bluuebunny/crossref_metadata_2025_split huggingface dataset:
MODL-25. REPLICATION REPAIR DEFICIENT MOUSE MODELS PROVIDE INSIGHT ON HYPERMUTANT BRAIN TUMOURS, MECHANISMS OF IMMUNE EVASION, AND COMBINATORIAL IMMUNOTHERAPY
Authors: Galati Melissa , Li Li , Sudhaman Sumedha , Lipman Tatiana , Stengs Lucie , Elshaer Dana , Bridge Taylor , Semenova Dar’ya , Edwards Melissa , Hodel Karl , Forster Victoria J , Nunes Nuno M , Martin Alberto , Bouffet Eric , Pursell Zachary , Hawkins Cynthia , Tabori Uri 
Published: December 2020

Abstract
Replication repair deficiency (RRD) is the leading cause of hypermutant brain tumours in children. RRD is caused by defects in one of four mismatch repair (MMR) genes and mutations in POLE or POLD1. Such tumours are resistant to common therapeutic agents and animal models are needed to study RRD in vivo and test novel therapies like immune checkpoint inhibitors (ICIs). To model RRD brain tumours specifically, we engineered a Pole mutant mouse model harbouring the S459F mutation (PoleS459F). We combined PoleS459F mice with conditional Msh2 knockout (Msh2LoxP) and Nestin-cre mice. All Nestin-cre+Msh2LoxP/LoxPPoleS459F/+ mice rapidly succumbed to posterior fossa brain tumours between 8.6 and 12.4 weeks. Importantly, tumours exhibited hallmark “ultrahypermutation” (~350 mutations/Mb) and the corresponding signatures characteristic of human combined MMR and POLE-proofreading glioblastoma. Interestingly, Nestin-cre+Msh2LoxP/LoxPPoleS459F/S459F mice failed to establish normal cerebella, suggesting such mutational loads may not support normal brain development. Furthermore, OLIG2-cre+Msh2LoxP/LoxPPoleS459F/+ mice failed to develop tumors. Tumors transplanted into syngeneic vs immunocompromised animals egrafted well orthotopically in the mouse hindbrain but significantly less efficiently when engrafted subcutaneously. Furthermore, immunocompromised and subcutaneous tumors revealed striking differences in mutational burden and clonal architecture, suggestive of nonautonomous immunoediting. Finally, anti-PD1 was sufficient to treat subcutaneously engrafted tumors in immunocompetent animals. This first mouse model of immunocompetent, hypermutant brain tumors can be used to uncover unique characteristics of RRD tumour evolution and allow for immune based therapeutic preclinical testing. Experiments to assess combinational ICIs and other therapeutic interventions in orthotopically transplanted tumors will also be presented.
MODL-26. CHILDREN’S BRAIN TUMOR NETWORK: ACCELERATING RESEARCH THROUGH COLLABORATION AND OPEN-SCIENCE
Authors: Lilly Jena , Mason Jennifer , Appert Elizabeth , Heath Allison , Zhu Yuankun , Zhang Bo , Koptyra Mateusz , Santi Mariarita , Pollack Ian , Goldman Stewart , Leary Sarah , Buccoliero Anna , Scagnet Mirko , Haussler David , Hanson Derek , Zhang Jiangguo , Wan Weiqing , Li Chunde , Firestein Ron , Cain Jason , Phillips Joanna , Gupta Nalin , Mueller Sabine , Grant Gerald , Monje-Deisseroth Michelle , Partap Sonia , Greenfield Jeffrey , Rood Brian , Nazarian Javad , Raabe Eric , Jackson Eric , Stapleton Stacie , Lober Robert , Kram David , Storm Phillip , Lulla Rishi , Prados Michael , Resnick Adam , Waanders Angela 
Published: December 2020

