bluuebunny/crossref_metadata_2025_split huggingface dataset:
CP-04. UNVEILING THE MYSTERIES OF PEDIATRIC ADAMANTINOMATOUS CRANIOPHARYNGIOMA - INSIGHTS FROM DIAGNOSIS TO ADVANCED THERAPEUTICS
Authors: Shatara Margaret , Abdelbaki Mohamed S 
Published: June 2024

Abstract

BACKGROUND
Adamantinomatous Craniopharyngiomas (ACPs) are rare tumors arising from the remnants of the craniopharyngeal duct epithelium. Their diagnosis poses unique challenges, often resulting in delayed identification due to their slow growth and nonspecific symptoms. Additionally, the prolonged overall survival (OS) is overshadowed by a substantial recurrence rate and late consequences, posing significant challenges, and impairing the patient’s quality of life (QoL). Recent advancements in understanding ACP’s genomic, transcriptomic, and proteomic aspects underscore the need for innovative treatments to mitigate these long-term consequences.

METHODS
We conducted an in-depth literature review, focusing on large clinical trials and major publications in ACP to provide a comprehensive perspective on the challenges in the diagnosis, treatment, and molecular aspects of pediatric ACP.

RESULTS
ACP’s clinical presentation involves increased intracranial pressure, endocrine abnormalities, and visual impairments. Despite their low-grade classification, ACPs exhibit aggressive clinical behavior, often invading or adhering to adjacent tissues, particularly critical neurovascular structures. Imaging techniques, including CT and MRI with a focus on hypothalamic involvement, play a crucial role in diagnosis, pre-operative evaluation, and surgical planning. Multidisciplinary approaches are essential for developing tailored treatment strategies. Neurosurgical management and radiotherapy, particularly proton therapy, are the primary therapeutic modalities. The molecular landscape reveals intricate and complex mechanisms and include the upregulation of the Wingless (WNT) signaling pathway driven by CTNNB1 mutations, along with involvement of inflammatory, programmed cell death, and the MAPK/ERK pathways. Ongoing trials exploring targeted therapies may play a pivotal role in refining treatment strategies and improving outcomes.

CONCLUSIONS
Navigating the complexities of ACP requires a multidisciplinary approach. Advances in diagnostics, surgical strategies, and targeted therapies, informed by molecular insights, offer promising avenues for improving outcomes and QoL. Ongoing collaborative efforts and participation in clinical trials are vital for refining treatment strategies and advancing the understanding of this challenging condition.
CP-13. MRI-DERIVED NUCHAL SKINFOLD THICKNESS AS AN INDEX OF BODY COMPOSITION IN CHILDHOOD-ONSET CRANIOPHARYNGIOMA
Authors: Vijay Eshaa , Crowley Julia , Fisher Michael J , Kline Cassie , Shekdar Karuna , McCormack Shana E 
Published: June 2024

Abstract

BACKGROUND
Survivors of childhood craniopharyngioma often develop obesity. Body mass index (BMI) is an imperfect estimate of adiposity. Nuchal skinfold thickness (NST) is a measure of upper body adiposity obtainable from routine surveillance brain MRIs. Our objective was to evaluate whether NST adds more information than BMI alone regarding excess adiposity in survivors of childhood craniopharyngioma.

METHODS
This was a single-site, retrospective review of children (all ages) diagnosed with craniopharyngioma between 2008 and 2020 with data at baseline, and 6 (±2) and 12 (±2) months follow-up (2008-2020). NST was measured on a mid-sagittal T1-weighted MRI image, on the line crossing the anterior and posterior margins of the foramen magnum. BMI Z-scores (BMI-Z) were calculated using extended CDC references. Mixed effects regression assessed change in NST related to time from diagnosis and BMI-Z, accounting for age and sex.

