Types Of Pediatric Brain Tumors Research Articles

Transcriptomic observations of intra and extracellular immunotherapy targets for pediatric brain tumors

ABSTRACT Objectives Despite surgical resection, chemoradiation, and targeted therapy, brain tumors remain a leading cause of cancer-related death in children. Immunotherapy has shown some promise and is actively being investigated for treating childhood brain tumors. However, a critical step in advancing immunotherapy for these patients is to uncover targets that can be effectively translated into therapeutic interventions. Methods In this study, our team performed a transcriptomic analysis across pediatric brain tumor types to identify potential targets for immunotherapy. Additionally, we assessed components that may impact patient response to immunotherapy, including the expression of genes essential for antigen processing and presentation, inhibitory ligands and receptors, interferon signature, and overall predicted T cell infiltration. Results We observed distinct expression patterns across tumor types. These included elevated expression of antigen genes and antigen processing machinery in some tumor types while other tumors had elevated inhibitory checkpoint receptors, known to be associated with response to checkpoint inhibitor immunotherapy. Conclusion These findings suggest that pediatric brain tumors exhibit distinct potential for specific immunotherapies. We believe our findings can guide investigators in their assessment of appropriate immunotherapy classes and targets in pediatric brain tumors.

MDB-52. MYC-DRIVEN PEDIATRIC BRAIN TUMORS SHARE A COMMON PHOTORECEPTOR IDENTITY

Abstract Mouse models serve as invaluable tools for improving the understanding and treatment of pediatric brain tumors. We recently published a highly aggressive MYC-driven brain tumor model (GMYC), which exhibits approximately 70% penetrance. Our transcription profiling indicates that GMYC tumors accurately resemble human Group 3 medulloblastoma (MB-G3). Interestingly, a strong photoreceptor program was activated in the tumor model. This is commonly upregulated in MB-G3 but also in pineoblastoma (PB), another malignant pediatric brain tumor. CRX, a transcription factor critical for pineal cell development is also a master regulator for MB-G3 maintenance. By studying early tumor initiation using Crx-lineage tracing and scRNA-seq, we confirmed that GMYC tumors originate from early pinealocytes. Exome sequencing of GMYC tumors further confirmed mutations of epigenetic regulators commonly reported in either PB or MB. To investigate tumor development from photoreceptor-positive progenitors in the developing brain, we performed Crx-lineage tracing with tamoxifen injections, confirming that Crx-positive cells exist in pineal gland progenitors. However, Crx-traced cells also marked granule neurons in the flocculonodular lobe of the cerebellum, which is the suggested site of MB-G3 origin arising from the developing rhombic lip. To investigate if the Myc oncogene can generate different types of pediatric brain tumors in Crx-positive cells, an XMYCT58A-Tomato mouse model was established by crossing Crx-CreERT2; LSL-MycT58A and Rosa26LSL-tdTomato strains. Here, MycT58A was turned on with tamoxifen injection after birth and tumor development followed using the tdTomato reporter. XMYCT58A-Tomato mice developed brain tumors from both the pineal gland and cerebellum after 2-6 months. Histologically, tumors were non-glial (GFAP-, Olig2-), showed neuronal activity (Neurod1+), and stained positive for photoreceptor identity markers (CRX+, OTX2+) similar to both MB-G3 and PB-MYC. Collectively, our data suggest that both MYC-driven MB-G3 and PB-MYC originate from photoreceptor-positive cells, which has implications for developing novel treatments targeting these devastating childhood malignancies.

BIOM-03. IMMUNO-ONCOLOGIC PROFILING OF PEDIATRIC BRAIN TUMORS REVEALS MAJOR CLINICAL SIGNIFICANCE OF THE TUMOR IMMUNE MICROENVIRONMENT

