Treatment Of Central Nervous System Tumors Research Articles

Association Between Heavy Metal Exposure and Central Nervous System Tumors: A Case-Control Study Using Single and Multi-Metal Models

(1) Background: Neoplasms of the central nervous system (CNS) encompass a cluster of malignant diseases originating from tissues or structures within the CNS. Environmental factors, including heavy metals, may contribute to their development. Therefore, this research was to investigate the association between heavy metal exposure and CNS tumor susceptibility using single and muti-metal models. (2) Methods: 63 CNS tumor patients and 71 controls were included. Urine samples from the CNS tumor patients and controls were analyzed for 47 metals using inductively coupled plasma-mass spectrometry in this study. Statistical analyses included conditional Wilcoxon rank-sum tests, logistic regression, Least Absolute Shrinkage and Selection Operator (LASSO) regression, and Bayesian Kernel Machine Regression (BKMR). (3) Results: In the single metal model, higher levels of seventeen metals might be associated with a lower incidence of CNS tumor, while higher exposure levels of five metals are associated with a higher incidence of tumor. LASSO regression selected nine metals for further BKMR analysis. The joint effects showed decreased tumor risk with increased metal mixture concentration. The level of the metals Ge, As, Rb, Zr, and Sn may be related to the incidence of meningiomas and gliomas. (4) Conclusions: This study explored the association between various metals and CNS tumors, providing ideas for future prospective cohort studies and laboratory studies, and providing a foundation for new ideas in the prevention and treatment of CNS tumors.

The impact of methylome analysis on the diagnosis and treatment of CNS tumours in children and adolescents: a population-based study in Greece.

BackgroundThe recently published WHO classification of central nervous system (CNS) tumours recognizes DNA methylation profiling as a desirable and, for some diagnoses, essential diagnostic tool adjunctive to conventional histopathology. DNA methylation profiling is not routinely available in many countries, including Greece. MethodsIn this collaborative study, we report the DNA methylation results in a series of children and adolescents with CNS tumours in Greece (2018-2023). In total, 130 tumour samples were analyzed using the latest applicable version of the Heidelberg brain tumour classifier. ResultsUpon initial analysis, 80% (104/130) achieved calibrated scores (Cs) ≥0.9 and matched an established methylation class family/subclass. Among them, methylation results confirmed (90/104, 86.5%), refined (50/104, 48%) or changed (10/104, 9.6%) the histological diagnosis. Only four results were regarded as non-contributing (4/104, 3.9%). Twenty-six tumour samples received Cs <0.9. Despite low scores, methylation results supported the initial diagnosis with lower confidence in 38.5% (10/26) and established the diagnosis in two tumours with non-conclusive histopathology. Additional t-distributed stochastic neighbour embedding (t-SNE) analysis allowed the possible classification of twelve tumours. Nine more samples reached high Cs using the newer brain tumour classifiers, since available. Samples co-tested in Greece demonstrated excellent test reproducibility, supporting the analysis' local implementation. Methylome profiling impacted the clinical management of 40% of patients, modifying stratification, prognosis, or treatment approach. ConclusionsThis study supports the need to integrate methylome analysis into routine diagnostics in our country and highlights the importance of collaboration between European pediatric oncology centres.

H3K27me3 Loss in Central Nervous System Tumors: Diagnostic, Prognostic, and Therapeutic Implications.

Central nervous system (CNS) tumors represent a formidable clinical challenge due to their molecular complexity and varied prognostic outcomes. This review delves into the pivotal role of the epigenetic marker H3K27me3 in the development and treatment of CNS tumors. H3K27me3, specifically the trimethylation of lysine 27 on the histone H3 protein, plays a crucial role in regulating gene expression and maintaining chromatin architecture (e.g., in X-chromosome inactivation). Notably, a reduction in H3K27me3 levels, frequently tied to mutations in the H3 gene family such as H3F3A and HIST1H3B, is evident in diverse brain tumor variants, including the diffuse midline glioma characterized by the H3K27M mutation and certain pediatric high-grade gliomas. The loss of H3K27me3 has been linked to more aggressive behavior in meningiomas, with the trimethylation loss associated with significantly shorter recurrence-free survival (RFS) among grade 2 meningiomas, albeit not within grade 1 tumors. Pediatric posterior fossa ependymomas characterized by a lowered H3K27me3 and DNA hypomethylation exhibit poor prognosis, underscoring the prognostic significance of these epigenetic alterations in CNS tumors. Comprehending the role of H3K27me3 in CNS tumors is vital for advancing diagnostic tools and therapeutic interventions, with the goal of enhancing patient outcomes and quality of life. This review underscores the importance of ongoing investigations into H3K27me to refine and optimize management strategies for CNS tumors, paving the way for improved personalized medicine practices in oncology.