Abstract
The Children’s Brain Tumor Network (formerly known as Children’s Brain Tumor Consortium- CBTTC) is a global organization pioneering a model of open-science medical research to improve treatment and discover cures. Started in 2011, our objective was to utilize a regulatory, agreement, and governance architecture to remove existing research barriers that slowed down the pace of research and collaboration. Our network now includes 17 institutions working together to empower research. As of December 2019, over 3,600 subjects have been enrolled resulting in collection of over 45,000 specimens. Clinical data collection is longitudinal and includes medical history, diagnosis, treatment, pathology slides and reports, radiology imaging and reports, and outcome data. The tissue is collected flash-frozen, in freezing media, and fresh for the generation of pre-clinical models including cell lines. Blood is collected from the subject, with blood or saliva collected from the parents for germline comparison. Additionally, the Children’s Brain Tumor Network- Pediatric Brain Tumor Atlas has generated 952 WGS and RNAseq, 221 proteomics, with annotated clinical data. All of this data, both generated raw and processed data, has been made available broadly to the scientific community via cloud-based platforms, including the Gabriella Miller Kids First Data Resource Portal, Cavatica, and PedCbioportal. As of January 2020, we have 45 approved biospecimen requests and 80 genomic/molecular data requests. In summary, the Children’s Brain Tumor Network’s goal is to accelerate the pace of discovery by providing resources and expanding the network of scientists working towards a cure.
MODL-27. MEK INHIBITION WITH TRAMETINIB SLOWS PROGRESSION OF MEDULLOBLASTOMA AND ATYPICAL TERATOID RHABDOID TUMOR IN ORTHOTOPIC XENOGRAFT MURINE MODEL
Authors: Mushrif Sujata , Hung Long , Muthugounder Sakunthala , Asgharzadeh Shahab 
Published: December 2020

Abstract

BACKGROUND
Combination of surgery, chemotherapy, autologous transplantation, irradiation constitutes treatment of CNS embryonal-cell tumors (Medulloblastoma-MBL, atypical teratoid rhabdoid tumor-AT/RT). Targeted agents to improve survival and decrease side effects are necessary. We hypothesize that inhibiting MAPK pathway in MBL and AT/RT may be beneficial.

METHODS
IHC(pERK) was performed on clinical tumors. Trametinib(MEK inhibitor) was tested on MBL(UW228, D283, DAOY); AT/RT(CHLA06, BT12) cell-lines. Luminescent cell-viability assay was done(72 hrs) and with crystal violet assay(10 days). Orthotopic, xenografts of MBL and AT/RT were made in NOD-Scid gamma mice. Mice were given Trametinib daily by gavage for 6 weeks(0.6mg/kg b.w). Western blot was performed on protein from cell lines and tumor xenografts incubated with Trametinib. H&E staining was done on murine tumors.

RESULTS
AT/RT(48%) and MBL(57%); Anaplastic(50%), Desmoplastic(40%), Classic(38%); Group 4(66%), Group 3(20%), SHH(55%), WNT(0%) showed presence of pERK(clinical samples). In-vitro, Trametinib completely abrogated the phosphorylation of ERK at 125nM in AT/RT and 50nM in MBL. The IC50 after 10 days exposure was 10nM for AT/RT and 35nM for MBL. Trametinib treated mice showed delay in tumor growth and significant survival advantage in both AT/RT (p=0.00336) and MBL (p=0.0069). Murine tumors showed decreased proliferation (H&E).

CONCLUSION
Trametinib decreased cell proliferation, increased survival in our murine model in both MBL and AT/RT. Pre-clinical results indicate benefits in subgroups of AT/RT and MBL with active MAPK pathway.
MODL-28. IMMUNE PRIMING WITH INTERFERON-Γ COMBINED WITH EPIGENETIC MODULATION IN PEDIATRIC BRAIN TUMORS
Authors: Crotty Erin , Morris Shelli , Brasel Ken , Girard Emily , Noll Alyssa , Mhyre Andrew , Olson James 
Published: December 2020

