bluuebunny/crossref_metadata_2025_split huggingface dataset:
MBRS-71. ATAXIA TELANGIECTASIA AND RAD3-RELATED PROTEIN ATTENUATES DNA DAMAGE AND IS A THERAPEUTIC TARGET IN Myc-DRIVEN MEDULLOBLASTOMA
Authors: Abdel-Hafiz Ahmed , Madhavan Krishna , Balakrishnan Ilango , Pierce Angela , Wang Dong , Danis Etienne , Serkova Natalie , Venkataraman Sujatha , Vibhakar Rajeev 
Published: December 2020

Abstract
Group 3 medulloblastoma tumors (Myc-MB), and particularly the 3γ subtype, have the worst prognosis and show a 5-year overall survival of less than 40%. Group 3 tumors are often accompanied by Myc amplification and have a higher rate of metastatic disease and relapse. Unfortunately, therapeutic strategies to target Mychave remained elusive. Further, the relapse of the MB has been linked to DNA replication stress. Ataxia telangiectasia and Rad3-related protein (ATR) senses persistent DNA damage, which arises due to replication stress, and activates damage checkpoints, thereby leading to increased cell survival. ATR is highly expressed in MB and is thought to contribute to undisturbed DNA replication to protect genomic integrity. Yet, the exact underlying mechanisms involving ATR are still unclear in MB. Inhibition of ATR (ATRi) using the ATR inhibitor, AZD6738, suppressed clonogenicity and cell self-renewal in Myc-MB. ATRi in Myc-MB cell lines downregulated Chk1 and upregulated P21. ATRi also induced cell cycle arrest and increased apoptosis in Myc-MB cell lines. Further, mice with orthotopic xenografts treated with ATR inhibitor survived significantly longer than control mice. High-throughput drug screening showed ATRi to be synergistic with chemotherapeutic agents including gemcitabine, cisplatin and topotecan. The treatment of Myc-MB cells with ATR inhibitor in combination with gemcitabine and with radiation increased in expression of DNA damage markers. These findings emphasize the role of ATR in alleviating DNA replication stress and that its inhibition is critical to the treatment of Myc-MB.
MBRS-72. MiR-212 FUNCTIONS AS A TUMOR SUPPRESSOR GENE IN GROUP 3 MEDULLOBLASTOMA VIA TARGETING NUCLEAR FACTOR I/B (NFIB)
Authors: Perumal Naveenkumar , Kanchan Ranjana , Atri Pranita , Venkata Ramakanth , Thapa Ishwor , Nasser Mohd , Batra Surinder , Mahapatra Sidharth 
Published: December 2020

Abstract
Medulloblastoma (MB), the most frequent malignant pediatric brain tumor is divided into four primary subgroups, i.e. wingless-type (WNT), sonic hedgehog (SHH), group 3, and group 4. Haploinsufficiency of chromosome 17p13.3 and c-myc amplification distinguish high-risk group 3 tumors and are associated with rapid recurrence and early mortality. We sought to identify the role of miR-212, which resides on chromosome 17p13.3, in the pathophysiology of group 3 medulloblastoma. RNA expression analyses revealed dramatically reduced levels of miR-212 in group 3 tumors and cell lines mainly through epigenetic silencing via histone modification (deacetylation). Restoring in vitro expression reduced tumor cell proliferation with decreased p-AKT and p-ERK levels, colony formation, migration and invasion in group 3 MB. Interestingly, a shift in differential c-myc phosphorylation (from serine-62 to threonine-58) was noted, resulting in reduced total c-myc levels, concurrent with elevated cellular apoptosis. In turn, pro-apoptotic binding partners of c-myc, i.e. Bin-1 and P19ARF, were upregulated in these cells. A dual luciferase assay confirmed direct targeting of miR-212 to NFIB, a nuclear transcription factor implicated in metastasis and recurrence. Concurrently, increased expression of NFIB was confirmed in group 3 MB tumors with poor survival in high NFIB-expressing patients. Transient NFIB silencing in vitro reduced tumor cell proliferation, migration and invasion, and medullosphere formation along with a reduction in stem cell markers (Nanog, Oct4, Sox2, CD133) and the multi-drug resistance maker, ABCG2. Taken together, these results substantiate the tumor suppressive role of miR-212 in group 3 medulloblastomas and provide a potential new therapeutic target, NFIB.
MBRS-73. AN EXPLORATORY ANALYSIS LOOKING AT THE ASSOCIATION OF GERMLINE CODING MUTATIONS WITH IMPAIRED DEVELOPMENT AND ADAPTIVE BEHAVIOR FUNCTION IN PEDIATRIC MEDULLOBLASTOMA PATIENTS TREATED ON HEAD START 4
Authors: Fleming Jessica L , Sells Blake E , Bell Erica H , McElroy Joseph P , Webb Amy , Zhao Yue , Graham Richard T , Guo Yingshi , Liu Tom , Timmers Cynthia , Dhall Girish , Sands Stephen , Finlay Jonathan , Chakravarti Arnab 
Published: December 2020

