bluuebunny/crossref_metadata_2025_split huggingface dataset:
CSIG-05. IS THERE ANY BRAIN TUMOR PREDISPOSITION IN RELATED PALLISTER-HALL SYNDROMES AT THE NEW GENOMICS ERA
Authors: Abdelmoula Nouha Bouayed , Kammoun Sonda , Rekik Mona , Amor Saloua Ben , Fatma Mzid Abid , Sellami Sahla , Sehli Mariem , Mrad Aymen Ben , Chaabouni Karim , Trigui Amira 
Published: November 2024

Abstract
Pallister-Hall Syndrome (PHS) and its related syndromes are a spectrum of congenital malformations. They are associated to GLI3 mutations and specific brain tumors. Considered as lethal, it is now well established that this disease may be miss-diagnosed with the report of adult cases. Here, we discuss the management of the genetic counselling and the risk of neurologic tumor predisposition in GLI3-related PHS. We comprehensively reviewed the scientific literature using various databases to explore the risk of neurologic tumors and evolving practice of neuro-cancer genetic counseling in GLI3-related PHS. The review of literature showed that GLI3 is involved in tissue development as well as in cancer. GLI3 was identified as either a pro or anti-cancerous protein. In fact, GLI3 is described as upregulated in multiple cancers and is found to positively regulate malignant behavior. In neuro-oncology GLI gene was first identified as a highly expressed gene in human glioma and then as having an anti-cancerous role in medulloblastoma where GLI3 seems act as a tumor suppressor. In mutational studies, GLI3-germinal mutations are characterized by a high recurrence of hypothalamic hamartoma in syndromic patients. GLI3-somatic alterations have been also demonstrated in cell samples of patients with non-syndromic hypothalamic hamartoma. In addition, while inactivation of GLI3 is suggested to be associated with medulloblastoma, mutations are not common in sporadic medulloblastoma. The association of germinal GLI3 variants in syndromic patients with medulloblastoma has been identified in only one patient harboring GLI3 H302X variant. Our review permitted us to conclude that germline GLI3 mutations may predispose to a specific non-severe form of delayed hypothalamic hamartoma, which can be revealed in pauci or asymptomatic and unrecognized mutated individuals. The likelihood of having a neuro-cancer predisposition in GLI3 mutated families seems to be insignificant.
CSIG-07. JAK1/STAT1/3 COOPERATES WITH THE CIC-FUSIONS TO DRIVE CIC-REARRANGED SARCOMAS
Authors: Kaloti Ramneet , Bunda Severa , Zadeh Gelareh 
Published: November 2024

Abstract
CIC-rearranged sarcoma (CRS) is an rare disease driven by a specific fusion protein involving the CIC gene. Occurrence in the brain is 3% in all CRS patients. The native CIC protein is a transcriptional repressor of the (RTK)/Ras/ERK signaling pathway, which is one of the most tumorigenic pathways in cancer. The most common rearrangement is with the double homeobox 4 (DUX4) transcription factor (CIC-DUX4), and others, such as CIC-NUTM1 fusions, have been identified in a subset of pediatric primitive neuroectodermal tumors. However, the molecular mechanisms by which CIC-fusions drive CRS remain unknown. Preliminary data shows that CIC-DUX4/NUTM1 fusions activate JAK and its downstream effector STAT1/3. We hypothesize that the JAK/STAT1/3 signal transduction pathway cooperates with CIC-fusions to induce the expression of oncogenic transcription factors ETV1/4/5 and drive these sarcomas. We show high levels of JAK1/STAT1/3 activation in patient-derived CRS cell lines (NCC-SCC-89/C) as compared to other sarcoma cell lines without the fusion. JAK1 inhibition using Solicitinib and Ruxolitinib reduced phosphorylation of STAT1/3 as well as protein and mRNA expression of ETV1/4/5, promoter activity of ETV5, cell proliferation and tumorgenicity. Interestingly DUX4 is involved in histone acetylation and STAT1 has been shown to activate p300/CBP complex which lead us to evaluating the role of STAT1 in the gene activation CRS. We elucidate mechanistically that the fusion proteins increase binding of STAT1/3 at the promoters of ETV 1/4/5. Importantly, JAK1 inhibition effectively reduces histone acetylation induced by CIC-fusions at the promoters of ETV1/4/5. To evaluate the pre-clinical effect of targeting the JAK1/STAT1/3 pathway, A CRS cell line (NCC-SCC-89/C) were grafted into NSG mice. Ruxolitinib treatment significantly reduced tumor volume, STAT activation, and ETV1/4/5. In conclusion, we show that the JAK1/STAT1/3 pathway plays a critical role in cooperating with CIC-fusions to drive CRS, providing insight into potential therapeutic avenues for these aggressive tumors.
CSIG-13. TARGETING GENETIC DEPENDENCIES EXPOSES DIFFUSE MIDLINE GLIOMA CELL OF ORIGIN VULNERABILITIES
Authors: Dun Matthew D , Jackson Evangeline , Vo Tuan , Savary Clara , Riley Madisen , Douglas Alicia , Findlay Izac , Germon Zacary , Mannan Abdul , Thomas Bryce , Duchatel Ryan , Jayaraman Ranjith 
Published: November 2024