Abstract With the success of immunotherapy in cancer, understanding the tumor immune microenvironment (TIME) has become increasingly important; however in pediatric brain tumors this remains poorly characterized. Accordingly, we developed a clinical immune-oncology gene expression assay, including the 18-gene tumor inflammation signature (TIS) as a marker of overall immune activation, and validated this with immunohistochemistry for key cell-type markers. We used this assay, in conjunction with public data from the Pediatric Brain Tumor Atlas (PBTA), to profile a diverse range of 1382 samples in total with detailed clinical and molecular annotation. Overall among the main types of pediatric brain tumors, low-grade gliomas (LGG) had the highest inflammation levels (regardless of genetic driver alteration) and medulloblastomas the lowest. In LGG we identified three distinct patterns of immune activation with prognostic significance in BRAF V600E-mutant tumors, specifically that higher inflammation predicted worse outcomes. In high-grade gliomas (HGG), we observed immune activation and T-cell infiltrates in tumors that have historically been considered exclusively immune cold. There were genomic correlates of inflammation levels, with BRAF-V600E-mutant HGG having the highest inflammation levels and suggesting these may be candidates for combination MEK inhibition and immunotherapy. In mismatch repair deficient HGG, we found that high TIS was a significant predictor of response to immune checkpoint inhibition, and demonstrated the potential for multimodal biomarkers (TIS plus tumor mutation burden) to improve treatment stratification. Importantly, while overall patterns of immune activation were observed for histologically and genetically defined tumor types, there was significant variability within each entity, indicating that the TIME must be evaluated as an independent feature from diagnosis. In sum, in addition to the histology and molecular profile, this work underscores the importance of reporting on the TIME as an essential axis of cancer diagnosis in the era of personalized medicine.

MDB-68. DISCOVERING DRUG SENSITIVITIES IN MEDULLOBLASTOMA USING PATIENT- AND PDX-DERIVED TUMOROIDS

Abstract BACKGROUND Medulloblastoma (MB) is one of the most common malignant pediatric brain tumor types and is subdivided into four major types: WNT, SHH, Group 3 and Group 4. Treatment, including resection, cranio-spinal radiotherapy, and chemotherapy, often leads to undesirable long-term side effects. MB prognosis depends on type, subtype, and genetic alterations, reflecting the high level of heterogeneity observed in these tumors and indicating that specific patient populations with particularly poor prognosis require alternative treatment approaches. Therefore, preclinical models are essential for recapitulating MB heterogeneity and developing subtype-specific treatments. METHODS Long-term in vitro MB tumoroid models were developed from patient and PDX tumors and molecularly characterized using DNA methylation and transcriptomic analyses. High-throughput single drug screening (225 compounds) and combination screening were performed to identify (subtype-specific) drug sensitivities. RESULTS Fifteen tumoroid lines were established from TP53-mutated SHH (n=6), Group 3 (G3) MYC-amplified (n=4) and non-amplified (n=5) patient (n=6) and PDX (n=9) tumors. DNA methylation analyses confirmed the maintenance of molecular identity in these tumoroids after long-term culture (>5 passages). Transcriptome analyses reveal a more proliferative, progenitor-like phenotype in these tumoroids compared to patient/PDX tumors. Hight-throughput drug screens identified both common and type-specific drug sensitivities within MB. Notably, drugs targeting CDK7, CDK12, CHECK1, BCL2L, and HDAC demonstrated efficacy in both G3 and TP53-mutated SHH-MB, while TOP1/2 and MDM2 inhibitors were specific for G3-MB. Currently, these drugs are being further investigated to select the most effective synergistic drug combinations for in vivo validation in PDX models. CONCLUSIONS Thus far, we have established already fifteen MB tumoroid models representing SHH-MB and G3-MB and identified several drug targets, including cell cycle kinases and HDACs. Tumoroids closely resemble patient tumors, based on methylome and transcriptome, enhancing their relevance for drug discovery applications in a high-throughput fashion and for prioritizing new treatment strategies for MB patients in clinical trials.

