple indications in the adult population.
After a number of successful treatments in individual cases and subsequent phase I–III clinical trials, certain therapies have now been approved for the pediatric population to use in routine clinical practice.
Dabrafenib a serine/threonine inhibitor that selectively blocks the serine/threonine kinase BRAF can be administered for BRAF V600E, V600K and V600D variants. Based on better tolerability and efficacy, dabrafenib should be combined with trametinib, a MEK inhibitor [13]. In 2022, a phase II trial was published showing an improved response in 47% of cases compared to the standard arm (carboplatin + vincristine), with only 11% [12]. Hence, in March 2023, the combination therapy was approved as first-line therapy for pLGG with verified BRAF mutations by the US Food and Drug Administration (FDA) and in December 2023 by the European Medicines Agency (EMA). Selumetinib is an approved MEK inhibitor in Europe for treatment of neurofibromatosis patients with plexiform neurofibromas.
The pan-RAF inhibitor DAY-101 is currently being investigated within the FIREFLY‑1 phase 2 study including pediatric patients with recurrent or progressive low-grade glioma. This broadens the spectrum of possible therapeutics targeting the RAS/MAP-kinase signaling pathway. This development may also have a role in some rare entities, such as primary diffuse leptomeningeal melanomatosis [14].
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High-grade tumors in the pediatric population have a more diverse molecular background, frequently lacking any targetable alteration. However, in some cases an oncogenic driver can be identified leading to significant survival improvement. A prime example are NTRK-fused tumors, in which treatment with TRK inhibitors such as entrectinib or larotrectinib led to continuous disease stabilization in selected high-grade cases [15, 16]. Similarly, tumors harboring FGFR alterations treated with a FGFR inhibitor, such as erdafitinib responded remarkably to targeted treatment [17, 18].
New approaches are also emerging for tumors lacking a specific druggable target but being characterized by other alterations such as a high mutational burden suggesting potential response to immunotherapy, for example, check-point inhibition by nivolumab, however, with limited response rates observed in CNS tumor patients so far [19]. However, they may have a particular role in patients suffering from constitutive mismatch repair deficiency (cMMRD) syndrome [20]. For diffuse midline gliomas with H3K27 alteration the DRD2 antagonist ONC201 has been investigated in several studies, without clear results at present [21]. A phase I/II trial is currently ongoing. An overview on targets, treatment options and open clinical trials is given in Table 1.
Table 1
Table listing most relevant targeted therapeutics used in central nervous system (CNS) tumor patientsa (Sources [33, 34])
Inhibitor
Molecular target
Approval (EMA if not further specified)
Crizotinib
ALK, MET, NTRK1/2/3 (minimal), ROS1
ALK/ROS1 alteration (NSCLC); pediatric patients with recurrent/refractory ALK-positive anaplastic large cell lymphoma or inflammatory myofibroblastic tumor
aSecond column outlines the primary target of each therapeutic, Third column summarizes approval details (approval for specific diagnosis/molecular alteration); age limitation
FDA U.S. Food and Drug Administration, EMA European Medicines Agency
Interestingly, a broader approach summarized under the acronym MEMMAT, combining well established drugs given orally, augmented by intravenous bevacizumab and intrathecal administration of chemotherapy led to a significantly improved survival in recurrent medulloblastoma patients. Its efficacy in other entities is currently being investigated within a randomized, multicenter, phase II trial.
Concluding, there are many additional treatment options emerging for all types of CNS tumors also within the pediatric age group. While some are already well established, others still need to be investigated within well-planned clinical trials. Meanwhile, decisions for off-label therapies should be based on decisions within interdisciplinary tumor boards such as is implemented at the Brain Tumor Center for Children and Adolescents Vienna since 2020 for Pediatric CNS tumors and patients receiving off-label treatment. Importantly, these real-world evidence is captured in international efforts to inform therapy and trial concepts [22, 23].