Abstract
Diffuse midline glioma (DMG), including diffuse intrinsic pontine glioma (DIPG), are uniformly fatal brain cancers affecting children, adolescents, and young adults. These tumors are characterized by ‘oncohistone’ mutations in histone H3 genes (H3F3A, HIST1H3B, HIST1H3C), resulting in the substitution of lysine 27 to methionine (H3K27M), resulting in dominant negative hypomethylation at lysine 27 (H3K27) and a global loss of gene silencing. CRISPR-Cas9 loss-of-function gene deletion screens identified mutation-independent dependencies on PIK3CA and MTOR genes for tumor growth and proliferation, highlighting a targetable molecular dependency across DMG patient-derived models (n=38). However, systemic PI3K/mTOR inhibition increased blood glucose and insulin levels, promoting hyperinsulinemia/hyperglycemia and reduced efficacy in vivo. To exploit genetic dependencies while maintaining compliance and therapeutic benefit, we optimized combinations of clinically relevant PI3K inhibitors (paxalisib, GCT007, everolimus) with the antiglycemic drug metformin to restore glucose homeostasis and decrease DMG insulin receptor activity in vivo, extending the survival of DIPG xenograft models. Phosphoproteomic profiling of DIPG models treated with PI3K/mTOR inhibitors promoted calcium-activated PKC signaling. The brain-penetrant PKC inhibitor enzastaurin in combination with paxalisib, synergistically extended the survival of DIPG xenograft models, including those mimicking disease progression, with further benefits potentiated using metformin in a multimodality approach. Combined PI3K-PKC inhibition in vivo promoted differentiation of OPC-like DMG to more OC-like cells, enhancing PDGFRA-JAK/STAT proinflammatory signaling, showing features of demyelination and MHC-II+ antigen expression, including PD1/PDL1. In parallel, combined PI3K/mTOR and PDGFRA inhibition using paxalisib and avapritinib synergistically extended the survival of patient-derived xenograft models, showing the preclinical relevance of simultaneously targeting these vulnerabilities. Together, we reveal that therapeutic inhibition of PI3K/mTOR and compensatory PKC signaling, while mitigating side effects with metformin, altered the chromatin architecture, leading to cellular differentiation and opening the door for clinically relevant checkpoint inhibitors. This combination strategy addresses DMG genetic dependencies, cellular and systemic responses to precision therapies, while harnessing the immune system for potential clinical translation.
CSIG-14. ACROLEIN INDUCES THE MIR-30A-5P/NCAM AXIS THROUGH THE AKT/GSK3Β/Β-CATENIN PATHWAY, PROMOTING GLIOMA PROGRESSION
Authors: Chen Pin-Yuan , Liu Pei-Yu , Huang Chy-In , Wang Hsiang-Tsui 
Published: November 2024