Abstract
Systemic interferon-γ (IFNγ) has been shown to induce major histocompatibility complex class I (MHC-I) and T cell infiltration in solid tumors in adult patients, demonstrating a potential strategy to abrogate tumor-intrinsic mechanisms of immune escape. Pediatric brain tumors (PBT) may be particularly sensitive to this approach but have a paucity of immunogenic tumor antigens for presentation on MHC-I. Decitabine and other DNA methyltransferase (DNMT) inhibitors promote expression of oncofetal antigens and endogenous immune responses through epigenetic alterations. We tested the convergence of these immune priming mechanisms using a novel combination of IFNγ and decitabine across a spectrum of PBT. Primary human cell lines (Med-411FH, PBT-05FH, GBM-511FH, CCHMC-GBM-1, CCHMC-GBM-4, ATRT-310FH) and murine transgenic models were treated with IFNγ alone or in combination with decitabine and evaluated expression of cell surface MHC-I and PD-L1, interferon response genes (ISGs), and oncofetal antigens. PBT showed exquisite sensitivity to IFNγ, increasing expression of MHC-1/PD-L1 along with ISGs (TAP1, MX1, IRF1). Decitabine enhanced IFNγ-induced gene expression of oncofetal antigens NY-ESO-1 and MAGE-A1. In a medulloblastoma flank tumor model, MHC-I was increased by 40-fold following intraperitoneal IFNγ treatment (p=0.01), with a 3-fold increase in PD-L1 (p=0.005) compared to untreated controls. Effect on CD8+ T cell killing and validation in humanized models is ongoing. Immune priming of PBT with IFNγ is feasible and results in more substantial MHC-I upregulation compared to hypomethylating agents alone. These results provide a strong rationale for priming prior to checkpoint inhibition as a compelling therapeutic strategy in immunologically-quiescent PBT.
MODL-30. DISSECTING THE ROLE OF MULTI-CILIOGENESIS NETWORK IN CHOROID PLEXUS TUMOR
Authors: Zhao Haotian , Zahran Tasneem 
Published: December 2020

Abstract
The choroid plexus (CP) in brain ventricles consists of a fibro-vascular core encapsulated by epithelial cells that possess clusters of primary cilia on cell surface. CP tumors are rare primary brain neoplasms that most commonly occur in young children. Compared to the benign CP papilloma, choroid plexus carcinoma (CPC) is poorly understood and highly lethal with few treatments available. Molecular, cytogenetics and genomics studies uncovered complex alterations in CPC including frequent chromosomal loss and recurrent focal aberrations, whereas abnormal NOTCH signaling is observed in many CP tumors. We showed that activation of both NOTCH and Sonic Hedgehog (SHH) signaling in mice drives the formation of aggressive CP tumor. Molecular and histology analyses demonstrated that these murine CP tumors closely resemble their human counterparts, which also display aberrant SHH and NOTCH signaling, suggesting they may represent potential therapeutic avenues. Indeed, treatment with vismodegib, an FDA-approved SHH pathway inhibitor, suppresses CP tumor growth. Unlike multi-ciliated CP epithelial cells, tumor cells in these animal models are characterized by a solitary primary cilium. Though key genes of the multi-ciliogenesis circuit driven by Geminin coiled-coil domain-containing protein 1 (GEMC1) are expressed in CP epithelium, GEMC1-dependent transcriptional program is suppressed in NOTCH-driven CP tumors. Importantly, CPCs in humans consist of tumor cells with a solitary primary cilium and exhibit profound defects multi-ciliogenesis program. Together, these results indicate that a solitary primary cilium is crucial for CPC development, whereas multi-ciliogenesis circuit possesses tumor suppressive functions and may represent a novel therapeutic target in CPC.
NFB-01. FUNCTIONAL CHARACTERIZATION OF ATRX LOSS IN NF1-ASSOCIATED GLIOMA AND MPNST
Authors: Yuan Ming , Reilly Karlyne , Pratilas Christine , Heaphy Christopher , Rodriguez Fausto 
Published: December 2020