Treatment decision and therapy monitoring utilizing liquid biopsy
In recent years, the application of liquid biopsy in cancer research has emerged as a promising approach for investigation. Liquid biopsies are a minimally invasive and easily accessible method for analyzing tumor-derived material. They enable both initial diagnosis and longitudinal monitoring of tumor progression. Molecular alterations in circulating-free DNA (cfDNA) and circulating tumor DNA (ctDNA)—including mutations, amplifications, gene fusions, and miRNA expression—can be tracked in real time to guide treatment decisions and assess therapeutic response. In Fig. 1, a concise overview of liquid biopsy applications in pediatric brain tumors is depicted.
Fig. 1
Overview of liquid biopsy applications in pediatric brain tumors. Blood (left side)—1) Isolation of cfDNA and RNA from plasma or serum samples; 2) Analysis of mutation detection in cfDNA with ddPCR or miRNA expression with qPCR; 3) Analysis of expression levels or rare mutation detection and 4) longitudinally monitoring of therapy or tumor disease. Cerebrospinal fluid (CSF; right side)—5) Isolation of cfDNA from CSF samples; 6) Sequencing of cfDNA and 7) Tumor classification and 8) monitoring of tumor evolution; 9) Detection of rare mutations in cfDNA samples; 10) Targeted treatment against specific mutations; 11) Therapy monitoring
In recent years, we and others have demonstrated the feasibility to monitor several gene alterations such as H3F3A K27M, BRAF V600E, NRAS and MYC amplifications in bodily fluids [14, 25‐27]. In 2022, the clinical practicability of detecting H3F3A K27M in serially collected plasma and CSF samples of patients diagnosed with a DMG H3K27M alteration was investigated [28]. The authors evaluated the novel monotherapeutic agent ONC201 and demonstrated the ability to use bodily fluids to monitor treatment efficacy [29]. This technique may also be employed for the monitoring of BRAF V600E mutation status. In this context we have recently shown that response to combined BRAF/MEK inhibition may be monitored by liquid biopsy of either CSF or blood [28].
Another promising marker for monitoring tumor growth and detection of minimal residual disease in liquid biopsy samples are miRNAs. These small RNAs are well preserved in blood and its derivates [24, 30, 31] and can easily cross the blood–brain barrier. In 2023, our group demonstrated the clinical applicability of longitudinal monitoring of an aberrant expressed miRNA in ETMR patients, a rare but highly aggressive tumor entity [32]. The miRNA levels measured in the plasma/serum samples of the ETMR patients correlated with tumor volume obtained from magnetic resonance (MR) images over time. Moreover, this analytic method has minimal costs and equipment requirements and can be completed within 4 h. This approach for disease monitoring will be included in future clinical trials.
Nevertheless, despite the numerous advantages of performing liquid biopsy analysis its clinical application still faces limitations. Major challenges are the preanalytical handling of samples and the detection limits of the analytical techniques. Therefore, within a pan-European consortium a project on Scanning the liquids Of paediatric brain tUmour patients to Personalize treatment (SOUP) funded by the Fight Kids cancer program (https://fightkidscancer.eu/project/call-2024/#call_5) a collaborative group within the SIOP Europe Brain Tumour Group—liquid biopsy group focuses on tackling this problem by investigating and comparing of different extraction techniques in CSF samples and analytical methods in a European interlaboratory comparison study.
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Conclusion
Precision oncology has transformed the approach to treating central nervous system (CNS) tumors in children and adolescents and has emerged as an additional pillar of standard-of-care. At the Brain Tumor Center for Children and Adolescents in Vienna, more than half of the patients receiving antineoplastic treatment now receive targeted and/or other innovative therapies.
However, treatment schedules, duration of treatment, and combination therapies still need to be elucidated for many of these novel therapeutics. To this end, international trials—many of which are available at the center in Vienna—are essential to developing novel therapies for hard-to-treat cancers and establishing evidence for future treatments.
In addition, therapy monitoring by liquid biopsy appears to be a promising emerging tool to guide precision therapy in the future.
Conflict of interest
N. Stepien and S. Madlener declare that they have no competing interests. J. Gojo is consultant, advisory board participant and received honoraria for Novartis and Roche.
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