Abstract
Glioblastoma (GBM), the most aggressive brain tumor, exhibits resistance to treatment and thrives in low-oxygen (hypoxic) environments, leading to the accumulation of reactive oxygen species (ROS). Hypoxia activates the hypoxia-inducible factor (HIF)-1α pathway, enhancing tumor malignancy. Acrolein, a reactive aldehyde produced during lipid peroxidation in hypoxia, induces toxicity through DNA damage, inflammation, mitochondrial dysfunction, and oxidative stress. Our previous study found elevated acrolein levels in hypoxic glioma cells and linked acrolein-induced DNA damage (Acr-dG) with poor GBM prognosis. However, the role of acrolein in GBM progression remains unclear. This study aims to elucidate the impact of acrolein on GBM. In vitro experiments demonstrated acrolein production under hypoxia, which increased glioma cell migration and spheroid formation. RNA sequencing identified five affected pathways: cell adhesion molecules, PI3K-AKT signaling, ECM-receptor interaction, MAPK signaling, and neuroactive ligand-receptor interaction. Acrolein downregulated NCAM (neural cell adhesion molecule) via the miR-30a-5p-AKT-GSK3β/β-catenin axis in GBM cell lines and patient-derived cells. Overexpressing NCAM reduced cell migration and spheroid formation. Lower NCAM levels in GBM tissues correlated with poor patient survival. This study suggests the potential of NCAM as a therapeutic target for GBM and provides insights into early detection and treatment strategies for this malignancy.
CSIG-19. IDENTIFICATION AND TARGETING OF TUMOR DRIVER SCHWANN(NF2LOSS) CELLS IN SPORADIC AND NF2-RELATED VESTIBULAR SCHWANNOMAS
Authors: Laws Maxwell , Asuzu David , Rampalli Ihika , Mullaney Dustin , Laraba Liyam , Mandel Debjani , Zhang Xiyuan , Elkahloun Abdel , Sisay Bayu , Maric Dragan , Johnson Kory , Abdullaev Zied , Aldape Kenneth , Shern John , Parkinson David , Chittiboina Prashant 
Published: November 2024

Abstract
Vestibular schwannomas (VS) arise from myelinating Schwann cells of CN VIII and are associated with severe morbidity due to local tumor growth. Sporadic and neurofibromatosis type 2 (NF2) associated VS are both characterized by NF2 (merlin) loss but the mechanisms remain unexplored. Using a multiomic approach, we dissected the role of NF2 loss in VS tumor formation and proliferation. We obtained surgical samples from 15 patients undergoing surgery for VS (sporadic, n=4; NF2, n=9), and performed single-cell or single-nucleus RNA sequencing (scRNAseq, n=4; snRNAseq, n=15), transposase-accessible chromatin (snATAC-seq, n=9), whole exome (n=12), and bulk DNA methylation assays (n=15). Transcription factor binding was assayed with ChIPseq. We validated our key findings with immunoblot, ELISA, RNAscope (n=8), and multiplex immunocytochemistry (mIHC; n=8). NF2fl/fl;Periostin-Cre+mice versus their Cre- control littermates treated with novel inhibitors of TEAD auto-palmitoylation (VTs). We mapped the VS transciptome and identified canonical Schwann cells, macrophages, T-cells and endothelial cells. Using the cells that had Chr22 loss (second hit deletions at the NF2 locus), we generated a NF2loss gene signature. We then identified Schwann(NF2loss) cells in all tumors, and found these enriched for YAP1/TAZ-TEAD, NRG1, and HIF-1α signaling pathways. Schwann(NF2loss) cells showed increased TEAD1 expression and chromatin accessibility for TEAD family transcription factor motifs. TEAD1 binding was observed at promoters of genes including VEGFA, EGFR, with strong enrichment for mitogenic pathways. We also found that VEFGA expression was restricted to Schwann(NF2loss) cells, and confirmed this with RNAscope and mIHC. Schwann(NF2loss) cells were key regulators of macrophages (M2-subtype, tissue resident) through M-CSF/IL-34 signaling. NF2fl/fl;Periostin-Cre+ mice showed increased VEGFA expression, and that was reversible by TEAD inhibition in-vivo with VTs. We report that Schwann(NF2loss) cells are key tumor drivers in VS. These cells are highly proliferative (YAP/TAZ-TEAD axis), drive angiogenesis (VEGFA expression), and promote tumor mass accretion (macrophage influx via M-CSF/IL-34 pathway) that can all be targeted via TEAD inhibition.
CSIG-21. THE ROLE OF GUT MICROBIOTA IN GLIOBLASTOMA: INSIGHTS FROM MICROBIOME-GENE EXPRESSION INTERACTIONS
Authors: Bekal Mahesh , Wang Isabel , Wang Daniel , Dono Antonio , Arjuna Srividya , Ballester Leomar , Esquenazi Yoshua 
Published: November 2024