Abstract 7578: BRD4 protein degradation for p53 mutant diffuse intrinsic pontine glioma (DIPG) via various delivery approaches for ARV-825 by using camel milk exosomes

Abstract DIPGs (diffuse intrinsic pontine gliomas) are a particularly aggressive and malignant type of pediatric brain tumor. Given the tumor's location, surgery has a restricted role, and it is insensitive to most chemotherapies. Although fractionated radiation is the standard of therapy for DIPG, the cancer invariably worsens in 6-12 months. TP53 tumor suppressor protein mutations are found in 70-80% of DIPG tumors. These TP53 mutations have been linked to radiation resistance in DIPG patients. Our goal was to find new pharmacological compounds that would improve the radiation sensitivity of p53 mutant DIPG cell lines and to determine their molecular mechanism of action. Numerous bromodomain-containing protein 4 (BRD4) inhibitors have entered clinical trials in recent years, yielding promising outcomes in tumor treatment since BRD4 expression in DIPG is substantially higher than in neighboring normal brain tissue. So consequently, BRD4 is a target for DIPG treatment. ARV-825 is an emerging PROTAC (Proteolysis Targeting Chimera) compound which can cause rapid and persistent BRD4 protein degradation. However, delivering ARV-825 to pons is a major challenge owing to poor oral bioavailability of PROTACS. In this study, we used camel milk derived exosomes (CME) for delivery of ARV-825 to pons by both nasal and oral routes. To begin with, goat milk exosomes were also considered but CME was chosen because of its innate cytotoxicity against DIPG cell lines. CME were isolated using ultracentrifugation and nanoparticle tracking analysis and revealed a size distribution of 112.5 ± 2.8 nm, zeta potential of -26.38 ± 0.12 mV. CME (1*1011) were cytotoxic to both SF8628 (with a H3.3 K27M mutation) and SF188 (grade IV pediatric glioblastoma with wild type H3.3) cell lines and had 51% and 44% cell viability respectively. ARV-825 showed IC50 of 546.58 ± 22.14 nM and 608.94 ± 30.04 nM in SF8628 cells and SF188 cells respectively. ARV-825’s IC50 was lowered when ARV-825 loaded CME were used. ARV-825 was loaded using sonication and entrapment efficiency was found to be 42.96 ± 2.14 % by HPLC analysis. CME were labelled with Vybrant DiO (CME-DIO) and instilled into each nostril of Sprague Dawley rats daily. Brain sections were viewed with fluorescent microscope and CME-DIO were seen in olfactory region after 3 days and in the pons region after 5 days demonstrating the ability of CME to reach the target site. In-vitro permeability studies using MDCK cells showed approximately 9µg/mL (60%), 15µg/mL (80%) and 16µg/mL (100%) of ARV-825 permeation in 2, 4 and 24 hours respectively when loaded into CME. The results of the present study suggest the possibility of using CME as a viable delivery strategy for ARV-825 against DIPG. Further in vitro and in vivo studies are currently undergoing to validate the results and understand kinetics and the molecular mechanisms of ARV-825 loaded CME. Citation Format: Aakash Nathani, Mounika Aare, Li Sun, Yan Li, Mandip Singh. BRD4 protein degradation for p53 mutant diffuse intrinsic pontine glioma (DIPG) via various delivery approaches for ARV-825 by using camel milk exosomes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7578.

Gene Expression of GABAA Receptor Subunits and Association with Patient Survival in Glioma.

Rapid neuronal inhibition in the brain is mediated by γ-aminobutyric acid (GABA) activation of GABAA receptors. The GABRA5 gene, which encodes the α5 subunit of the GABAA receptor, has been implicated in an aggressive subgroup of medulloblastoma (MB), a type of pediatric brain tumor. However, the possible role of GABAA receptor subunits in glioma remains poorly understood. Here, we examined the expression of genes encoding GABAA receptor subunits in different types of glioma, and its possible association with patient prognosis assessed by overall survival (OS). Data were obtained from the French and The Cancer Genome Atlas Brain Lower Grade Glioma (TCGA-LGG) datasets and analyzed for expression of GABAA receptor subunit genes. OS was calculated using the Kaplan-Meier estimate. We found that genes GABRA2, GABRA3, GABRB3, GABRG1, and GABRG2 showed a significant association with OS, with higher gene expression indicating better prognosis. In patients with GBM, high expression of GABRA2 was associated with shorter OS, whereas, in contrast, higher levels of GABRB3 were associated with better prognosis indicated by longer OS. In patients with lower grade gliomas, GABRA3, GABRB3, GABRG1, and GABRG2, were associated with longer OS. High GABRB3 expression was related to longer survival when low grade glioma types were analyzed separately. Our results suggest an overall association between higher expression of most genes encoding GABAA receptor subunits and better prognosis in different types of glioma. Our findings support the possibility that down-regulation of GABAA receptors in glioma contributes to promoting tumor progression by reducing negative inhibition. These findings might contribute to further evaluation of GABAA receptors as a therapeutic target in glioma.