Abstract
Children with brain tumors often carry germline mutations known to contribute to tumorigenesis and treatment response; however, little is known about how these mutations impact developmental and behavioral outcomes. As the molecular mechanisms governing cancerous and normal tissues expand, we hypothesize that specific germline variants may impact baseline neurocognitive function and/or treatment-induced toxicities. In this pilot study, ten children on the Head Start 4 (HS4) clinical trial diagnosed with medulloblastoma were assessed for baseline adaptive functioning using the Adaptive Behavior Assessment System Third Edition (ABAS-III) and germline whole-exome sequencing was performed. After filtering for high impact variants, Welch’s T-tests were used to identify mutations associated with lower ABAS-III General Adaptive Composite (GAC) scores, reflecting developmental and adaptive behavior delays compared with peers their age. We found twenty genes with alterations associated with lower scores with p-values less than 0.05. Genes found to be significant included LAMC1 (p=0.04) and KRTAP1-1 (p=0.045), which encode members of the laminin and keratin family respectively and are involved in extracellular matrix adhesion. Mutations in PITX1, a known suppressor of RAS, were also associated with lower ABAS-III GAC scores (p=0.007). We hypothesize that additional analyses of HS4 patients will reveal alterations in cell-to-cell communication and signal transduction pathways, common molecular perturbations in tumors that would likely impact central nervous system function. Validation studies are essential to improve our understanding of the functional impact of germline variants on both tumor and regular tissue biology, allowing for novel strategies to circumvent these delays.
MODL-03. ADAPTING PALBOCICLIB FOR MEDULLOBLASTOMA THERAPY BY IMPROVING DRUG DELIVERY AND ADDRESSING RESISTANCE
Authors: Dismuke Taylor , Gershon Timothy 
Published: December 2020

Abstract
CDK4/6 inhibition may be a promising therapy for medulloblastoma. All medulloblastoma subgroups show D-cyclin/CDK4/RB pathway activity, suggesting broad potential for efficacy. To address drug delivery and systemic toxicity limitations, we developed a nanoparticle formulation of CDK 4/6 inhibitor, palbociclib, in poly (2-oxazoline) micelles (POx-palbo). POx-palbo showed reduced systemic toxicity in transgenic mice engineered to develop medulloblastoma, allowing for higher dosing. Pharmacodynamic studies showed POx-palbo suppressed RB phosphorylation acutely and after 24hrs, the effect diminished. This inhibition produced a longer lasting suppression of SHH pathway activity, demonstrated by Gli-luc reporter tumor mice. Importantly, POx-palbo therapy, administered daily, reduced tumor growth and improved the survival of mice with medulloblastoma. While POx-palbo was clearly effective as a single agent, all mice treated with POx-palbo eventually developed progressive disease, as resistant populations of tumors cells emerged. To understand the mechanisms of resistance, we compared tumors early and late in the course of therapy. We found that after 5 days of treatment, palbociclib altered cell cycle progression to produce an extended period of S-phase and that the fractions of cell expressing the stem cell marker Olig2 were markedly increased. Based on these data, we propose that tumors respond to the initial suppressive effect of palbociclib by increasing the pool of Olig2+ stem cells, that these cells show discernably different cell cycle kinetics and are resistant to CDK4/6 inhibition. Combining POx-palbo with additional therapies that target Olig2+ stem cells, by disrupting their prolonged S-phase, or by disrupting Olig2 function, may lead to newly effective medulloblastoma treatment.
MODL-06. PRECLINICAL EFFICACY OF THE IMIPRIDONE ONC-206 AGAINST MEDULLOBLASTOMA
Authors: Malhotra Anshu , Liu Jingbo , Zhang Hongying , Ma Minhui , Vega Jose Velazquez , Schniederjan Matthew , Prabhu Varun , Allen Joshua , MacDonald Tobey 
Published: December 2020

