Nanoparticles for Diagnosis and Target Therapy in Pediatric Brain Cancers

Pediatric brain tumors represent the most common types of childhood cancer and novel diagnostic and therapeutic solutions are urgently needed. The gold standard treatment option for brain cancers in children, as in adults, is tumor resection followed by radio- and chemotherapy, but with discouraging therapeutic results. In particular, the last two treatments are often associated to significant neurotoxicity in the developing brain of a child, with resulting disabilities such as cognitive problems, neuroendocrine, and neurosensory dysfunctions/deficits. Nanoparticles have been increasingly and thoroughly investigated as they show great promises as diagnostic tools and vectors for gene/drug therapy for pediatric brain cancer due to their ability to cross the blood–brain barrier. In this review we will discuss the developments of nanoparticle-based strategies as novel precision nanomedicine tools for diagnosis and therapy in pediatric brain cancers, with a particular focus on targeting strategies to overcome the main physiological obstacles that are represented by blood–brain barrier.

Compressed SENSE in Pediatric Brain Tumor MR Imaging

Purpose To compare the image quality, examination time, and total energy release of a standardized pediatric brain tumor magnetic resonance imaging (MRI) protocol performed with and without compressed sensitivity encoding (C-SENSE). Recently introduced as an acceleration technique in MRI, we hypothesized that C‑SENSE would improve image quality, reduce the examination time and radiofrequency-induced energy release compared with conventional examination in a pediatric brain tumor protocol. Methods This retrospective study included 22 patients aged 2.33–18.83 years with different brain tumor types who had previously undergone conventional MRI examination and underwent follow-up C‑SENSE examination. Both examinations were conducted with a 3.0-Tesla device and included pre-contrast and post-contrast T1-weighted turbo-field-echo, T2-weighted turbo-spin-echo, and fluid-attenuated inversion recovery sequences. Image quality was assessed in four anatomical regions of interest (tumor area, cerebral cortex, basal ganglia, and posterior fossa) using a 5-point scale. Reader preference between the standard and C‑SENSE images was evaluated. The total examination duration and energy deposit were compared based on scanner log file analysis. Results Relative to standard examinations, C‑SENSE examinations were characterized by shorter total examination times (26.1 ± 3.93 vs. 22.18 ± 2.31 min; P = 0.001), reduced total energy deposit (206.0 ± 19.7 vs. 92.3 ± 18.2 J/kg; P < 0.001), and higher image quality (overall P < 0.001). Conclusion C‑SENSE contributes to the improvement of image quality, reduction of scan times and radiofrequency-induced energy release relative to the standard protocol in pediatric brain tumor MRI.

Central Role of C2H2-Type Zinc Finger-Containing Genes in Pediatric Brain Tumors

Zinc fingers consist of one of the most abundant motifs in transcription factors and DNA-binding proteins. Recent studies provide evidence on the pathological implication of zinc finger proteins in various neurodevelopmental disorders and malignancies but their role in pediatric brain tumors is largely unexplored. To this end, we investigated the differential expression of zinc finger-containing genes along with relevant biological processes and pathways among four main brain tumor categories (pilocytic astrocytomas, ependymomas, medulloblastomas and glioblastomas). By employing an extended bioinformatic toolset, we performed a preliminary in silico study in order to identify the expression of zinc finger-containing genes and associated functions in pediatric brain tumors. Our data analysis reveals the prominent role of C2H2-type zinc finger-containing genes in the molecular mechanisms underlying pediatric brain tumors followed by the Ring and PHD finger types. Significant dysregulation of ABLIM2 and UHFR1 genes was detected in all tumor types drawing attention to the dysregulation of cell polarization process and Ubiquitin-Proteasome System (UPS) in the pathogenesis of pediatric brain tumors. Moreover, significant gene clustering was observed in multiple locations with two highly visible clusters revealing a contrast in gene regulation between medulloblastomas and the other three brain tumor types, indicating a promising area of future research.