Germline BRCA2 pathogenic variants in pediatric ganglioglioma: Case report and review of the literature.

BRCA1 and BRCA2 are tumor suppressor genes associated with increased risk of breast and ovarian cancer in adulthood. Patients with germline pathogenic variants in these genes have also been reported to develop brain tumors, although it is unclear whether these syndromes are associated with significant increased risk of brain tumor formation. Here, we report a case of a child with germline BRCA2 pathogenic variant presenting with a symptomatic ganglioglioma. To our knowledge, this is the first such patient to be reported. We discuss prior cases of brain tumors in BRCA1/2 patients and evidence for a potential role for BRCA1/2 pathogenic variants in brain tumor formation. BRCA2 germline variants may increase the risk of developing some types of pediatric brain tumors, but further study is needed to determine its effect on low-grade glioma formation.

The unique immune ecosystems in pediatric brain tumors: integrating single-cell and bulk RNA-sequencing.

The significant progress of immune therapy in non-central nervous system tumors has sparked interest in employing the same strategy for adult brain tumors. However, the advancement of immunotherapy in pediatric central nervous system (CNS) tumors is not yet on par. Currently, there is a lack of comprehensive comparative studies investigating the immune ecosystem in pediatric and adult CNS tumors at a high-resolution single-cell level. In this study, we comprehensively analyzed over 0.3 million cells from 171 samples, encompassing adult gliomas (IDH wild type and IDH mutation) as well as four major types of pediatric brain tumors (medulloblastoma (MB), ependymoma (EPN), H3K27M-mutation (DIPG), and pediatric IDH-mutation glioma (P-IDH-M)). Our approach involved integrating publicly available and newly generated single-cell datasets. We compared the immune landscapes in different brain tumors, as well as the detailed functional phenotypes of T-cell and myeloid subpopulations. Through single-cell analysis, we identified gene sets associated with major cell types in the tumor microenvironment (gene features from single-cell data, scFes) and compared them with existing gene sets such as GSEA and xCell. The CBTTC and external GEO cohort was used to analyze and validate the immune-stromal-tumor patterns in pediatric brain tumors which might potentially respond to the immunotherapy. From the perspective of single-cell analysis, it was observed that major pediatric brain tumors (MB, EPN, P-IDH-M, DIPG) exhibited lower immune contents compared with adult gliomas. Additionally, these pediatric brain tumors displayed diverse immunophenotypes, particularly in regard to myeloid cells. Notably, the presence of HLA-enriched myeloid cells in MB was found to be independently associated with prognosis. Moreover, the scFes, when compared with commonly used gene features, demonstrated superior performance in independent single-cell datasets across various tumor types. Furthermore, our study revealed the existence of heterogeneous immune ecosystems at the bulk-RNA sequencing level among different brain tumor types. In addition, we identified several immune-stromal-tumor patterns that could potentially exhibit significant responses to conventional immune checkpoint inhibitors. The single-cell technique provides a rational path to deeply understand the unique immune ecosystem of pediatric brain tumors. In spite of the traditional attitudes of "cold" tumor towards pediatric brain tumor, the immune-stroma-tumor patterns identified in this study suggest the feasibility of immune checkpoint inhibitors and pave the way for the upcoming tide of immunotherapy in pediatric brain tumors.

Rapid Peroxide Removal Limits the Radiosensitization of Diffuse Intrinsic Pontine Glioma (DIPG) Cells by Pharmacologic Ascorbate.