Abstract
Treatment for medulloblastoma (MB) is typically ineffective for MYC amplified or metastatic SHH, Group 3 and 4 subgroups. Promising preclinical and clinical results have been obtained in brain cancers treated with ONC-201, a selective antagonist of DRD2, a G-protein coupled receptor that regulates prosurvival pathways. Herein, we report the activity of ONC-201 and ONC-206, which has increased non-competitive antagonism of DRD2, against MB. We treated three different MB cell types representative of SHH- and Group 3-like cells, with varied levels of DRD2 expression, and consistently observed increased cell death in a dose-dependent manner at lower doses of ONC-206 compared to ONC-201. We also evaluated ClpP as an additional drug target in MB. ClpP is a mitochondrial protease that has been shown to directly bind and be activated by ONC 201, and is highly expressed at the protein level across pediatric MB, malignant glioma and ATRT, but not normal brain. We observed that similar to ONC-201, ONC-206 treatment of MB cells induces the restoration of mitochondrial membrane potential to the non-proliferative state, degradation of the mitochondrial substrate SDHB, reduction in survivin and elevation in ATF4 (integrated stress response). Importantly, ONC-206 treatment induced significant cell death of patient-derived SHH, WNT, and Group 3 tumors ex vivo and Group 4 cells in vitro, while having no observable toxicity in normal brain. Efficacy studies of ONC-206 against MB in vivo will be reported in preparation for a planned Phase I study of ONC-206 in children with malignant brain tumors.
MODL-14. SMALL MOLECULE TARGETING OF ONCOGENIC FGF2-FGFR SIGNALING IN BRAIN TUMORS
Authors: Kumar Karthiga Santhana , Brunner Cyrill , Schuster Matthias , Zerbe Oliver , Grotzer Michael , Schneider Gisbert , Baumgartner Martin 
Published: December 2020

Abstract
FGF2, the ligand of FGF receptors (FGFRs), is expressed in the developing and adult brain. FGF2-FGFR1 signaling causes the induction and maintenance of cancer stem cells through ERK-dependent up-regulation of ZEB1 and Olig2 in glioblastoma. In SHH medulloblastoma, Olig2 triggers tumor initiation from GCPs, maintains quiescent stem-like cells during the disease and contributes to tumor outgrowth at recurrence. We found that FGF2-FGFR signaling causes increased growth and tissue invasion through the FGFR adaptor protein FRS2 in SHH and group-3 medulloblastoma 1. Thus, targeting of FGFR-FRS2 signaling could abrogate brain tumor growth and spread by repressing tumor-promoting functions that are induced by microenvironmental FGF2. Using virtual screening combined with functional validation, we identified protein-protein interaction inhibitors (F2i) that bind FRS2 and abrogate FGFR signaling to the MAP-ERK pathway. Consistent with the requirement of FRS2 for pro-invasive signaling downstream of FGFR1 in medulloblastoma, F2i also efficiently block FGF2-induced migration and invasion in medulloblastoma-derived cells. Selected F2i display excellent binding kinetics with a similar Kd as the natural ligand domain of FGFR and cause steric alterations in the targeted protein domain. On-target activity was confirmed by thermal proteome profiling. Neither in silico screening nor empirical testing revealed significant off-target activity of the compounds. No toxicity of F2i was observed in cell-based models with confirmed functional activity on invasion and MAPK activation. Thus, we identified novel, low molecular weight pharmacological protein-protein interaction inhibitors with an excellent potential to specifically block FGFR functions relevant for brain tumor progression. 1. Santhana Kumar et al., CellReports23, 3798–3812.e8 (2018).
MODL-19. DIPG HARBOUR ALTERATIONS TARGETABLE BY MEK INHIBITORS, WITH ACQUIRED RESISTANCE MECHANISMS OVERCOME BY COMBINATORIAL UP- OR DOWN-STREAM INHIBITION
Authors: Izquierdo Elisa , Carvalho Diana , Mackay Alan , Temelso Sara , Boult Jessica K R , Molinari Valeria , Stubbs Mark , Depani Sarita , O’Hare Patricia , Robinson Simon P , Hubank Michael , Hargrave Darren , Jones Chris 
Published: December 2020