Zika virus and brain cancer: Can Zika be an effective treatment for brain cancer? A systematic review.

Many studies have highlighted the use of oncolytic viruses as a new class of therapeutic agents for central nervous system (CNS) tumors, especially glioblastomas (GMB). Zika Virus (ZIKV) proteins targeted to specific stem cells have been studied in vitro and animal models with promising results. A systematic review was evaluated the efficacy and safety of the ZIKV use for CNS tumors treatment. Data were extracted and the in vivo studies were evaluated using the Robins-I tool. We assessed bias in each study using criteria such as selection bias, performance bias, detection bias, attrition bias, reporting bias, and others. According to Cochrane guidelines, bias was classified as high, low, or uncertain. High bias occurred when studies did not meet the criteria. Low bias was assigned when criteria were clearly met. Uncertain bias reflected insufficient information for a clear classification. The 14 included studies shown that ZIKV reduced cell viability or inhibited the growth, proliferation of glioma stem cells (GSCs), and Bcl2 expression - which could potentially enhance the effect of chemotherapy/radiotherapy; caused cytopathic effects, induced tumor cell damage, manifested oncolytic properties, and even selectively safely killed GSCs; ultimately, it led to significant tumor remission and enhanced long-term survival through enhanced T-cell response. Although current evidence suggests ZIKV as a promising treatment for CNS tumors and may improve survival when combined with surgery and radiotherapy. Despite limited human evidence, it shows potential benefits. Further research is needed to confirm safety, efficacy, and optimize treatment in humans.

Factors Influencing the Central Nervous System (CNS) Distribution of the Ataxia Telangiectasia Mutated and Rad3-Related Inhibitor Elimusertib (BAY1895344): Implications for the Treatment of CNS Tumors.

Glioblastoma (GBM) is a disease of the whole brain, with infiltrative tumor cells protected by an intact blood-brain barrier (BBB). GBM has a poor prognosis despite aggressive treatment, in part due to the lack of adequate drug permeability at the BBB. Standard of care GBM therapies include radiation and cytotoxic chemotherapy that lead to DNA damage. Subsequent activation of DNA damage response (DDR) pathways can induce resistance. Various DDR inhibitors, targeting the key regulators of these pathways such as ataxia telangiectasia mutated and Rad3-related (ATR), are being explored as radio- and chemosensitizers. Elimusertib, a novel ATR kinase inhibitor, can prevent repair of damaged DNA, increasing efficacy of DNA-damaging cytotoxic therapies. Robust synergy was observed in vitro when elimusertib was combined with the DNA-damaging agent temozolomide; however, we did not observe improvement with this combination in in vivo efficacy studies in GBM orthotopic tumor-bearing mice. This in vitro-in vivo disconnect was explored to understand factors influencing central nervous system (CNS) distribution of elimusertib and reasons for lack of efficacy. We observed that elimusertib is rapidly cleared from systemic circulation in mice and would not maintain adequate exposure in the CNS for efficacious combination therapy with temozolomide. CNS distribution of elimusertib is partially limited by P-glycoprotein efflux at the BBB, and high binding to CNS tissues leads to low levels of pharmacologically active (unbound) drug in the brain. Acknowledging the potential for interspecies differences in pharmacokinetics, these data suggest that clinical translation of elimusertib in combination with temozolomide for treatment of GBM may be limited. SIGNIFICANCE STATEMENT: This study examined the disconnect between the in vitro synergy and in vivo efficacy of elimusertib/temozolomide combination therapy by exploring systemic and central nervous system (CNS) distributional pharmacokinetics. Results indicate that the lack of improvement in in vivo efficacy in glioblastoma (GBM) patient-derived xenograft (PDX) models could be attributed to inadequate exposure of pharmacologically active drug concentrations in the CNS. These observations can guide further exploration of elimusertib for the treatment of GBM or other CNS tumors.

The Role of Bacteria in Central Nervous System Tumors: Opportunities and Challenges.