RESULTS
Thirty-two patients met criteria (female, n=9 [28%]; median age 8.3y [range, 2.1-15.5] at diagnosis). Mean BMI Z-scores were 0.82 (SD 1.38) at diagnosis, 1.44 (1.07) at 6 months (p=0.004 vs. diagnosis), and 1.40 at 12 months (p=0.01 vs. diagnosis). Median nuchal thickness was 7.1 mm (IQR 5.8, 9.5) at diagnosis, 9.7 mm (IQR 7.8, 10.7) at 6 months (p=0.001 vs. diagnosis), and 10.1 mm (IQR 8.1, 12.6) at 12 months (p=0.0001 vs. diagnosis). As expected, nuchal thickness positively associated with BMI-Z (β, 1.3, p&lt;0.001). Even after accounting for age, sex, and change in BMI-Z, NST was higher at 12 months as compared to diagnosis (β, 1.8, p=0.004).

CONCLUSION
BMI-Z and NST increase over time in children with craniopharyngioma. Increases in NST are not explained by increases in BMI-Z alone, suggesting that NST reflects an additional dimension of body composition. Next, we will evaluate how including NST along with BMI improves cardiometabolic risk prediction in childhood craniopharyngioma.

FUNDING
Finamore Family Research Fund.
DIPG-05. CHARACTERIZATION OF THE EFFECTS OF H3K27M VARIANTS ON THE DNA-DAMAGE RESPONSE AND TUMOR EVOLUTION IN DIFFUSE MIDLINE GLIOMA
Authors: Poux Nicolas , Kebede Adam F , Beroukhim Rameen , Bandopadhayay Pratiti 
Published: June 2024

Abstract
Diffuse midline gliomas (DMGs) are universally-fatal pediatric brain tumors driven by K27M alterations in histone 3 (H3K27M). Histone 3 is encoded by several variants, including the canonical H3.1, and H3.3 which replaces H3.1 at transcriptionally active and repetitive genomic regions. Both H3.3K27M and H3.1K27M are present as driver events in DMGs and recent single-cell-RNA and whole-genome sequencing experiments have demonstrated that they define distinct subsets of disease, with varying secondary genetic alterations and different gene-expression patterns. The cause of the divergence in routes of tumor evolution between these subsets remains an open question. Previous work by our group has shown that H3.3K27M DMGs show greater genomic instability than H3.1K27M tumors – with a greater number and higher complexity of genomic structural variants resulting from errors in double-stranded DNA break repair. This raises the possibility that histone variants differentially influence the generation of, or response to, DNA breaks. Here we present an early-stage project that aims to investigate whether H3K27M variants are sufficient to produce differences in genomic instability and in directing the path of tumor evolution. Using isogenic cell-line models expressing H3.1K27M or H3.3K27M, we aim to characterize whether H3K27M variants produce varying levels of replicative stress and P53 activation, leading to varying selective pressures for P53 loss. In turn, we seek to demonstrate that loss of P53 produces a greater growth advantage in H3.3K27M cells, and that P53 loss leads to increased tolerance of genomic instability in DMG models. Together, these experiments seek to provide new insight on the mechanisms of divergence between H3.1K27M and H3.3K27M-driven DMGs, and a better understanding of the sources of genomic instability in DMGs. Given that ionizing radiation remains the only approved treatment modality for DMGs, a greater understanding of DMG response to DNA-damage is critical to improving therapeutic outcomes.
DIPG-13. TIM-3 TARGETED APTAMER IN COMBINATION WITH LOCO-REGIONAL RADIOTHERAPY IMPROVES SURVIVAL BY MODULATING THE IMMUNE INFILTRATION IN DIFFUSE MIDLINE GLIOMA MODELS
Authors: Ausejo-Mauleon Iker , de la Nava Daniel , Martinez-Velez Naiara , Nuin Sara , Morales Sandra , Palacios-Alonso Daniel , Pastor Fernando , Alonso Marta M 
Published: June 2024

Abstract

BACKGROUND
Diffuse midline gliomas (DMG) are the most aggressive pediatric brain tumors. Their meager survival has not changed in the last decades emphasizing the urgent need for effective treatments. TIM-3 has emerged as a new target expressed in multiple immune cell types, regulating adaptive and innate immunity. In this work, we used an aptamer against TIM-3 to modify the tumor microenvironment and enhance the antitumor effect.

