tbuckley/cabot-search huggingface dataset:
NURS-09. FERTILITY PRESERVATION AND PALLIATIVE CARE: RECOGNIZING THE NURSING ROLE IN THE PROMPT IMPLEMENTATION OF SUPPORTIVE CARE INTERVENTIONS IN THE PEDIATRIC CENTRAL NERVOUS SYSTEM TUMOR PATIENT POPULATION
Authors: Michele McHugh, Kaaren Waters, Courtney Baker Briamonte, Micah Higgins, Carly Hoffman, Susan Holtzclaw, Ashley Meyer, Shannon Raber, Kasey Rangan, Cindy Schmus, Kenny Seidl, Marylynne Strachan, Lanipua Yeh-Nayre
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Given the complexity of pediatric central nervous system (CNS) tumors, an interdisciplinary approach is necessary to incorporate supportive care interventions that complement oncologic treatment plans. However, early implementation of both palliative care and fertility preservation services presents challenges within the pediatric neuro-oncology population. METHODS An extensive literature review was conducted for articles published between 2013-2023 using PubMed, Google Scholar, and CINAHL databases. The articles focused on nurses’ roles in pediatric oncology, palliative care, fertility preservation, and barriers to supportive care. Furthermore, the review incorporated collective knowledge sharing among pediatric neuro-oncology nursing specialists. This joint initiative applied evidence-based practices to showcase the successful implementation of palliative care and fertility preservation services, broadening this project’s scope. RESULTS One prevalent theme that emerged highlighted the delay in supportive care referrals attributed to perceived obstacles by healthcare team members. The misconception that palliative care is solely for end-of-life situations or the assumption that families are not ready to acknowledge an incurable diagnosis causes delays in palliative care referrals. Fertility preservation in pediatric oncology encounters obstacles, including the urgency to commence treatment, determining optimal candidate criteria, and navigating discussions with younger patients. Nurses are uniquely positioned in their role to bridge gaps between oncologic treatment interventions and the incorporation of supportive care measures. Recognizing the supportive care needs of patients, nurses can educate families, advocate for early referrals, and coordinate integrative care. Advanced Practice Nurses (APNs) can offer clinical consultation, and order appropriate screening, testing, medications, and referrals. CONCLUSION Disseminating nursing education across pediatric oncology practices and institutions is essential for identifying perceived barriers and reforming the early supportive care intervention process. This collaborative and proactive approach is designed to optimize the overall care experience, with the goal of enhancing the delivery of supportive care for pediatric neuro-oncology patients.
MDB-93. A TRANSCRIPTOME-BASED APPROACH TO DRUG REPURPOSING FOR AGGRESSIVE GROUP 3 MEDULLOBLASTOMAS
Authors: David Doss, Ranjana K Kanchan, Naveenkumar Perumal, Surinder K Batra, Sidharth Mahapatra
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Medulloblastoma (MB) is the most common malignant brain tumor in children, representing 20% of pediatric brain tumors. International consensus has identified molecular subgroups: WNT, SHH, group 3 (G3), and group 4 (G4). Current treatments, guided by histologic tumor grade and stage, do not fully harness these subgroups, resulting in varying prognoses. G3MB particularly faces challenges with rapid recurrence and aggressive disease, necessitating focused intervention. METHODS We conducted differential expression analysis on MB patient datasets (GSE148389, GSE164677) to generate a G3MB gene expression signature. This gene expression signature was analyzed against the LINCS database, yielding candidate antineoplastic compounds. Candidates were filtered for blood-brain barrier permeability and FDA approval. Functional assays evaluated drug effects on cytotoxicity, clonogenicity, wound healing, cell cycle, and apoptosis in G3MB cell lines (HDMB03 and D425). RNA sequencing of treated cells identified differentially regulated pathways to infer mechanism, followed by in vitro validation. Mitochondrial function and membrane potential were measured by Seahorse and TMRM assays, respectively. RESULTS Eighty-one candidates passed filtering. The leading drug class identified was antidepressants. Based on MTT assays, the top four candidates were nortriptyline, simvastatin, fluoxetine, and sertraline. Nortriptyline (NT) emerged as the lead compound, with IC50 values of ~7uM (HDMB03) and ~11uM (D425). Amongst the four drugs, NT induced consistent anti-neoplastic effects on wound healing, colony formation, medullosphere generation, and apoptosis. Mechanistically, NT induced mitochondrial stress, escalated mitochondrial superoxide, and decreased mitochondrial membrane potential. CHRM3, a receptor antagonized by NT and upregulated in G3MB samples was downregulated by NT treatment. Western blotting confirmed the inhibition of CHRM3 downstream effectors. CONCLUSIONS Our pipeline identified cytotoxic compounds against G3MB, including NT, which we hypothesize induces mitochondrial stress via CHRM3 modulation. This approach offers repurposable FDA-approved candidates for high-risk G3MB, potentially reducing current treatment toxicity and improving outcomes.