Tumors of the central nervous system (CNS) are severe and refractory diseases with poor prognosis, especially for patients with malignant glioblastoma and brain metastases. Currently, numerous studies have explored the potential role of bacteria and intestinal flora in tumor development and treatment. Bacteria can penetrate the blood-brain barrier (BBB), targeting the hypoxic microenvironment at the core of tumors, thereby eliminating tumors and activating both the innate and adaptive immune responses, rendering them promising therapeutic agents for CNS tumors. In addition, engineered bacteria and derivatives, such as bacterial membrane proteins and bacterial spores, can also be used as good candidate carriers for targeted drug delivery. Moreover, the intestinal flora can regulate CNS tumor metabolism and influence the immune microenvironment through the "gut-brain axis". Therefore, bacterial anti-tumor therapy, engineered bacterial targeted drug delivery, and intervention of the intestinal flora provide therapeutic modalities for the treatment of CNS tumors. In this paper, we performed a comprehensive review of the mechanisms and therapeutic practices of bacterial therapy for CNS tumors and discussed potential future research directions in this field.

Identifying tumor type and cell type-specific gene expression alterations in pediatric central nervous system tumors.

Central nervous system (CNS) tumors are the leading cause of pediatric cancer death, and these patients have an increased risk for developing secondary neoplasms. Due to the low prevalence of pediatric CNS tumors, major advances in targeted therapies have been lagging compared to other adult tumors. We collect single nuclei RNA-seq data from 84,700 nuclei of 35 pediatric CNS tumors and three non-tumoral pediatric brain tissues and characterize tumor heterogeneity and transcriptomic alterations. We distinguish cell subpopulations associated with specific tumor types including radial glial cells in ependymomas and oligodendrocyte precursor cells in astrocytomas. In tumors, we observe pathways important in neural stem cell-like populations, a cell type previously associated with therapy resistance. Lastly, we identify transcriptomic alterations among pediatric CNS tumor types compared to non-tumor tissues, while accounting for cell type effects on gene expression. Our results suggest potential tumor type and cell type-specific targets for pediatric CNS tumor treatment. Here we address current gaps in understanding single nuclei gene expression profiles of previously under-investigated tumor types and enhance current knowledge of gene expression profiles of single cells of various pediatric CNS tumors.

Development of Magnetic Resonance-Compatible Head Immobilization Device and Initial Experience of Magnetic Resonance-Guided Radiation Therapy for Central Nervous System Tumors

PurposeWe aimed to develop and investigate positional reproducibility using a fixation device (Unity Brain Tumor Immobilization Device, UBID) in brain tumor patients undergoing magnetic resonance (MR)-guided radiotherapy (RT) with a 1.5 Tesla (T) MR-linear accelerator (LINAC) to evaluate its feasibility in clinical practice and report representative cases of central nervous system (CNS) tumor patients. Materials and MethodsQuantitative analysis was performed by comparing images obtained by placing only the MR phantom on the couch with those obtained by placing UBID next to the MR phantom. Twenty patients who underwent RT for CNS tumors using 1.5T MR-LINAC between June 2022 and October 2022 were retrospectively analyzed. Among them, five did not use UBID, whereas 15 used UBID. The positional reproducibility of UBID was evaluated using the median interfractional and intrafractional errors in the first 10 fractions. ResultsEach MR quality factor of the MR phantom with UBID satisfied the criteria presented by Elekta. Median values of median shifts in the mediolateral, anteroposterior, and craniocaudal axes for interfractional errors were 2.98-mm, 2.35-mm, and 1.40-mm, respectively. For intrafractional errors, the median values were 0.05-mm, 0.03-mm, and 0.06-mm, respectively. The median values of the median rotations in pitch, roll, and yaw for both interfractional and intrafractional rotations were 0.00°. One patient diagnosed with an optic nerve sheath meningioma received RT with motion monitoring during irradiation. In two patients, changes in the tumor cavity and residual lesions were observed in the MR images obtained using 1.5T MR-LINAC on the day of the first treatment and immediately before the 21st fraction, respectively; therefore, offline/online adaptation was performed. ConclusionThe reproducible and immobile UBID is clinically feasible in patients with CNS tumors receiving RT with 1.5T MR-LINAC. Based on our initial experience, we developed a workflow for 1.5T MR-LINAC treatment of CNS tumors.