Deficiency in the Treatment Description of mTOR Inhibitor Resistance in Medulloblastoma, a Systematic Review

Medulloblastoma is a common fatal pediatric brain tumor. More treatment options are required to prolong survival and decrease disability. mTOR proteins play an essential role in the disease pathogenesis, and are an essential target for therapy. Three generations of mTOR inhibitors have been developed and are clinically used for immunosuppression and chemotherapy for multiple cancers. Only a few mTOR inhibitors have been investigated for the treatment of medulloblastoma and other pediatric tumors. The first-generation mTOR, sirolimus, temsirolimus, and everolimus, went through phase I clinical trials. The second-generation mTOR, AZD8055 and sapanisertib, suppressed medulloblastoma cell growth; however, limited studies have investigated possible resistance pathways. No clinical trials have been found to treat medulloblastoma using third-generation mTOR inhibitors. This systematic review highlights the mechanisms of resistance of mTOR inhibitors in medulloblastoma and includes IDO1, T cells, Mnk2, and eIF4E, as they prolong malignant cell survival. The findings promote the importance of combination therapy in medulloblastoma due to its highly resistant nature.

Mapping pediatric brain tumors to their origins in the developing cerebellum

Understanding the cellular origins of childhood brain tumors is key for discovering novel tumor-specific therapeutic targets. Previous strategies mapping cellular origins typically involved comparing human tumors to murine embryonal tissues, a potentially imperfect approach due to spatio-temporal gene expression differences between species. Here we use an unprecedented single-nucleus atlas of the developing human cerebellum (Sepp, Leiss, et al) and extensive bulk and single-cell transcriptome tumor data to map their cellular origins with focus on three most common pediatric brain tumors - pilocytic astrocytoma, ependymoma, and medulloblastoma. Using custom bioinformatics approaches, we postulate the astroglial and glial lineages as the origins for posterior fossa ependymomas and radiation-induced gliomas (secondary tumors after medulloblastoma treatment), respectively. Moreover, we confirm that SHH, Group3 and Group4 medulloblastomas stem from granule cell/unipolar brush cell lineages, whereas we propose pilocytic astrocytoma to originate from the oligodendrocyte lineage. We also identify genes shared between the cerebellar lineage of origin and corresponding tumors, and genes that are tumor specific; both gene sets represent promising therapeutic targets. As a common feature among most cerebellar tumors, we observed compositional heterogeneity in terms of similarity to normal cells, suggesting that tumors arise from or differentiate into multiple points along the cerebellar "lineage of origin".

Nuchal Skinfold Thickness in Pediatric Brain Tumor Patients

BackgroundSevere obesity and tumor relapse/progression have impact on long-term prognosis in pediatric brain tumor patients.MethodsIn a cross-sectional study, we analyzed nuchal skinfold thickness (NST) on magnetic-resonance imaging (MRI) follow-up monitoring as a parameter for assessment of nuchal adipose tissue in 177 brain tumor patients (40 World Health Organization (WHO) grade 1–2 brain tumor; 31 grade 3–4 brain tumor; 106 craniopharyngioma), and 53 healthy controls. Furthermore, body mass index (BMI), waist-to-height ratio, caliper-measured skinfold thickness, and blood pressure were analyzed for association with NST.ResultsCraniopharyngioma patients showed higher NST, BMI, waist-to-height ratio, and caliper-measured skinfold thickness when compared to other brain tumors and healthy controls. WHO grade 1–2 brain tumor patients were observed with higher BMI, waist circumference and triceps caliper-measured skinfold thickness when compared to WHO grade 3–4 brain tumor patients. NST correlated with BMI, waist-to-height ratio, and caliper-measured skinfold thickness. NST, BMI and waist-to-height ratio were associated with increased blood pressure. In craniopharyngioma patients with hypothalamic involvement/lesion or gross-total resection, rate and degree of obesity were increased.ConclusionsNST could serve as a novel useful marker for regional nuchal adipose tissue. NST is highly associated with body mass and waist-to-height ratio, and easily measurable in routine MRI monitoring of brain tumor patients.

Therapeutic Targets in Diffuse Midline Gliomas—An Emerging Landscape

Diffuse midline gliomas (DMGs) are invariably fatal pediatric brain tumours that are inherently resistant to conventional therapy. In recent years our understanding of the underlying molecular mechanisms of DMG tumorigenicity has resulted in the identification of novel targets and the development of a range of potential therapies, with multiple agents now being progressed to clinical translation to test their therapeutic efficacy. Here, we provide an overview of the current therapies aimed at epigenetic and mutational drivers, cellular pathway aberrations and tumor microenvironment mechanisms in DMGs in order to aid therapy development and facilitate a holistic approach to patient treatment.