Abstract
To identify the biologic relevance of ATRX loss in NF1-associated gliomagenesis, we studied the effects of Atrx loss using four previously characterized Nf1+/-Trp53+/- murine glioma lines. Lines 130G#3 and 158D#8 (corresponding to grade IV and III gliomas, respectively) displayed preserved ATRX protein expression compared to NIH-3T3 cells. We studied the effects of Atrx knockdown in these two lines in the presence and absence of the TERT inhibitor, BIRBR1532. Using a telomere-specific FISH assay, we identified increased signal intensity after Atrx knockdown, only in the presence of the TERT inhibitor. These features are reminiscent of ALT, although there were no significant alterations in cell growth. Next, we studied the effect of ATRX loss in MPNST lines ST88-14, NF90-8, STS-26T. These cell lines all expressed ATRX and DAXX. However, STS-26T contained a TERT promoter mutation and ST88-14 had a known SNP in the TERT promoter, while NF90-8 had no alterations. ATRX siRNA knockdown showed no significant effects in cell proliferation or apoptosis. However, ATRX knockdown resulted in rare ultra-bright foci, indicative of ALT. Next, we studied the in vitro effect of the ATR inhibitor VE-821 in MPNST cell lines. Only NF90-8 (lacking TERT alterations) demonstrated a decrease in growth after ATRX knockdown and VE-821 treatment. However, ATRX knockdown alone did not affect sensitivity to carboplatin. Our findings further support a role for ATRX loss with subsequent ALT activation in a biologic subset of NF1-associated malignancies, thereby opening an opportunity for therapeutic targeting of these aggressive tumors using specific classes of drugs.
NFB-03. TRAMETINIB FOR ORBITAL PLEXIFORM NEUROFIBROMAS IN YOUNG CHILDREN WITH NF1
Authors: Toledano Helen , Dotan Gad , Friedland Rivka , Cohen Rony , Yassur Iftach , Toledano Hagit , Constantini Shlomi , Rootman Mika Shapira 
Published: December 2020

Abstract
Plexiform neurofibromas (PN) in NF1 are diagnosed in early childhood and may grow rapidly during this period. In 10% of patients they involve the orbital-periorbital area and may cause visual problems including glaucoma and visual loss from amblyopia (deprivational, strabismic, or refractive), optic nerve compression or keratopathy. Ptosis, proptosis and facial disfigurement lead to social problems and decreased self-esteem. Complete surgical removal is usually impossible and there is a tendency for regrowth after debulking. Recently inhibitors of the RAS/MAPK pathway have been investigated for their activity in PN. We describe 5 young children with NF1 and PN of the orbital area treated with the MEK inhibitor trametinib followed clinically and by volumetric MRI. Treatment was initiated at mean age 26.8 months (SD ±12.8) and continued for median 25 months (range 17– 48). Reasons for initiating treatment were visual compromise and progressive tumor growth. Doses were as recommended. One child reported decreased orbital pain after one week and another, with involvement of the masseters, had increased ability to chew food. Toxicities were mostly to skin and nails grades 1–2 as expected. Additionally, 60% had debulking surgery of preseptal eyelid tumor in first year of medical treatment. Volumetric MRI measurements showed reduction of 8–26% at 1 year from baseline with a maximal reduction of 45% in two patients at 22 & 45 months. No change in visual function was recorded following treatment initiation. In conclusion, trametinib may decrease tumor size in young children with orbital PN and may prevent progressive disfigurement.
NFB-06. TREATMENT CHALLENGES IN PEDIATRIC GLIOBLASTOMA MULTIFORME WITH CONCURRENT SOMATIC AND GERMLINE NF1 MUTATIONS WITH GERMLINE MISMATCH REPAIR MUTATIONS: TWO UNIQUE CASES
Authors: Baig Muhammed , Mork Maureen , Khatua Soumen , Slopis John , Zaky Wafik , Bingham Racheal , Gupta Sumit , Fuller Greg , Sadighi Zsila 
Published: December 2020

Abstract

INTRODUCTION
We report the first known cases of pediatric glioblastoma (GBM) with prior clinical NF1 diagnoses, one with concurrent germline Lynch syndrome (LS) and NF1, and the other with somatic NF1 mutation and germline constitutional mismatch repair deficiency (CMMRD).