Abstract
Glioblastoma, the most aggressive form of primary brain tumor, remains a formidable clinical challenge due to its invasiveness and resistance to therapy. Emerging evidence suggests that the gut microbiome plays a crucial role in modulating cancer progression through complex interactions with host physiology. In this study, we investigated the influence of gut microbiota and tumor gene expression by analyzing stool and tissue samples from glioblastoma patients. Utilizing 16S rRNA sequencing of stool samples and NanoString gene expression analysis of tumor tissue samples, we explored the relationship between gut microbiome taxa and gene expression levels in tissue. Pathway analysis using KEGG and Gene Ontology databases was employed to elucidate the functional implications of these interactions. Our findings reveal contrasting effects of specific gut microbiota taxa and gene expression, with Fusobacterium demonstrating a potential oncogenic role, while Bifidobacteriaceae and Akkermansiaceae display potential tumor-suppressive effects. Fusobacterium is associated with the upregulation of key oncogenes and pathways promoting cancer cell survival, growth, and metabolism, whereas Bifidobacteriaceae and Akkermansiaceae are linked to the downregulation of genes involved in pathways promoting cancer cell survival and proliferation, such as MAPK signaling and stress response pathways, potentially inhibiting cancer cell growth. These results highlight the intricate interplay between gut microbiota composition and cancer biology and underscore the potential of gut microbiota modulation as a therapeutic strategy in glioblastoma management.
CSIG-22. PHARMACOLOGIC INHIBITION AND KNOCKDOWN OF CAMK2 IMPAIR GROWTH OF PATIENT-DERIVED GLIOBLASTOMA CULTURES
Authors: Ronnen Rebecca , Wang Shuai , Haddock Sara , Ravn-Boess Niklas , Golub Danielle , Stephan Gabriele , Sabio Jonathan , Donaldson Hayley , Bonanni Luke , Zuniga Adler Guerrero , Karnavas Theodoros , Placantonakis Dimitris 
Published: November 2024

Abstract

INTRODUCTION
Glioblastoma (GBM), a primary brain malignancy with a median survival of 15-18 months, presents a pressing challenge in neuro-oncology. Patient-derived GBM cultures (PDGCs) exhibit spontaneous calcium (Ca2+) waves, which are thought to drive tumor growth and represent a therapeutic target. The mechanisms underlying the generation and the effectors of these Ca2+ waves remain elusive. We hypothesize CAMK2, a Ca2+/calmodulin-dependent protein kinase expressed as four distinct isoforms, is a key effector of such Ca2+ waves by phosphorylating substrates that promote tumor growth.

METHODS
Using multiple PDGCs, CAMK2 isoform-specific mRNA levels were assessed via qRT-PCR both at baseline and after shRNA-mediated knockdown (KD). Tumorsphere formation and WST-8 assays were performed to assess PDGC clonogenic potential after either KD or pharmacologic inhibition with the cell-permeable CAMK2 inhibitor KN93.

RESULTS
The relative mRNA levels of CAMK2 isoforms across three PDGC lines were, in decreasing order: CAMK2D, CAMK2G, CAMK2B, and CAMK2A. Expression of CAMK2D- and CAMK2B-specific shRNAs significantly reduced tumorsphere growth compared to control shRNA. CAMK2D KD reduced sphere formation by 55.13 ± 3.54% (p=0.0001) and 47.72 ± 9.55% (p=0.008) in separate PDGC lines, while CAMK2B KD reduced sphere formation by 41.15 ± 11.51% (p=0.021) and sphere size by 41.78% ± 10.50% (p=0.049) (n=3/experiment). KN93 treatment reduced tumorsphere formation by 59.23 ± 1.40% (p=0.0006) and 42.94 ± 13.0% (p=0.032) in two PDGC lines (n=3) and PDGC viability, while CAMK2-inactive analogue KN92 and DMSO minimally impacted viability (p&lt;0.0001, two-way ANOVA).