METHODS
For in vivo experiments, DMG murine cells were injected orthotopically into the pons of mice using a screw-guided system. The aptamer was administered intracranially (380pmol) on day 5 with the same system and three times intravenous (320pmol/mouse) 8-11-14 days after tumor implantation. In the radiotherapy experiments, 6Gy was given on day 7. Tumor and immune populations were analyzed by flow cytometry.

RESULTS
TIM-3 aptamer as monotherapy increases immune infiltration and elicits a specific immune response with a modest tendency to improve overall survival. Interestingly, we observed that radiotherapy, DMG standard of care, significantly induced TIM-3 expression in tumor and immune cells in the tumor microenvironment (TME). The combination of TIM-3 aptamer with radiotherapy increased the overall survival (3-fold), led to long-term survivors (30-50%), and generated immune memory in three different glioma models. Importantly, combination treatment significantly increases the infiltration of immune cells (3-fold) in the TME compared with the control groups. Radiotherapy and TIM-3 Apt treatment significantly increased the number and proliferative state of microglia, dendritic, NK, CD4, and CD8 T-cells. Interestingly, TIM-3 aptamer decreased the number and proliferative state of Tregs increasing the pro-inflammatory ratio of CD8: Tregs in the TME compared to non-treated groups after radiotherapy.

CONCLUSIONS
In conclusion, we provide evidence that combining radiotherapy with a TIM-3 aptamer increases overall survival, leads to the expansion of myeloid and T-cells in the TME, and generates immune memory in DMG models.
DIPG-61. ARGININE DEPRIVATION USING ADI-PEG20 IMPROVES SURVIVAL IN A SYNGENEIC DIFFUSE MIDLINE GLIOMA MOUSE MODEL
Authors: Chattenton Dani , Brooks Molly , Perryman Richard , Mussa Hamida , Chatziathanasiadou Maria , Syed Nelofer 
Published: June 2024

Abstract

BACKGROUND
Diffuse midline glioma (DMG-H3K27) presents a significant challenge in paediatric oncology, with a &lt;10% two-year survival rate despite standard palliative radiotherapy. Tumour infiltration behind the blood-brain barrier hampers drug delivery, contributing to clinical trial failures. ADI-PEG20 exploits tumour metabolic vulnerabilities: lack of argininosuccinate synthetase and reliability on extracellular arginine for proliferation. This study investigates ADI-PEG20’s efficacy in a syngeneic DMG mouse model.

METHODS
Twenty C57BL/6J mice were intracranially injected with a DMG cell line (H1H3BK27M, DNp53, PDGFRAD642V, Acvr1G328V) and monitored via bioluminescence imaging from day 7. Weekly treatments began on day 10, comprising ADI-PEG20 (5 I.U.) alone, ADI-PEG20 with concurrent radiation (2 Gy), radiation alone, or saline (0.9%), with each group comprising n=5. Radiation was administered 24 hours post-drug treatment. Bioluminescence imaging was conducted twice weekly, with mice culled upon symptom onset. Immunohistochemistry was performed on brain tissue.

RESULTS
The combination and ADI-PEG20 monotherapy cohorts exhibited comparable median survival rates, both surpassing those of the radiation-only and saline groups, with the latter exhibiting the lowest median survival. A significant disparity in survival curves was observed overall (p&lt;0.0001), confirmed by log-rank (Mantel-Cox) test. Pairwise comparisons revealed significant differences in survival curves between the combination and radiation-only (p=0.0066), ADI-PEG20 monotherapy and radiation-only (p=0.0018), and ADI-PEG20 monotherapy and saline (p=0.0062) groups. Minimal divergence in IVIS signal intensity was noted across groups. Histological examination via H&E staining demonstrated marked tumour regression in mice treated with ADI-PEG20 ± radiation, contrasting with the persistent tumour mass evident in the radiation-only and saline cohorts, alongside discernible heterogeneity in cellular phenotypes within the ADI-PEG20 ± groups.