Abstract B013: In vitro stability and in vivo pharmacokinetic behavior of panobinostat in mouse models for the treatment of CNS tumors

Abstract Aberrant alterations of histone deacetylases (HDACs), an epigenetic regulator, are common in central nervous system (CNS) tumors and HDAC inhibitors have been found to have therapeutic potential for the treatment of CNS tumors. Panobinostat is a pan-HDAC inhibitor that has shown potency against multiple CNS tumors. Panobinostat has a hydroxamic acid side chain, a structural element reported to be susceptible to esterase activity in multiple compounds. Therefore, in vitro stability of panobinostat may allow the prediction of in vivo pharmacokinetic behavior. The objective of this study is to discover the mechanisms influencing the in vitro stability of panobinostat in multiple matrices and evaluate the in vivo pharmacokinetics in mouse models. In vitro stability studies in mouse plasma at different temperatures showed that panobinostat was unstable in mouse plasma and the decomposition rate was temperature-dependent. Meanwhile, panobinostat was stable in phosphate-buffered saline (PBS, pH7.4) tested at the same incubation conditions. Therefore, we propose that enzymatic activity is a contributor of the in vitro instability of panobinostat. Panobinonstat stability was also measured in plasma from different species. Data show that panobinostat was stable in human, monkey and dog plasma while unstable in mouse and rat plasma. The species difference observed was in line with the carboxylesterase 1c (Ces1c) expression among these species, where rodent plasma has abundant Ces1c expression while the other species have no Ces1c in plasma. With this in mind, we evaluated the impact of Ces1c removal from the matrices. We found that panobinostat was stable in plasma collected from Ces1c knockout mice (B6.Cg-Ces1ctm1.1Loc/J), indicating that Ces1c is contributing to the in vitro instability of panobinostat in plasma. To evaluate the influence of Ces1c on its pharmacokinetic behaviors, we studied the plasma and CNS distribution of panobinostat in wild-type C57BL6/J mice and Ces1c knockout mice following an intravenous bolus dose of 10 mg/kg via tail vein. Despite improved in vitro stability of panobinostat in plasma from Ces1c knockout mice compared with that in plasma from wild-type C57BL6/J, in vivo plasma concentration-time profiles were superimposable between these two genotypes. In addition, the CNS delivery of panobinostat was not influenced by the lack of Ces1c. Studies are ongoing to find potential in vivo mechanisms that are protecting the compound from robust in vitro degradation in the plasma. Citation Format: Wenqiu Zhang, Ju-Hee Oh, Wenjuan Zhang, Rachael W. Sirianni, William F. Elmquist. In vitro stability and in vivo pharmacokinetic behavior of panobinostat in mouse models for the treatment of CNS tumors [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr B013.

The regulatory role and clinical application prospects of circRNA in the occurrence and development of CNS tumors.

Central nervous system (CNS) tumors originate from the spinal cord or brain. The study showed that even with aggressive treatment, malignant CNS tumors have high mortality rates. However, CNS tumor risk factors and molecular mechanisms have not been verified. Due to the reasons mentioned above, diagnosis and treatment of CNS tumors in clinical practice are currently fraught with difficulties. Circular RNAs (circRNAs), single-stranded ncRNAs with covalently closed continuous structures, are essential to CNS tumor development. Growing evidence has proved the numeral critical biological functions of circRNAs for disease progression: sponging to miRNAs, regulating gene transcription and splicing, interacting with proteins, encoding proteins/peptides, and expressing in exosomes. This review aims to summarize current progress regarding the molecular mechanism of circRNA in CNS tumors and to explore the possibilities of clinical application based on circRNA in CNS tumors. We have summarized studies of circRNA in CNS tumors in Pubmed. This review summarized their connection with CNS tumors and their functions, biogenesis, and biological properties. Furthermore, we introduced current advances in clinical RNA-related technologies. Then we discussed the diagnostic and therapeutic potential (especially for immunotherapy, chemotherapy, and radiotherapy) of circRNA in CNS tumors in the context of the recent advanced research and application of RNA in clinics. CircRNA are increasingly proven to participate in decveloping CNS tumors. An in-depth study of the causal mechanisms of circRNAs in CNS tomor progression will ultimately advance their implementation in the clinic and developing new strategies for preventing and treating CNS tumors.

Delivery versus Potency in Treating Brain Tumors: BI-907828, a MDM2-p53 Antagonist with Limited BBB Penetration but Significant In Vivo Efficacy in Glioblastoma.