Diffuse intrinsic pontine gliomas (DIPG) are an aggressive type of pediatric brain tumor with a very high mortality rate. Surgery has a limited role given the tumor's location. Palliative radiation therapy alleviates symptoms and prolongs survival, but median survival remains less than 1 year. There is no clear role for chemotherapy in DIPGs as trials adding chemotherapy to palliative radiation therapy have failed to improve survival compared to radiation alone. Thus, there is a critical need to identify tissue-specific radiosensitizers to improve clinical outcomes for patients with DIPGs. Pharmacologic (high dose) ascorbate (P-AscH-) is a promising anticancer therapy that sensitizes human tumors, including adult high-grade gliomas, to radiation by acting selectively as a generator of hydrogen peroxide (H2O2) in cancer cells. In this study we demonstrate that in contrast to adult glioma models, P-AscH- does not radiosensitize DIPG. DIPG cells were sensitive to bolus of H2O2 but have faster H2O2 removal rates than GBM models which are radiosensitized by P-AscH-. These data support the hypothesis that P-AscH- does not enhance DIPG radiosensitivity, likely due to a robust capacity to detoxify and remove hydroperoxides.

BIOL-17. DISSECTING THE EXPRESSION AND FUNCTION OF ANGIOPOIETIN-1 IN PEDIATRIC BRAIN TUMORS

Abstract BACKGROUND Angiopoietin-1 (Angpt1) is a secreted protein that promotes angiogenesis and vascular stability in development and certain disease states through activation of the Tie2 receptor. However, little is known about its expression or function within pediatric brain tumors. METHODS We utilized available datasets from patient samples and created murine models of pediatric high-grade glioma and ependymoma by in utero electroporation. Using a combination of transcriptomics and Angpt1-GFP reporter tumor models we evaluated Angpt1 expression across different types of pediatric brain tumors. We also applied inducible Angpt1 floxed mice to generate tumor-specific knock-out models. RESULTS Angpt1 is upregulated in glial brain tumors, including high-grade gliomas and ependymomas. We find Angpt1 is expressed by specific cell populations within gliomas and ependymomas, along with non-tumor reactive astrocytes and perivascular mural cells. Leveraging our in vivo brain tumor platform we have created tumor specific Angpt1 knock-out models by including a plasmid expressing Cre-recombinase. Ongoing studies aim to delineate the function of Angpt1 in tumor pathogenesis, including tumor angiogenesis and blood-brain barrier function. CONCLUSION Current work finds that Angpt1 is upregulated in glial brain tumors and nominates it as a potential modulator of brain tumor vascular biology, including tumor angiogenesis and permeability.

Addressing blood-brain-tumor-barrier heterogeneity in pediatric brain tumors with innovative preclinical models.

Brain tumors represent the leading cause of disease-related mortality and morbidity in children, with effective treatments urgently required. One factor limiting the effectiveness of systemic therapy is the blood-brain-barrier (BBB), which limits the brain penetration of many anticancer drugs. BBB integrity is often compromised in tumors, referred to as the blood-brain-tumor-barrier (BBTB), and the impact of a compromised BBTB on the therapeutic sensitivity of brain tumors has been clearly shown for a few selected agents. However, the heterogeneity of barrier alteration observed within a single tumor and across distinct pediatric tumor types represents an additional challenge. Herein, we discuss what is known regarding the heterogeneity of tumor-associated vasculature in pediatric brain tumors. We discuss innovative and complementary preclinical model systems that will facilitate real-time functional analyses of BBTB for all pediatric brain tumor types. We believe a broader use of these preclinical models will enable us to develop a greater understanding of the processes underlying tumor-associated vasculature formation and ultimately more efficacious treatment options.

Advances in the Treatment of Pediatric Brain Tumors.

Pediatric brain tumors are the most common solid malignancies in children. Advances in the treatment of pediatric brain tumors have come in the form of imaging, biopsy, surgical techniques, and molecular profiling. This has led the way for targeted therapies and immunotherapy to be assessed in clinical trials for the most common types of pediatric brain tumors. Here we review the latest efforts and challenges in targeted molecular therapy, immunotherapy, and newer modalities such as laser interstitial thermal therapy.