CONCLUSIONS
In conclusion, ADI-PEG20 shows promise as a therapeutic strategy for DMG, offering a significant survival advantage over radiation and saline. Ongoing efforts will elucidate its mechanistic underpinnings, explore its efficacy across diverse DMG models, and assess synergistic interactions with immune-based therapies.
DIPG-67. RE-IRRADIATION PRACTICES AND OUTCOMES IN PATIENTS WITH DIPG/DMG: A REPORT FROM THE INTERNATIONAL DIPG REGISTRY
Authors: Pillay-Smiley Natasha , Webster Aaron , Lane Adam , Hawkins Cynthia , Hassall Tim , Leach James , Jones Blaise , Dorris Kathleen , Hansford Jordan R , Zaghloul Mohamed , Cheng Sylvia , Hummel Trent R , Hoffman Lindsey M , Warren Katherine E 
Published: June 2024

Abstract

BACKGROUND
Given that radiation therapy is the only treatment modality demonstrated to result in any clinical benefit for children with DIPG, re-irradiation therapy has been explored as a treatment option for progressive DIPG. Several studies suggest re-irradiation is feasible, and may lengthen survival for children with progressive DIPG. However, any re-irradiation benefits are unclear and no standard of care (dose, fractionation, volume, timing, clinical status) has been defined. The aims of this study are to evaluate re-radiation therapy practices for children with progressive DIPG/DMG and to define a historical cohort of children with DIPG/DMG who have received re-radiation (re-XRT) for progressive DIPG/DMG.

METHODS
Data was extracted from the International DIPG Registry, and analyzed with descriptive statistics.

RESULTS
Of 1214 patients in the iDIPG Registry, 113 receiving re-XRT. Patients were diagnosed between 2002-2022, with the majority of patients diagnosed over the last decade. Of those 113 patients with specified data, at re-irradiation, n=68 (60%) received photon and n= 4 (4%) were treated with proton radiation. The median dose at re-XRT was 25 Gy (20-30 IQR) in 10 fractions (10-14 IQR). Time between initial XRT and re-XRT was 41.5 weeks (29.5-54 weeks). OS from diagnosis was 18 months (range, 15-23 mo); OS from re-XRT was 6 months (range, 4-10 mo).

CONCLUSIONS
Re-radiation therapy for children with DIPG/DMG is becoming a more common practice and appears to have OS benefit, with post-progression OS of 6 mo comparing favorably to historical data of 2.3 mo. [Cooney T et al, Neuro Oncol 2017] Efforts are underway to define patient selection and tolerability. Data extraction from the SIOPE DIPG/DMG Registry is also ongoing; data from both registries will be collated and uniformly presented.
DIPG-68. FLAG-003, A NOVEL, DUAL-ACTION THERAPEUTIC, DEMONSTRATES IN-VITRO ACTIVITY AGAINST DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Authors: Bhatia Sonam , Quinn Thomas , Ligon Keith L , Bandopadhayay Pratiti , Warren Katherine 
Published: June 2024

Abstract

BACKGROUND
FLAG-003 is a novel, rationally-designed, CNS-penetrant, dual-acting agent that inhibits receptor tyrosine kinase activity and microtubule polymerization. Preclinical studies in glioblastoma (GBM) demonstrated decreased cell viability, reduced tumor volumes, decreased microvessel density, and increased survival. Remarkably, using an orthotopic DIPG model, all mice treated with FLAG-003 at 275 mg/day/orally displayed tumor regression, tumor reduction and increased survival. Given the significant preclinical activity against DIPG, as well as the known heterogeneity of DIPG, we evaluated the efficacy of FLAG-003 in vitro against a panel of DIPG cell lines.

METHODS
Eight DIPG cell lines hosted at the Center for Patient Derived Models (CPDM) were selected based on genomic and growth characteristics. Cells were plated on 384-well plates; 24 hours after plating, cells were dosed with 1nM to 50uM (12 step log curve) FLAG-003. Three technical replicates were performed per step. Controls consisted of positive kill control Staurosporine, negative growth control of 0.5% DMSO, or no DMSO for baseline growth. ONC201, a small molecule antagonist of DRD2/3 currently in clinical trials for DIPG, was used as a comparator. We also evaluated two GBM patient-derived models.