Abstract
The survival of children with DIPG remains dismal, with new treatments desperately needed. In the era of precision medicine, targeted therapies represent an exciting treatment opportunity, yet resistance can rapidly emerge, playing an important role in treatment failure. In a prospective biopsy-stratified clinical trial (BIOMEDE), we combined detailed molecular profiling (methylation BeadArray, exome, RNAseq, phospho-proteomics) linked to drug screening in newly-established patient-derived models of DIPG in vitro and in vivo. We identified a high degree of in vitro sensitivity to the MEK inhibitor trametinib (GI50 16-50nM) in samples which harboured genetic alterations targeting the MAPK pathway, including the non-canonical BRAF_G469V mutation, and those affecting PIK3R1. Treatment of PDX models and the patient with trametinib at relapse, however, failed to elicit a significant response. We generated trametinib-resistant clones (62-188-fold, GI50 2.4–5.2µM) in the BRAF_G469V model through continuous drug exposure, and identified acquired mutations in MEK1/2 (MEK1_K57N, MEK1_I141S and MEK2_I115N) with sustained pathway up-regulation. These cells showed the hallmarks of mesenchymal transition, with overexpression of key proteins involved in invasion/migration, such as collagen-family proteins, integrins, MMPs and AHNAK2, amongst others. Resistant clones were conversely sensitive to the upstream receptor tyrosine kinase inhibitor dasatinib (GI50 36-93nM), and combinations of trametinib with dasatinib and the downstream ERK inhibitor ulixertinib showed synergistic effects in vitro. These data highlight the MAPK pathway as a therapeutic target in DIPG, and show the importance of parallel resistance modelling and rational combinatorial treatments likely to be required for meaningful clinical translation.
MODL-23. DNA METHYLATION AND COPY NUMBER VARIATION PROFILE FOR CHARACTERIZATION OF PEDIATRIC BRAIN TUMOR PRIMARY CELL LINES
Authors: Pedace Lucia , Vinci Maria , Pizzi Simone , Pericoli Giulia , Catanzaro Giuseppina , Abballe Luana , Del Bufalo Francesca , Caruana Ignazio , Camassei Francesca Diomedi , Rossi Sabrina , Giangaspero Felice , Ferretti Elisabetta , Ciolfi Andrea , Tartaglia Marco , Locatelli Franco , Mastronuzzi Angela , Miele Evelina 
Published: December 2020

Abstract

BACKGROUND
In vitro models of pediatric brain tumors (pBT) are instrumental for both understanding the oncogenic molecular mechanisms and identifying/testing new therapeutic strategies. DNA methylation (DM) is a stable epigenetic modification recently used to classify tumors. We aim to apply DM and Copy Number Variation (CNV) profiling to characterize pBT primary cell lines and tumors.

METHODS
We included 36 pBT tissues from different histology (13 LGG, 9 DIPG, 9 HGG, 3 MB, and 2 Ependymomas), paired to their derived primary cultures. Cultures were established in two-dimensional (2D) or three-dimensional (3D) condition, as stem-cell or in serum-supplemented medium. For 9 cultures, both early (P2-P3) and long-term passages (&gt;P4) were considered. Samples were analyzed for DM and CNV profiles using Illumina EPIC arrays and data compared with those of the brain tumor classifier.