MDM2-p53 inhibition may be effective in glioblastoma (GBM). This study evaluates the pharmacokinetics/pharmacodynamics of BI-907828, a potent antagonist of MDM2, in GBM, and demonstrates a translational paradigm with a focus on a unified "Delivery - Potency - Efficacy" relationship in drug development for central nervous system(CNS) tumors. BI-907828 was tested for cytotoxicity and MDM2-p53 pathway inhibition. Systemic pharmacokinetics and transport mechanisms controlling CNS distribution were evaluated in mice. BI-907828 free fractions in cell media, mouse and human specimens were measured to determine "active" unbound concentrations. Efficacy measures, including overall survival and target expression were assessed in mouse orthotopic GBM xenografts. BI-907828 exhibited potent inhibition of MDM2-p53 pathway and promoted cell death in GBM TP53 wild-type cells. MDM2-amplified cells are highly sensitive to BI-907828, with an effective unbound concentration of 0.1 nmol/L. The CNS distribution of BI-907828 is limited by blood-brain barrier (BBB) efflux mediated by P-gp, resulting in a Kp,uu_brain of 0.002. Despite this seemingly "poor" BBB penetration, weekly administration of 10 mg/kg BI-907828 extended median survival of orthotopic GBM108 xenografts from 28 to 218 days (P < 0.0001). This excellent efficacy can be attributed to high potency, resulting in a limited, yet effective, exposure in the CNS. These studies show that efficacy of BI-907828 in orthotopic models is related to high potency even though its CNS distribution is limited by BBB efflux. Therefore, a comprehensive understanding of all aspects of the "Delivery - Potency - Efficacy" relationship is warranted in drug discovery and development, especially for treatment of CNS tumors.

IMMU-05. TUMOR INFLAMMATION-ASSOCIATED NEUROTOXICITY (TIAN): A TOXICITY SYNDROME IN PATIENTS TREATED WITH IMMUNOTHERAPY FOR CENTRAL NERVOUS SYSTEM TUMORS

Abstract Immunotherapies have transformed the therapeutic landscape for various cancer indications; currently several preclinical and clinical studies are exploring immune-based therapies for the treatment of central nervous system (CNS) tumors. The recognition of toxicity syndromes and establishment of toxicity grading scales for cytokine release syndrome (CRS) and immune effector-cell associated neurotoxicity syndrome (ICANS) have improved the administration and management of chimeric antigen receptor (CAR)-based therapies for B cell malignancies. We have observed a localized neurotoxicity syndrome, distinct from CRS and ICANS, in patients treated with immunotherapies for CNS tumors, which we term tumor inflammation-associated neurotoxicity (TIAN). TIAN arises secondary to localized inflammation at the tumor site causing local neuronal dysfunction and/or local inflammation-induced edema leading to tissue shifts and increased intracranial pressure (ICP). Although TIAN can be associated with inflammation-induced tumoral edema and may share similarities with “pseudoprogression,” TIAN can also occur in the absence of edema due to neural-immune interactions causing primary local neural dysfunction. We distinguish two types of TIAN:1) type 1 TIAN occurs when tumor inflammation-induced edema leads to mechanical space constraints and results in increased ICP, hydrocephalus, and if unmanaged, may cause a herniation syndrome 2) type 2 TIAN reflects inflammation-induced local neural electrophysiological dysfunction resulting in transient worsening/development of new neurological symptoms. In order to facilitate the safe administration of immunotherapies for CNS tumors and standardize reporting and clinical management, we have proposed a TIAN grading scale that encompasses both types of TIAN. Even though type 1 TIAN typically consists of higher-grade toxicities than type 2 TIAN, high-grade toxicities can also be seen in type 2 TIAN when tumor inflammation affects critical cardiopulmonary functions. As the promise of immunotherapies for the treatment of CNS tumors materializes, recognizing TIAN as a distinct, local neurotoxicity syndrome will be essential for patient safety and clinical management.

Focused ultrasound for treatment of peripheral brain tumors.

Malignant brain tumors are the leading cause of cancer-related death in children and remain a significant cause of morbidity and mortality throughout all demographics. Central nervous system (CNS) tumors are classically treated with surgical resection and radiotherapy in addition to adjuvant chemotherapy. However, the therapeutic efficacy of chemotherapeutic agents is limited due to the blood-brain barrier (BBB). Magnetic resonance guided focused ultrasound (MRgFUS) is a new and promising intervention for CNS tumors, which has shown success in preclinical trials. High-intensity focused ultrasound (HIFU) has the capacity to serve as a direct therapeutic agent in the form of thermoablation and mechanical destruction of the tumor. Low-intensity focused ultrasound (LIFU) has been shown to disrupt the BBB and enhance the uptake of therapeutic agents in the brain and CNS. The authors present a review of MRgFUS in the treatment of CNS tumors. This treatment method has shown promising results in preclinical trials including minimal adverse effects, increased infiltration of the therapeutic agents into the CNS, decreased tumor progression, and improved survival rates.