RESULTS
FLAG-003 demonstrated efficacy in all DIPG and GBM cell lines tested with IC50 less than 100nM. FLAG-003 was more potent compared to ONC201 in all models evaluated.

CONCLUSIONS
Single agent FLAG-003 demonstrated activity against a panel of DIPG cell lines. As next steps, we are exploring the efficacy of this drug in orthotopic DIPG PDX models. Continued development of FLAG-003 as a potential therapeutic candidate for DIPG patients is warranted and underway.
DIPG-74. TARGETING TRANSCRIPTIONAL DYSREGULATION IN DMG THROUGH CDK9 AND HDAC INHIBITOR COMBINATION THERAPY
Authors: Eberl Brittany R , Murdaugh Rebecca L , Nnyagu Adanze N , Richard Rosemary U , Deneen Benjamin , Yu Kwanha , Anastas Jamie N 
Published: June 2024

Abstract

BACKGROUND
With no successful treatment options available, diffuse midline glioma (DMG) are fatal brain tumors with a median survival of ∼12 months. DMG are characterized by transcriptional dysregulation induced by the H3K27M driver mutations. Since these histone mutations cannot yet be directly targeted pharmacologically, our goal is to identify druggable targets of aberrant transcription in DMG. Previous studies identified RNA polymerase 2 (Pol2)-targeting cyclin-dependent kinase 9 inhibitors (CDK9i) and histone deacetylase inhibitors (HDACi) as potential DMG therapeutics, and CDK9i and HDACi are under investigation in ongoing glioma clinical trials. This study aims to develop CDK9i+HDACi combination therapies for DMG.

METHODS
We determined the consequences of CDK9i+HDACi combination treatment in DMG using in vitro dose curve analyses, orthotopic xenograft models, and molecular profiling through immunofluorescence imaging, Western blotting, flow cytometry and RNA-seq analysis.

RESULTS
We find that CDK9i+HDACi combination therapy synergistically reduces DMG growth in vitro and alters DMG protein post-translational modifications associated with gene regulation by reducing phos-Pol2-Ser2 and increasing histone acetylation. Further RNA-seq analysis identified unique transcriptional changes induced by CDK9i+HDACi, including the downregulation of genes associated with mitochondrial function, cell division, and DNA repair. In line with these gene expression changes, additional studies suggest that CDK9i+HDACi treatment induces DNA damage and cell cycle defects. Finally, preliminary pre-clinical studies using an orthotopic DMG xenograft model reveal that CDK9i and HDACi treatment reduces DMG tumor growth as measured by bioluminescent imaging.

CONCLUSIONS
Together, these studies suggest that CDK9i and HDACi co-treatment alters DMG protein modifications and gene expression leading to cell cycle defects, DNA damage, and reduced tumor growth. In view of the proposed synergistic role of CDK9i and HDACi in DMG, additional ongoing studies are examining if this combination may represent a novel approach for the treatment of DMG.
DIPG-75. PHARMACOLOGICAL INHIBITION OF LSD1/KDM1A IN DIFFUSE MIDLINE GLIOMA MODELS AND IMPACT ON KINASE SIGNALING
Authors: Hernandez Faith A , Stitzlein Lea M , Nam Deokhwa , Adams Jack , McCabe Caitlin , Monje Michelle , Waranecki Piotr , Hulleman Esther , Becher Oren , Chandra Joya 
Published: June 2024

Abstract

BACKGROUND
High grade gliomas (HGGs) in both adults and children confer poor prognosis, with median survival rates under two years post-diagnosis. Diffuse midline gliomas (DMG) are a subset of HGG characterized by histone mutations, typically occurring in children. Genetic alterations in chromatin modifiers and receptor tyrosine kinases (RTKs) are seen in both adult and pediatric glioblastoma, however the interplay between these pathways requires further investigation to design therapeutic strategies. Our past work has evaluated KDM1A/ LSD1 (Lysine-Specific Demethylase 1) inhibition through gene silencing and small molecules; here we assessed crosstalk between LSD1 and kinase signaling networks to uncover potential compensatory resistance mechanisms using clinically relevant pharmacological inhibitors of LSD1.