METHODS
Two pediatric GBM cases with prior NF1 clinical diagnoses based on neurocutaneous criteria were reviewed. Next generation sequencing and immunohistochemical staining were used for somatic and germline NF1 and MMR gene mutation detection, and for MMR protein expression, respectively.

RESULTS
Sixteen year old male with prior NF1 clinical diagnosis had resection of right frontal GBM revealing somatic mutations of POLE and PMS2, but not NF1. His father had confirmed LS with MSH2 mutation and no neurocutaneous stigmata. Patient’s germline testing revealed both pathogenic MSH2 plus NF1 mutations confirming LS and NF1. Treatment consisted of chemoradiation with temozolomide followed by adjuvant temozolomide with stable disease at 8 cycles. Nineteen year old male with former NF1 clinical diagnosis had 2 GBMs, first in left midbrain biopsied revealing somatic PMS2 and NF1 mutations underwent radiation then 7 cycles of temozolomide, then new left frontal GBM underwent resection followed by radiation and 5 cycles of pembrolizumab stable at 5th cycle.

CONCLUSION
Children with NF1 stigmata and GBM can have concurrent NF1 and LS, or CMMRD with NF1 somatic mutations. Our patients tolerated alkylating agents, despite risk for secondary malignancies as upfront therapy and at recurrence checkpoint inhibitors. Upfront therapy in GBM with mismatch repair syndrome with checkpoint inhibitors should be studied.
NFB-12. TRAMETINIB THERAPY FOR PEDIATRIC PATIENTS WITH REFRACTORY LOW GRADE GLIOMA OR EXTENSIVE SYMPTOMATIC PLEXIFORM NEUROFIBROMA
Authors: Hounjet Celine D , Ronsley Rebecca , Cheng Sylvia , Rassekh S Rod , Duncan Walter J , Dunham Christopher , Gardiner Jane , Ghag Arvindera , P, Ludemann Jeffrey , Wensley David , Rehmus Wingfield , Sargent Michael A , Evans Naomi , Popovska Vesna , Hukin Juliette 
Published: December 2020

Abstract

OBJECTIVE
Refractory symptomatic plexiform neurofibromas (PNF) and inoperable refractory low grade gliomas (LGG) pose a clinical challenge that may be life threatening. Phase 1 and 2 clinical trials of MEK inhibition with selumetinib in inoperable PNF and LGG have demonstrated promising results in pediatrics, however access has been limited to enrollment on clinical trial. Phase 1 clinical trial for trametinib a MEK 1 and 2 inhibitor has been completed, publication is pending. Thus we have treated a series of children on a compassionate basis with extensive PN or LGG refractory disease with trametinib, as this is available in Canada.

METHODS
We have treated children with trametinib on a compassionate basis in our province since 2017. Review of the clinical data regarding this therapy has been IRB approved.

RESULTS
Two young patients were treated for indication of life threatening extensive PNF and have had tumor shrinkage and improvement of clinical status. Treatment has been complicated by paronychiae, eczema exacerbation, chondrodermatitis nodularis helicis, RSV and influenza B infection and CTCAE grade 2 pneumonia. In spite of the side effects these two patients remain on treatment due to clear benefit from therapy including: improved respiratory compromise, hearing and dysphagia. We will present the data of additional patients treated with trametinib.

CONCLUSION
Trametinib is an effective therapy for life threatening PNF by changing the natural history of tumor growth in young children. Further data is required in terms of tolerance, efficacy and durability of response in such patients in the setting of clinical trials.
NFB-16. mTOROPATHIES AND SUBEPENDYMAL GIANT CELL ASTROCYTOMAS: PREDICTIVE VALUE OF GERMINAL TSC1/2 MUTATIONS SCREENING IN FAMILIAL CASES
Authors: Abdelmoula Nouha Bouayed , Smaoui Walid , Abdelmoula Balkiss , Aloulou Samir , Masmoudi Imen , Bouaziz Imen , Lamloum Ines , Chaari Hadil , Yaich Asma , Dhouib Rafik , Sellami Sonia , Keskes Mariem , Fellah Sourour , Khlifi Khawla , Medhioub Amir , Mhiri Nabil 
Published: December 2020