EANO guideline on rational molecular testing of gliomas, glioneuronal, and neuronal tumors in adults for targeted therapy selection.

The mainstay of treatment for adult patients with gliomas, glioneuronal and neuronal tumors consists of combinations of surgery, radiotherapy, and chemotherapy. For many systemic cancers, targeted treatments are a part of the standard of care, however, the predictive significance of most of these targets in central nervous system (CNS) tumors remains less well-studied. Despite that, there is increasing use of advanced molecular diagnostics that identify potential targets, and tumor-agnostic regulatory approvals on targets also present in CNS tumors have been granted. This raises the question of when and for which targets it is meaningful to test in adult patients with CNS tumors. This evidence-based guideline reviews the evidence available for targeted treatment for alterations in the RAS/MAPK pathway (BRAF, NF1), in growth factor receptors (EGFR, ALK, fibroblast growth factor receptor (FGFR), neurotrophic tyrosine receptor kinase (NTRK), platelet-derived growth factor receptor alpha, and ROS1), in cell cycle signaling (CDK4/6, MDM2/4, and TSC1/2) and altered genomic stability (mismatch repair, POLE, high tumor mutational burden (TMB), homologous recombination deficiency) in adult patients with gliomas, glioneuronal and neuronal tumors. At present, targeted treatment for BRAF p.V600E alterations is to be considered part of the standard of care for patients with recurrent gliomas, pending regulatory approval. For approved tumor agnostic treatments for NTRK fusions and high TMB, the evidence for efficacy in adult patients with CNS tumors is very limited, and treatment should preferably be given within prospective clinical registries and trials. For targeted treatment of CNS tumors with FGFR fusions or mutations, clinical trials are ongoing to confirm modest activity so far observed in basket trials. For all other reviewed targets, evidence of benefit in CNS tumors is currently lacking, and testing/treatment should be in the context of available clinical trials.

Events in CNS Tumor Pathology Post-2016 WHO CNS: cIMPACT-NOW Updates and Other Advancements: A Comprehensive Review Plus a Summary of the Salient Features of 2021 WHO CNS 5.

The 2016 World Health Organization Classification (WHO) of Tumors of the Central Nervous System (CNS) represented a major change. It recommended an "integrated diagnosis" comprising histologic and molecular information facilitating a more precise diagnosis of specific CNS tumors. Its goal was to provide greater diagnostic precision and reproducibility resulting in more clinical relevance and predictive value, ultimately leading to better patient care. Advances in molecular classification, mostly resulting from DNA methylation array profiling of CNS tumors, were occurring at a very rapid pace and required more rapid integration into clinical practice. cIMPACT-NOW updates and other recent papers plus salient features of 2021 WHO CNS5 in this comprehensive write-up were reviewed. CNS tumor classification needs to be updated at a rapid pace and mechanisms put into place to guide diagnosticians and clinicians in the interim period if major changes in the classification of tumor types came to light. Recognizing the need to integrate these into clinical practice more rapidly and without inordinate delay, the International Society of Neuropathology (ISN) 2016 sponsored an initiative called cIMPACT-NOW. Goal of cIMPACT-NOW was to provide clarification regarding contentious issues arising in the wake of the 2016 WHO CNS update as well as report new advancements in molecular classification of CNS tumors and new tumor entities emerging as a result of these advancements. cIMPACT-NOW updates: It thus laid the foundation for the 5th edition of the WHO Classification of CNS tumors (2021 WHO CNS 5). We have discussed cIMPACT updates in detail in this review. In addition, molecular diagnostics including DNA methylation-based classification of CNS tumors and the practical use of molecular classification in the prognostication and treatment of CNS tumors is discussed. Finally, the salient features of the new CNS tumor classification are summarized.