METHODS
RNA-Seq and GSEA in high grade glioma cells bearing LSD1 knockdown were evaluated for kinase signaling pathway enrichment. A panel of DMG lines (SU-DIPGIV (MDM4, ACVR1), SU-DIPGVI (TP53), VUMC-DIPG10 (NF1, MYCN), and SU-DIPGXIII and DMG data sets were probed for LSD1 expression, activity and kinase expression and treated with pharmacological inhibitors of LSD1 in vitro and in vivo.

RESULTS
Pharmacological inhibition of LSD1 using clinically relevant agents revealed IC50s in the micromolar range across DMG lines. DMG lines varied with respect to LSD1 expression and baseline activation of ERK and AKT pathways. With LSD1 inhibition at subtoxic doses, increased phospho-ERK/ERK and phospho-AKT/AKT was noted in several DMG models and co-inhibition of these pathways suggests improved efficacy.

CONCLUSIONS
Our data reveals that LSD1 inhibition causes an increase in kinase signaling at subtoxic doses which may alter drug response. These results urge the assessment of combination treatments with kinase inhibitors and additional in vivo analysis, which are currently underway.
DIPG-82. RADIOSENSITIZATION WITH RAD52 INHIBITION IN DIFFUSE MIDLINE GLIOMA
Authors: Uchida Eita , Ishi Yukitomo , Watanabe Jun , Abdala-Valencia Hiam , Singer Benjamin , Gadd Samantha , Hashizume Rintaro 
Published: June 2024

Abstract

BACKGROUND
Diffuse midline glioma (DMG) is one of the most devastating childhood cancers that limited response to radiation therapy (RT). There is a critical need for new therapeutics that enhance the radiation effect. We, therefore, tested the hypothesis that targeting RAD52 activity sensitizes the radiation response of DMG.

METHODS
Genome-wide CRISPR/Cas9 screening was performed to identify the potential therapeutic target. RAD52 inhibition was used by shRNA-mediated RAD52 depletion and treatment with RAD52 inhibitor, D-I03. The protein expression, cell proliferation, DNA damage marker expression, DNA repair pathway, and transcriptional alteration were analyzed by western blotting, MTS assay, colony formation assay, immunocytochemistry, DNA repair pathway assay, and RNA sequencing. Mice with DMG patient-derived xenograft (PDX) models were treated with RAD52 inhibitor alone or combination with RT.

RESULTS
Genome-wide CRISPR/Cas9 screening identified RAD52 as a potential therapeutic target in DMG cells. RAD52 inhibition suppressed DMG cell proliferation. Importantly, RAD52 inhibition in combination with RT further increased the radiosensitivity of DMG cells. Immunocytochemistry of DNA double-strand breaks (DSB) marker γH2AX and repair marker 53BP1 showed that RAD52 inhibition sustained DNA damage with high levels of γH2AX at 24 hours following radiation while the level of 53BPI was decreased, thereby inhibiting DNA DSB repair. Western blotting also revealed that RAD52 inhibition causes a sustained level of phosphorylated Rad50 and γH2AX in irradiated DIPG cells over 24 hours. DNA repair assay showed that RAD52 inhibition suppressed homologous recombination DNA repair pathway. RNA sequencing showed that RAD52 inhibition downregulated genes associated with the DNA repair pathway. Finally, the combination therapy of RAD52 inhibitor and RT further suppressed tumor growth and increased survival of mice bearing DMG PDXs, outperforming either monotherapy.

CONCLUSIONS
these results highlight RAD52 inhibition as a potential radiosensitization and provide a rationale for developing combination therapy with radiation in the treatment of DMG.