Abstract
mTOR controls several important aspects of cell function particularly in the nervous system. Its hyperactivation has been involved in tuberous sclerosis complex (TSC) and other mTORopathies as well as drug-resistant epilepsy. Mutations in TSC1 and TSC2 genes cause loss of normal inhibition of mTORC1 complex, leading to cell overgrowth and disruptions in synaptogenesis. Many children and adults with TSC harbour neurologic defects especially subependymal giant cell astrocytomas (SEGAs) in the brain. Here, we have performed mutational analysis followed by a genetic counselling for a Tunisian family from Sfax town harboring epileptic seizures associated to a neurocutaneous disorder. Index cases were referred for renal angiolipomas (RAL) associated to seizures crisis and were diagnosed as having TSC. The first 26-year-old patient complained of epilepsy since the age of 22 with left temporal crisis related to cortical tubers near the Heschl’s gyrus. His brother, a 36-year-old man presented more severe epileptic crisis (since 15 years-old), multiples RAL, subependymal nodules, and a rapid evolution of his mTORopathy with tumoral progression of his renal and central nerve lesions: renal cell carcinoma and SEGAs. TSC1 gene mutation screening showed heterozygous two bp deletion at codons 213 and 214 of exon 5. SEGAs are rare, low-grade glioneuronal brain tumors that occur almost exclusively in TSC patients but can lead to nervous complications. We showed through this report, the predictive value of germinal TSC mutations screening in familial cases, because early recognition of the molecular defect may lead to appropriate management of the tumoral progression.
NFB-17. MEK INHIBITOR BINIMETINIB SHOWS CLINICAL ACTIVITY IN CHILDREN WITH NEUROFIBROMATOSIS TYPE 1- ASSOCIATED PLEXIFORM NEUROFIBROMAS: A REPORT FROM PNOC AND THE NF CLINICAL TRIALS CONSORTIUM
Authors: Mueller Sabine , Reddy Alyssa T , Dombi Eva , Allen Jeffrey , Packer Roger , Clapp Wade , Goldman Stewart , Schorry Elizabeth , Tonsgard James , Blakeley Jaishri , Ullrich Nicole J , Gross Andrea , Walsh Karin , Thomas Coretta , Edwards Lloyd , Prados Michael , Korf Bruce , Fisher Michael J 
Published: December 2020

Abstract

BACKGROUND
Plexiform neurofibromas (PNs) can cause significant morbidity. In this phase 2 study, we assessed imaging and functional outcomes to the MEK-inhibitor Binimetinib in pediatric patients with PNs.

METHODS
Children (age 1–17 years) with PN that were progressive or causing significant morbidity were eligible. Binimetinib is dosed twice-daily (starting dose of 32mg/m2) for maximum of 24 four-week courses. Participants with partial response (PR; &gt;20% decrease in PN volume on central MRI review) at cycle 12 may stay on therapy. Participants undergo MRI and functional assessments at baseline and after courses 4, 8, 12, 18 and 24. Functional assessments are based on PN location.

RESULTS
Here we present 1-year response data. Twenty participants (55% male) with median age 12 years (range 2–16 years) enrolled; 19 are evaluable for response. Median baseline tumor volume was 326 ml (range, 8-6661 ml). Fourteen participants (74%) met criteria for PR, with 11 achieving PR by course 5. Median maximal PN volume reduction was 25.5% (range, 9–54%). As of August 2020, 14 participants received at least 12 cycles of Binimetinib; 10 remain on therapy. Off study reasons include treatment associated toxicities (n=2), subject withdrawal (n=2), non-compliance (n=2), prolonged treatment delay (n=1), and lack of response (n=3). Thirteen participants underwent dose reduction. Institution-reported related grade 3 toxicities included dry skin, weight gain, muscle weakness, rash, paronychia, cellulitis, diarrhea, gastric hemorrhage and CPK increase.

CONCLUSIONS
Binimetinib appears reasonably well-tolerated and shows promising activity in children with NF1-associated PNs. Outcomes on functional improvement will be reported at the meeting.