EXTH-96. BIOPROCESSING OF SURGICAL PEDIATRIC BRAIN TUMOR SPECIMENS FOR GENOME-GUIDED PERSONALIZED DRUG TESTING

Abstract Novel treatment approaches for pediatric central nervous system (CNS) tumors are urgently needed. A lack of patient-derived tumor cells impedes progress towards developing such new therapies. We intended to overcome this challenge by establishing methods to create a biorepository of viable single cell suspensions of pediatric brain tumor surgical specimens. Quantitative and qualitative comparisons of tissue processing strategies were performed to preserve viability of heterogeneous tumor and immune cells. Novel drug targets were identified by analyzing pathways affected by RNA transcripts that are highly expressed (outliers) in a patients’ tumor; outliers for each patient were determined by RNA-seq data from individual patients’ tumors compared with a compendium of 12,747 pediatric and adult samples harmonized by the Treehouse Childhood Cancer Initiative at the UCSC Genomics Institute. The predicted anti-tumor efficacy of small molecule inhibitors of the outlier pathways was tested in cell viability assays against short-term cultured cells from matched patients. Successful tissue collection required obtaining informed consent, standard operating procedures, and sample recording using a Laboratory Inventory Management Software (LIMS). Since 2020 we have banked 67 pediatric CNS brain tumor specimens at Stanford. Amongst those, 51 cases yielded sufficient tissue for RNA-seq and cryoprotection. The most common tumor histology was low-grade glioma (LGG, 26 of 67), the majority of which were pilocytic astrocytoma (18 of 26). The second and third most common tumor types are embryonal tumors (6 medulloblastoma, 3 AT/RT) and ependymoma (4), respectively. We identified significant differences in cell viability with different preservation media. An outlier pathway previously not implicated in LGG was identified and sensitivity to a small molecule inhibitor of this outlier pathway was demonstrated. Taken together, we established feasibility for validating therapeutic vulnerabilities identified by a genome-guided approach in short-term cultures from surgical specimens. This works facilitates the rapid development of personalized CNS tumor treatment.

Результати лікування дітей, хворих на злоякісні пухлини центральної нервової системи, в Харківському регіоні

Tumors of the central nervous system (CNS) in children among other tumors are second only to leukemia 17.6%. According to statistics, about 10.000 diseases are registered in the world every year. The range of histological forms of CNS tumors is extremely wide and diverse. Today there are more than 120 forms and varieties of such tumors. However, approximately 80% of cases in pediatric practice are represented by the following histological forms: medulloblastoma, juvenile pilocytic astrocytoma, diffuse infiltrative astrocytomas, ependymoma and craniopharyngioma. Other tumors of the central nervous system in children are much less common [2; 3;5]. There may be some discrepancies between the histological features and the biological behavior of CNS tumors. This is most pronounced in some cases of well-differentiated meningiomas, which can grow invasively into the surrounding tissues (skull bones and brain) and even metastasize to internal organs. At the same time in the primary center vascular invasion is not defined. Thus, when diagnosing and determining the degree of malignancy, it is necessary to consider the individual characteristics of each specific CNS tumor, which is not always possible in full when using existing research methods. The variety of histological forms of tumors, the difference of their molecular biological markers requires a balanced and differentiated approach to the choice of treatment. And the prognosis of the disease directly depends on the correct choice of tactics. Treatment of CNS malignancies is a complex multidisciplinary process that includes immunogenetic studies, stages of neurosurgical treatment, chemotherapy and radiation therapy. Moreover, the treatment strategy depends not only on the histological structure of the tumor, but also on the age of the child, the presence of local or widespread tumor, as well as the localization of tumor foci in the structures of the brain and spinal cord. The article presents the results of treatment of CNS tumors in children according to the municipal non-profit enterprise of the Kharkiv Regional Council “Regional Children’s Clinical Hospital No. 1” for 5 years. An analysis of various modern treatment options and the effectiveness of therapy. The treatment of malignant tumors of the CNS is a complex multidisciplinary process that includes immunogenetic studies, stages of neurosurgical treatment, chemotherapy and radiation therapy. Moreover, the treatment strategy depends not only on the histological structure of the tumor, but also on the age of the child, the presence of a local or widespread tumor, and also on the localization of tumor foci in the structures of the brain and spinal cord. The article presents the results of treatment of CNS tumors in children according to the municipal non-profit enterprise of the Kharkiv Regional Council “Regional Children’s Clinical Hospital № 1” for 5 years. An analysis of various modern treatment options and the effectiveness of therapy was carried out.

The renin-angiotensin system in central nervous system tumors and degenerative diseases.