Selected Articles from This Issue

Highlights| October 03 2022 Selected Articles from This Issue Author & Article Information Online ISSN: 1557-3265 Print ISSN: 1078-0432 ©2022 American Association for Cancer Research2022American Association for Cancer Research Clin Cancer Res (2022) 28 (19): 4159. https://doi.org/10.1158/1078-0432.CCR-28-19-HI Related Content A commentary has been published: Clinical, Pathologic, and Molecular Prognostic Factors in Patients with Early-Stage EGFR-Mutant NSCLC A commentary has been published: Detection of Occult Recurrence Using Circulating Tumor Tissue Modified Viral HPV DNA among Patients Treated for HPV-Driven Oropharyngeal Carcinoma A commentary has been published: Microsatellite Instability–High Endometrial Cancers with MLH1 Promoter Hypermethylation Have Distinct Molecular and Clinical Profiles View more A commentary has been published: OLIG2 Is a Determinant for the Relapse of MYC-Amplified Medulloblastoma View less Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Tools Icon Tools Get Permissions Cite Icon Cite Search Site Article Versions Icon Versions Version of Record October 3 2022 Citation Selected Articles from This Issue. Clin Cancer Res 1 October 2022; 28 (19): 4159. https://doi.org/10.1158/1078-0432.CCR-28-19-HI Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest Search Advanced Search Patients with MYC-amplified medulloblastoma (MB) have poor prognosis and frequently develop recurrence; thus new therapeutic approaches to prevent recurrence are needed. Here, Xu and colleagues demonstrate that OLIG2-expressing tumor cells are highly enriched in therapy resistant and recurrent MYC-amplified MB and high levels of OLIG2 correlated with poor prognosis. Genetic or pharmacological inhibition of OLIG2 in combination with radiotherapy significantly suppressed the progression of OLIG2-high tumors in patient-derived xenograft mouse models, indicating that OLIG2 represents a novel therapeutic target in high-risk MB. CT-179 is a highly potent and selective small molecule OLIG2 inhibitor. The study provides evidence for CT-179 to potentially act as an adjunctive therapy for patients with high-risk MB as well as other types of pediatric brain tumors where OLIG2 is highly expressed. Thus patients with these cancers may also benefit from CT-179 treatment. Cell-free tumor tissue modified viral (TTMV)-HPV DNA is a unique biomarker, present... You do not currently have access to this content.

Development of GPC2-directed chimeric antigen receptors using mRNA for pediatric brain tumors

BackgroundPediatric brain tumors are the leading cause of cancer death in children with an urgent need for innovative therapies. Glypican 2 (GPC2) is a cell surface oncoprotein expressed in neuroblastoma...

HGG-50. Specific sensitivity of pediatric high-grade glioma with ATRX inactivation to PARP inhibitor combinations

Pediatric high-grade gliomas (pHGG) account for approximately 12% of pediatric brain tumors. Despite advances in molecular diagnosis and identification of discrete molecular subtypes, pHGG are the leading cause of cancer-related death in children. Thus, current research focuses on identifying novel therapeutic targets. Sequencing analyses across pediatric cancer types identified DNA repair perturbations as potentially targetable events in certain types of pediatric brain tumors. Herein, we investigated the potential of PARP inhibitors (PARPi), impeding the central role of PARP in DNA damage repair, in pHGG. We screened a patient-derived primary pHGG cell line panel (n=7) for their sensitivity towards 6 different PARPi (niraparib, olaparib, pamiparib, rucaparib, talazoparib, veliparib) using cell viability assays. Basal expression of DNA repair related proteins was assessed by immunoblot, and propidium iodide-based flow cytometry was used for cell cycle analysis. All pHGG were resistant towards single compound PARP inhibition. Interestingly, two H3F3A-G34R mutant pHGG models harboring inactivating ATRX mutations were characterized by elevated basal levels of pH2AX, suggesting increased stress resulting from DNA damage. Consequently, simultaneous targeting of PARP and other components of DNA repair in the respective models showed strong synergistic effects on cell viability, which was not observed to a comparable extent in other models such as BRAFV600E/TERT promotor mutant pHGG. Combination of talazoparib and irinotecan resulted in S-phase arrest. Within a precision oncology approach, we treated a 11-year-old child suffering from H3F3A-G34R mutant pHGG with ATRX mutation, that progressed during radiation, with niraparib and topotecan. The patient achieved partial remission and disease stabilization for 1 year. Taken together, PARPi combinations show potential for the treatment of pHGG with ATRX mutations. Currently, all cell models are characterized for DNA repair signatures by DNA sequencing. Further, in depth characterization of DNA damage responses upon concomitant PARP and topoisomerase inhibition in ATRX-mutated pHGG are ongoing.