CONCLUSION
CAMK2D and CAMK2B KD, as well as KN93 treatment, reduce tumorsphere formation, suggesting CAMK2 has a tumorigenic role in GBM. Further investigation of CAMK2 isoforms and in vivo validation are underway. Future aims include directly testing the link between spontaneous Ca2+ waves and CAMK2 activation and identifying CAMK2 phosphorylation targets that mediate tumor growth.
CSIG-29. BRAF INHIBITOR THERAPY IN BRAF-MUTATED PRIMARY BRAIN TUMORS: A SINGLE-CENTER EXPERIENCE
Authors: Baykal Duru , Ser Hazal , White Jessica , Neth Bryan , Uhm Joon , Ruff Michael , Sarkaria Jann , Wilson Jessica , Yan Elizabeth , Meyer Fredric , Celda Maria Peris , Sener Ugur 
Published: November 2024

Abstract

BACKGROUND
BRAF pathway alterations are frequent in glial/neuroepithelial tumors. BRAF-targeted therapy with BRAF inhibitors (BRAFi) and/or MEK inhibitors (MEKi) has proven efficacy in clinical trials, though mainly enrolling pediatric patients. We sought to investigate real-world data for adult patients with BRAF-pathway mutant glial/neuroepithelial neoplasms treated with BRAFi/MEKi.

METHODS
Adults with BRAF-pathway mutated glial/neuroepithelial neoplasms treated with BRAFi/MEKi were retrospectively reviewed.

RESULTS
Five patients (n=4 female, median age at diagnosis 36) were identified (tumor types: glioblastoma n=1, high-grade astrocytoma with epithelioid features n=1, low-grade neuroepithelial tumor n=1, pilocytic astrocytoma n=1, pleomorphic xanthoastrocytoma n=1). Four had BRAF V600E and one had NF1 p.S2687Cfs*5 mutant tumors. Prior to targeted therapy initiation, patients underwent a median 2.4 treatments including surgery (n=4), radiation therapy (n=4), chemotherapy (temozolomide n=4; carboplatin/vincristine n=1). BRAF-targeted therapies included dabrafenib/trametinib (n=4), binimetinib/encorafenib (n=2), binimetinib (n=2). One NF1-mutant glioblastoma received binimetinib followed by binimetinib/bevacizumab. Median BRAFi/MEKi treatment was 15.2 months (range: 6-36 months). Toxicities included leukopenia (n=3), peripheral edema (n=1), reduced ejection fraction (n=1), skin rash (n=5), transaminitis (n=1) with all patients requiring dose reductions and 3 cases requiring discontinuation. Among patients where BRAFi/MEKi was discontinued due to toxicity, 2 received other treatments at progression, then switched to a different BRAFi/MEKi combination, which they tolerated (duration 6-10months). Best radiographic response was partial response, noted in 3 patients treated with dabrafenib/trametinib. Four patients remain alive and continue BRAFi/MEKi.

CONCLUSIONS
In this cohort of heavily-pretreated patients with glial/neuroepithelial neoplasms, BRAF-targeted therapy was associated with durable responses. Interestingly, two patients who were unable to tolerate one combination of BRAFi/MEKi were able to tolerate a different combination with sustained response. Our findings support ongoing use of BRAF targeted therapy for CNS tumors. Optimal timing and duration of treatment requires further prospective evaluation in adult patients.
CSIG-30. EXPLORING THE ROLE OF CAPICUA (CIC) IN RESISTANCE MECHANISMS OF MEK INHIBITORS IN GLIOBLASTOMA
Authors: Persaud Phooja 
Published: November 2024