RESULTS
At early passages all cells retained the same DM and genetic patterns of original tumors, with no differences related to 2D/3D methods or presence of serum in media. Primary cell lines analyzed at &gt; P4 and cultured in serum diverged from the primary tumor.

CONCLUSIONS
DM profiles and CNV are useful tools to detect the recapitulation of pBT-derived primary cell-lines from the original tumor. Whatever subgroups tested, results suggest that in vitro models should be passaged as little as possible to retain the epigenetic and genetic alterations of the tumors and thus to be considered relevant for basic and translational biology. Ongoing experiments are aimed to determine how stable DM and CNV are in other conditions/tumor subgroups.
NFB-04. EXAMINING DIFFUSION, ARTERIAL SPIN-LABELED PERFUSION, AND VOLUMETRIC CHANGES IN THE NEUROFIBROMATOSIS TYPE 1 BRAIN USING AN ATLAS-BASED, MULTI-PARAMETRIC APPROACH
Authors: Tam Lydia , Ng Nathan , Moon Peter , Zheng Jimmy , McKenna Emily , Forkert Nils , Campen Cynthia , Yeom Kristen 
Published: December 2020

Abstract

BACKGROUND
Neurofibromatosis Type 1 (NF1) is a multisystem disorder with wide ranging clinical implications. Patients may present with macrocephaly, stroke, and cognitive deficits, all of which may impede normal neural development. We applied atlas-based, multi-parametric MRI analysis of regional brain to evaluate diffusion, arterial spin-labeled (ASL) perfusion, and volumetric changes in children with NF1.

METHODS
Children evaluated for NF1 from 2009 to 2018 at Stanford University (n=78) were retrospectively reviewed and compared to healthy controls (n=100). All patients underwent diffusion-weighted (DWI) magnetic resonance imaging at 3T, and children with brain tumors were excluded. Using atlas-based DWI analyses, we assessed volume, median apparent diffusion coefficient (ADC), and cerebral blood flow in the cerebral cortex, thalamus, caudate, putamen, globus pallidus, hippocampus, amygdala, nucleus accumbens, brain stem, and cerebral white matter. We also measured volume of the lateral ventricles. Multivariate analysis of covariance was used to test for differences between controls and NF1 patients, controlling for gender and age at time of imaging.

RESULTS
Comparing NF1 to controls, we detected increased volume and decreased ASL cerebral blood flow in white matter and all subcortical and cortical structures except for brainstem volume. Median ADC was also increased in the thalamus, pallidum, hippocampus, and brainstem.

CONCLUSIONS
Using a multi-parametric approach, we demonstrate quantitative measures of microstructural and physiologic changes of the NF1 brain. Atlas-based, quantitative MRI brain signatures may serve as biomarkers of neural development and further provide insight into associated cognitive dysfunction or risks for vasculopathy-related strokes in children with NF1.
NFB-11. WHITE MATTER DIFFERENCES IN CHILDREN WITH NF1 COMPARED TO CONTROLS
Authors: Bruckert Lisa , Travis Katie , McKenna Emily , Yeom Kristen , Campen Cynthia 
Published: December 2020

Abstract

INTRODUCTION
Neurofibromatosis type 1 (NF1) is a genetic condition in which children develop learning challenges and glioma. White matter tracts (WMT) are implicated in these cognitive functions, while oligodendroglial precursor cells are implicated in both gliomagenesis and white-matter development. Specific WMTs have not been well characterized in NF1.

METHODS
Twenty NF1 patients aged 1.4–17.6 years (M = 9.5 years, 24 male) and 20 age-and-sex-matched controls underwent dMRI at 3T (25 directions, b=1000 s/mm2). Automated segmentation of WMTs extracted fractional anisotropy (FA) and mean diffusivity (MD) of 18 major WMTs. Covariance analysis examined the effect of group (NF1/controls) on FA/MD after controlling for intracranial volume. Regression analyses for WMTs determined the interaction of FA/MD with age for NF1 patients compared to controls. Significance was set at p&lt;0.05 after correcting for multiple comparisons using false discovery rate.