MODL-01. Targeting replication stress in pediatric brain tumors

Previously, we have found that Embryonal Tumors with Multilayered Rosettes (ETMR) tumor cells harboring high levels of R-loops, a potential marker for replication stress and genomic instability, are vulnerable to a combination of topoisomerase and PARP inhibitors. To follow up on this, we investigated whether other pediatric brain tumor types with high levels of R-loops, such as MYC-amplified Group 3 medulloblastoma (MB) and ZFTA-fusion positive ependymoma, are also sensitive to these inhibitors. First, we performed in vitro drug screens using HD-MB03, a Group 3 MB cell line, and the ETMR cell line BT183, and in both screens PARP inhibitors were identified as the most synergistic combination partners for the topoisomerase inhibitor Irinotecan, respectively the active metabolite SN-38. Normal Astrocytes were not sensitive to these combinations. Secondly, we performed in vivo studies using patient-derived xenograft (PDX) models injected subcutaneously or intracranially into NSG mice, and treated with the PARP inhibitor Pamiparib, Irinotecan or a combination of both. For a MYC-amplified Group 3 MB and a ZFTA-fusion positive Ependymoma model, both injected intracranially, treatment with Irinotecan or the combination led to a significant survival benefit and inhibition of tumor growth including transient tumor shrinkage, but addition of Pamiparib did not add any further benefit in vivo, even though intratumoral PARP was inhibited by at least 80%. In contrast, in the subcutaneously injected ETMR model, the combination treatment with Irinotecan and Pamiparib led to a synergistic effect and complete regression of the tumors. Further refinements of the treatment strategy as dose adaptations and the use of a pegylated version of SN-38 (PLX038A) did also not induce a synergistic effect of the drugs for the intracranial tumors. Additional in vivo studies to evaluate the differences in efficacy and whether these are tumor specific or due to incomplete brain penetrance of the drugs are ongoing.

Determining Pediatric Radiotherapy Capacity in Mexico

A 2019 report demonstrated that Mexico and Central America have the highest total incidence of childhood cancers in the Western Hemisphere. Mexican children face disparities in cancer outcome. In Mexico, the 5-year survival estimates for ependymoma and intracranial germ cell tumors, two pediatric brain tumor types, are approximately 20%, which is dramatically lower than the survival outcomes reported in the US of 80% or higher. We sought to determine the self-identified treatment patterns, needs, and concerns of Mexican radiation oncologists for pediatric cancer management.Stakeholder planning began the summer of 2019. Partnering with local experts and the national Sociedad Mexicana de Radioterapeutas (SOMERA), we reviewed and designed a Spanish-language survey to ascertain pediatric radiotherapy capacity. The survey consisted of 35 questions and was distributed through the SOMERA listserv with promotion on social media. The survey was open from July 11 through August 30, 2020. Descriptive statistics were conducted. For frequencies, we report median (range). Surveys were stored in Qualtrics.A total of 94 radiation oncologists attempted, and 79 completed, the survey and identified as working in Mexico, representing 20 different cities. Of those, 58 (73%) responded saying they had treated a pediatric patient within the past year with median 9 years of practice (1-38). Forty-four (76%) felt comfortable with treating a pediatric patient, and 36 (62%) said they were familiar with national protocols for pediatric cancer treatment. The median number of pediatric cases seen in the past year by respondents was 9.5 (0 - 195). The three most common tumors treated were Hodgkin lymphoma (2; 0-21), medulloblastoma (1.5; 0-20), and Wilms tumor (1; 0-20), respectively. The median percentage of pediatric patients treated palliatively was 10%. Also, 26% responded having access to a multidisciplinary tumor board. Regarding supports, the majority had access to nutrition, rehabilitation, endocrinology, and anesthesia; 14% had access to fertility services, 27% had access to neurocognitive support, 11% responded noting no support, and only 1 respondent had child-life support. When asked what challenges they face as physicians, 20% expressed a lack of treatment spots and extended delay to new start, and 16% noted challenges with access to pediatric oncology and multidisciplinary teams.We present the first national survey of Mexican radiation oncologists with an intent to explore pediatric radiotherapy capacity. Through partnership with SOMERA, many centers were represented across the country. The majority of respondents who had treated a child patient felt comfortable doing so. Limited resources include access to fertility, child-life, and neurocognitive services. Wait times and lack of treatment spots were the most common physician challenges identified by respondents.