Abstract
Glioblastoma multiforme (GBM) is the most common and fatal primary brain tumor, resistant to conventional therapy. Despite its heterogeneous nature, a key feature of GBM is aberrant kinase signaling. Specifically, hyperactivation of receptor tyrosine kinases (RTK) and their downstream tumorigenic effectors Ras/MEK/Extracellular Signal Regulated Kinase (ERK) pathway are attributed to the aggressive nature of GBM. Capicua (CIC) is a High Mobility Group (HMG) box transcriptional repressor that directly binds to DNA and counteracts the transcription of genes typically expressed only in response to RTK activation such as oncogenic transcription factors ETV1/4/5. Hyperactive MEK/ERK signaling in GBM causes CIC degradation. The mechanism of CIC’s repressor function is not well understood, however, transcriptional repressors (like CIC) typically form co-repressor complexes to repress target genes. We discovered a novel interaction between CIC and the transcriptional regulator yin yang 1 (YY1), a context-dependent transcription factor that can repress or activate gene expression. We uncovered that 90-kDa ribosome S6 protein kinase (p90RSK), a downstream effector of ERK and a known CIC regulator, mediates the CIC/YY1 interaction. Interestingly, we found re-activation of p90RSK following MEK/ERK inhibition implicating p90RSK in the resistance mechanism of RTK/MEK/ERK inhibition in GBM. We hypothesize that p90RSK inhibition will stabilize the CIC/YY1 co-repressor complex and re-sensitize towards MEK/ERK inhibition. Patient-derived glioma stem-like cells (GSCs) were treated with increasing doses of BI-D1870 or LJI308 (p90RSK inhibitors) with and without selumetinib (MEK inhibitor) and various functional assays were performed to examine the effect of p90RSK inhibition on the CIC/YY1 complex and sensitization to MEK/ERK inhibition. Treatment with BI-D1870 and LJI308 markedly reduced viability and mRNA expression of ETV1/4/5 indicating that p90RSK inhibition may mediate CIC /YY1 DNA binding ability. Importantly, inhibiting p90RSK sensitized GSCs to MEK/ERK inhibition. These results highlight the importance of downstream p90RSK inhibition in stabilizing CIC/YY1 repressor complex function and sensitizing cells to RTK/MEK/ERK inhibition.
CSIG-33. CERAMIDE-1-PHOSPHATE/CERK ARE REGULATORS OF ETMR GROWTH AND POTENTIAL THERAPEUTIC TARGETS
Authors: Maas Allison , Liapis Evangelos , O’Neill Kelly , Hanson Derek , Carter Claire 
Published: November 2024

Abstract
Embryonal tumor with multilayered rosettes (ETMR) is a highly aggressive CNS neoplasm which occurs almost exclusively in infants and is associated with an extremely poor prognosis. To identify functional signaling lipids that contribute to the aggressive nature of ETMR and that can be targeted therapeutically, we carried out mass spectrometry imaging on human ETMR patient samples, the patient-derived cell line BT183, and normal neural stem cells. We identified an accumulation of ceramide-1-photphate (C1P) within the rapidly proliferating embryonal tumor cells in patient samples and the cell model. We also detected high accumulation of C1P within the aberrant vascular proliferations in patient samples. Ceramide-1-phosphate is a pleiotropic bioactive signaling lipid that controls cell fate. C1P and its synthesizing enzyme, ceramide kinase (CERK), are known mitogens that have been shown to regulate cell proliferation in several non-CNS cancers. C1P is known to mediate the upregulation of PI3K/Akt/mTOR, MAPK/MEK/ERK1/2, Rho kinase, JNK, to promote cell survival and migration. After spatially mapping C1P accumulation in patient samples and our in vitro 3D models, we next carried out IHC to correlate lipid accumulation with its synthesizing enzyme, CERK. CERK was found to be abundantly accumulated in both endothelial and tumor cells within the tumor microenvironment of patient samples. Western blot analysis of CERK demonstrated a significant increase in the ETMR 3D tumorspheres compared to the NSC neurospheres. Treatment of the ETMR 3D tumorspheres with the CERK inhibitor, NVP-231, potently reduced cell growth and viability. Western blot analysis of ETMR tumorspheres at 8 and 24 hours post-treatment demonstrated a time-dependent decrease in N-MYC and a subsequent increase in p53. Studies are ongoing to validate these findings in vivo and to elucidate the signaling pathways that C1P/CERK regulate in both the vascular and tumor cells in ETMR.