RESULTS
Compared to controls, children with NF1 had significantly decreased FA in 8 and increased MD in 12/18 tracts. Differences held after controlling for intracranial volume. The interaction between group and age accounted for a significant proportion of the variance in FA in 9 and in MD in 16/18 tracts. FA and MD differences between children with NF1 and controls were greater at younger than older ages.

CONCLUSION
Microstructural differences were observed in WMTs in children with NF1 compared to controls. These differences were not explained by intracranial volume and were most pronounced in younger children with NF1 compared to controls. These findings have implications for understanding neurocognitive deficits and gliomagenesis observed in children with NF1.
NFB-14. PSYCHOSOCIAL OUTCOMES IN CHILDREN WITH NEUROFIBROMATOSIS TYPE 1 AND PLEXIFORM NEUROFIBROMAS
Authors: Damodharan Sudarshawn , Mission Paige , Puccetti Diane 
Published: December 2020

Abstract

OBJECTIVE
This case series seeks to examine neurocognitive outcomes, social-emotional functioning, and family burden in young children diagnosed with Neurofibromatosis, type 1 (NF1) with early growing plexiform neurofibromas (PNFs).

BACKGROUND
Neurofibromatosis, type 1 (NF1) is a common predisposing chronic disease arising in early childhood, with an incidence of approximately 1:3000. Though NF1 displays a wide range of phenotypic variability, the primary feature of the disease is peripheral nerve sheath tumors called neurofibromas. Less is well known regarding the broader neurocognitive and social-emotional profile in presentations with more complex tumor growths, namely PNFs, which are present in at least half of the NF1-affected population.

METHODS
Participants with NF1 and PNFs (n=2) aged 6-7years completed comprehensive neuropsychological evaluations and parents completed measures of quality of life, social-emotional/behavioral functioning of child, parental stress, family adaptability, and family cohesion.

RESULTS
Outcomes suggest broad neurocognitive dysfunction (e.g., executive functioning deficits, attention problems, visual-motor delays, and poor motor coordination), social-emotional challenges (e.g., symptoms of anxiety and depression, and poor social skills), and familial distress.

CONCLUSIONS
Findings indicate the value of early and frequent monitoring of children with PNFs in medical systems and multi-disciplinary teams, and the importance of early intervention for both children and families.
NURS-03. DEVELOPMENT OF A PATIENT-HELD TREATMENT SUMMARY FOR PAEDIATRIC CNS TUMOUR PATIENTS
Authors: McAndrew Rachel , Wilkie Bernadine , Brougham Mark , Phillips Jo 
Published: December 2020

Abstract

BACKGROUND
Following the Scottish Government Cancer Plan 2012–15(1) ‘End of Treatment’ summaries for paediatric oncology patients treated in SE Scotland have been successfully implemented. However, it became evident that the particular needs of patients with CNS tumours were not adequately captured on the standardised documentation.

METHODS
In view of these difficulties an alternative document was prepared specifically for this patient cohort by the multi-disciplinary team, including Nurse Specialists, Paediatric Neuro-oncology and Neuro-psychology. This was designed to be a flexible, fluid summary to be used for all such patients regardless of tumour grade or treatment modality and included those undergoing surveillance only. OUTCOMES: The document is primarily completed by the Neuro-Oncology Nurse Specialist alongside the patient and family, usually following initial treatment and is used alongside their holistic needs assessment. The document is circulated to all involved professionals, including Primary Care, and a copy is retained by the patient. This then provides a concise source of information detailing diagnosis and treatment, any specific ongoing sequelae and details of red flag symptoms to alert patients and health professionals to the potential of relapse or other associated significant health problems. These treatment summaries are currently being piloted and have been well received thus far. They will be formally audited in due course with the aim to use nationally throughout Scotland in future.