Despite their differences, central nervous system (CNS) tumors and degenerative diseases share important molecular mechanisms underlying their pathologies, due to their common anatomy. Here we review the role of the renin-angiotensin system (RAS) in CNS tumors and degenerative diseases, to highlight common molecular features and examine the potential merits in repurposing drugs that inhibit the RAS, its bypass loops, and converging signaling pathways. The RAS consists of key components, including angiotensinogen, (pro)renin receptor (PRR), angiotensin-converting enzyme 1 (ACE1), angiotensin-converting enzyme 2 (ACE2), angiotensin I (ATI), angiotensin II (ATII), ATII receptor 1 (AT1R), ATII receptor 2 (AT2R) and the Mas receptor (MasR). The RAS is integral to systemic and cellular pathways that regulate blood pressure and body fluid equilibrium and cellular homeostasis. The main effector of the RAS is ATII which exerts its effect by binding to AT1R and AT2R through two competitive arms: an ACE1/ATII/AT1R axis, which is involved in regulating oxidative stress and neuroinflammation pathways, and an ATII/AT2R and/or ATII/ACE2/Ang(1-7)/MasR axis that potentiates neuroprotection pathways. Alterations of these axes are associated with cellular dysfunction linked to CNS diseases. The generation of ATII is also influenced by proteases that constitute bypass loops of the RAS. These bypass loops include cathepsins B, D and G and chymase and aminopeptidases. The RAS is also influenced by converging pathways such as the Wnt/β-catenin pathway which sits upstream of the RAS via PRR, a key component of the RAS. We also discuss the co-expression of components of the RAS and markers of pluripotency, such as OCT4 and SOX2, in Parkinson's disease and glioblastoma, and their potential influences on transduction pathways involving the Wnt/β-catenin, MAPK/ERK, PI3K/AKT and vacuolar (H+) adenosine triphosphatase (V-ATPase) signaling cascades. Further research investigating modulation of the ACE1/ATII/AT1R and ACE2/Ang(1-7)/MasR axes with RAS inhibitors may lead to novel treatment of CNS tumors and degenerative diseases. The aim of this review article is to discuss and highlight experimental and epidemiological evidence for the role of the RAS, its bypass loops and convergent signaling pathways in the pathogenesis of CNS tumors and degenerative diseases, to direct research that may lead to the development of novel therapy.

Neuroprotective Effects of Quercetin in Pediatric Neurological Diseases.

Oxidative stress is a crucial event underlying several pediatric neurological diseases, such as the central nervous system (CNS) tumors, autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). Neuroprotective therapy with natural compounds used as antioxidants has the potential to delay, ameliorate or prevent several pediatric neurological diseases. The present review provides an overview of the most recent research outcomes following quercetin treatment for CNS tumors, ASD and ADHD as well as describes the potential in vitro and in vivo ameliorative effect on oxidative stress of bioactive natural compounds, which seems like a promising future therapy for these diseases. The neuroprotective effects of quercetin against oxidative stress can also be applied in the management of several neurodegenerative disorders with effects such as anti-cancer, anti-inflammatory, anti-viral, anti-obesity and anti-microbial. Therefore, quercetin appears to be a suitable adjuvant for therapy against pediatric neurological diseases.

Abstract 2883: A transformable delivery system for the effective treatment of pediatric central nervous system tumors

Abstract Malignancies of the central nervous system (CNS) are the most common type of solid tumor affecting children and a leading cause of cancer-related death in children. With the deterioration of brain tumors, blood-brain barrier (BBB)/blood-brain tumor barrier (BBTB) with poor permeability, and relatively weak enhanced permeability and retention effect become major obstacles in delivering therapeutics to brain tumors. Vincristine (VCR) is a mainstay of treatment of a variety of cancers including brain tumors due to its well-defined mechanism of action and demonstrated anticancer activity. However, the clinical application of VCR in brain tumors was limited by its neurotoxicity and inability to penetrate BBB/BBTB resulting in unsatisfactory anti-cancer efficacy. In this project, we developed a transformable nanoparticle, named Ninja-nanoparticle, which is capable overcoming several important barriers for drug delivery to CNS tumors resulting in better efficacy and toxicity profile. Ninja-NP was stable during circulation due to crosslinking and could transpass BBB/BBTB through glucose receptor-mediated transcytosis. Ninja-NP could further transform into smaller nanoparticle upon encountering acidic microenvironment and revealed hidden moiety to target tumor surface overexpressed sialic acid. Ninja-NP employed a unique strategy which could sequentially target BBB/BBTB and brain tumor cells. Our study confirmed that VCR loaded Ninja-NP significantly accumulated at the orthotopic brain tumor sites, and exhibited superior anti-cancer efficacy in orthotopic diffuse intrinsic pontine glioma (DIPG), the most deadly pediatric CNS tumor, then free VCR or Liposomal VCR with limited systemic toxicity. Ninja-NP addresses multiple challenges for CNS tumor treatment and exhibits great potential to be translated into an effective theranostic nano-platform which could be seamlessly integrated into standard human brain tumor management (imaging-guided drug delivery) with reduced long term toxicity. Citation Format: Tzu-yin Lin. A transformable delivery system for the effective treatment of pediatric central nervous system tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2883.