FREQUENCY OF PEDIATRIC BRAIN TUMORS IN TERTIARY CARE INSTITUTE OF PAKISTAN AND COMPARISON WITH INTERNATIONAL DATA

Objective: To analyze the histological spectrum of pediatric brain tumors (PBT) in Pakistani population and to compare the results with international data.
 Study Design: Retrospective observational study.
 Place and Duration of Study: Armed Forces Institute of Pathology, Rawalpindi, from Jan 2015 and Dec 2019.
 Methodology: This data was analyzed using the latest World Health Organization (WHO) classification of Tumors of Central Nervous System 2016. The cases were divided in 5 categories according to age (0-2, 3-5, 6-8, 9-11 & 12-14 years).
 Results: A total of 43 cases were included in the study. Of these cases, 26 (60.46%) were male and 17 (39.5%) were female. Male to female ratio was 1.5-1. The 6-8 year age group had the highest number of tumors while 0-2 year age group had the least. Mean age of diagnosis was 7.6 years. Ependymoma wasthe most common morphological type with 12 cases (28%) followed by pilocytic astrocytoma, diffuse glioma with 10 cases each (23%) and medulloblastoma with 9 cases (21%). Least common tumor subtype was Ewing sarcoma. Ependymoma were mostly of grade 3 (64%), pilocytic astrocytoma and medulloblastoma were of grade 1 and grade 4 respectively by definition, and diffuse gliomas were mainly of grade 2 (57%) type.
 Conclusion: Ependymoma and pilocytic astrocytomaare the most frequent types of pediatric brain tumors in our region which follows the same trend as mentioned in western and regional literature.

Deep Learning-Based Studies on Pediatric Brain Tumors Imaging: Narrative Review of Techniques and Challenges.

Brain tumors diagnosis in children is a scientific concern due to rapid anatomical, metabolic, and functional changes arising in the brain and non-specific or conflicting imaging results. Pediatric brain tumors diagnosis is typically centralized in clinical practice on the basis of diagnostic clues such as, child age, tumor location and incidence, clinical history, and imaging (Magnetic resonance imaging MRI / computed tomography CT) findings. The implementation of deep learning has rapidly propagated in almost every field in recent years, particularly in the medical images’ evaluation. This review would only address critical deep learning issues specific to pediatric brain tumor imaging research in view of the vast spectrum of other applications of deep learning. The purpose of this review paper is to include a detailed summary by first providing a succinct guide to the types of pediatric brain tumors and pediatric brain tumor imaging techniques. Then, we will present the research carried out by summarizing the scientific contributions to the field of pediatric brain tumor imaging processing and analysis. Finally, to establish open research issues and guidance for potential study in this emerging area, the medical and technical limitations of the deep learning-based approach were included.

Tumor-Treating Fields Therapy for Pediatric Brain Tumors.

Tumor-treating fields (TTFields) are alternating electric fields applied continuously to the brain by attaching two-pair arrays on the scalp. Although TTFields therapy has demonstrated efficacy against supratentorial glioblastoma (GBM) in adults, its safety and efficacy in children have not been confirmed. Despite differences in the genetic etiology of the adult and pediatric forms of GBM, both have certain clinical behaviors in common, allowing us to test TTFields therapy in pediatric GBM. Recently, several, pediatric case-series using TTFields therapy have been published, and a few, prospective, pediatric studies are ongoing. Because GBMs are extremely rare in pediatric patients, where they comprise a wide variety of genetic subtypes, these pediatric studies are feasibility studies targeting various types of malignant brain tumor. Although they are important for confirming the safety and feasibility of TTFields therapy in the pediatric population, confirming its efficacy against each type of pediatric brain tumor, including the GBM, is difficult. Our clinical research team, therefore, planned an investigator-initiated clinical trial targeting pediatric supratentorial GBMs (as in adults) with the aim of expanding regulatory approval of TTFields therapy for pediatric GBM treatment based on safety and exploratory efficacy data in combination with the accumulated evidence on adult GBMs.