MDB-87. REAL-LIFE EXPERIENCE WITH A “MEMMAT-LIKE” METRONOMIC REGIMEN FOR RELAPSED/REFRACTORY MEDULLOBLASTOMA
Authors: Antonella Cacchione, Federica D’Antonio, Valentina Di Ruscio, Giacomina Megaro, Giada Del Baldo, Ilaria Liguoro, Assunta Tornesello, Alessandro Cocciolo, Sabina Vennarini, Silvia Chiesa, Andrea Carai, Giovanna Stefania Colafati, Angela Mastronuzzi
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Standard salvage regimen for medulloblastoma’s relapse is currently lacking. An evolving alternative approach is metronomic chemotherapy, which aims to interfere with tumor angiogenesis. We report our experience on a modified combinatorial metronomic chemotherapic/antiangiogenic approach, the Medulloblastoma European Multitarget Metronomic Anti-Angiogenic Trial (MEMMAT) regimen. Our study aimed to test efficacy and tolerance of that approach in pediatric patients with relapsed/refractory medulloblastoma treated in outpatient unit. METHODS The study was conducted from January 2017 to December 2022 at Bambino Gesù Children’s Hospital in Rome. MEMMAT-like regimen consisted of daily oral thalidomide, fenofibrate, celecoxib, and alternating 21-day cycles of low-dose oral etoposide and cyclophosphamide supplemented by intravenous bevacizumab and intrathecal topotecan. RESULTS Fourteen patients met the eligibility criteria. At diagnosis, six patients (43%) presented a localized disease, the other eight patients (57%) metastatic one; eight patients had the first recurrence and six had multiple recurrences at the start of MEMMAT-like therapy. At relapse, all the recurrences had a metastatic pattern. Methylation profiling classification showed three subgroups 3, six subgroups 4, three with SHH subgroup, and two WNT. The median overall survival after the recurrence that prompted to the use of MEMMAT like regimen, for the whole group, was 17,9 months (range, 8-32 months), with 79% (60%,100%) at 12 months and 19% (5,7%-64%) at 24 months; the mean progression-free survival (PFS) at 12 and 24 months was 57% (36%-90%) and 26% (10%-66%). When the one-year PFS rate was evaluated according to the MEMMAT-like number of treatment lines (after the first relapse or third and beyond), we found respectively 62% (37%-100%) and 50% (22%100%). CONCLUSIONS The metronomic outpatient MEMMAT-like combination is feasible, well tolerated, and can lead to sustained control of relapse in medulloblastoma. The best setting seems to be after the first relapse to achieve a higher PFS.
MDB-28. THE CYTOSKELETON REGULATORS FORMINS CONTROL THE SHH PATHWAY AND ARE INVOLVED IN MEDULLOBLASTOMA TUMORIGENESIS
Authors: Paola Infante, Marilisa Conenna, Gennaro Adabbo, Francesca Bufalieri, Marta Bottero, Ludovica Lospinoso Severini, Francesca Bartolini, Lucia Di Marcotullio
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Medulloblastoma (MB) is a lethal pediatric malignancy of the cerebellum. Among MB’s molecular subgroups, Sonic Hedgehog (SHH) is the most abundant and it is characterized by alterations of key components of the SHH development pathway. However, the molecular mechanisms driving SHH-MB require to further be unveiled to design more effective therapies. Recently, we identified formins, well-known players of cytoskeletal dynamics, as regulators of SHH signaling able to affect SHH-MB growth. METHODS Luciferase functional assays, western-blot and RT-qPCR have been performed to analyze the effect of formins on GLI1 (the final effector of SHH signaling) transcriptional activity and expression. Proliferation assays and Brillouin microscopy have been carried out on primary murine SHH-MB cells to test the effect of formins on SHH-MB growth and stiffness. RESULTS We demonstrated that formins have a dual role in the regulation of SHH signaling, either positive or negative. The modulation of formins expression in SHH-dependent cell models affect GLI1 transcriptional activity and expression. Moreover, formins show opposite protein expression levels during the development of murine cerebellum, and their modulation impair the proliferation of granule cell progenitors (GCPs), the cells of origin of MB. Interestingly, formins protein levels are highly altered in SHH-MB samples. Notably, the overexpression or the genetic silencing of formins in SHH-MB primary cells from Math1-Cre/Ptc1fl/fl mice significantly impact on the cell proliferation as consequence of modulated GLI1 expression levels and the stiffness of primary SHH-MB cells, thus suggesting that formins could affect tumor cell motility and invasiveness. CONCLUSIONS Our findings identify formins as regulators of SHH signaling and illuminate on the role of cytoskeleton in SHH-MB for the design of innovative interventions.
MDB-29. SALL4 IS A CRL3REN/KCTD11 SUBSTRATE THAT DRIVES SONIC HEDGEHOG-DEPENDENT MEDULLOBLASTOMA
Authors: Ludovica Lospinoso Severini, Elena Loricchio, Shirin Navacci, Irene Basili, Romina Alfonsi, Flavia Bernardi, Marta Moretti, Marilisa Conenna, Antonino Cucinotta, Sonia Coni, Marialaura Petroni, Enrico De Smaele, Giuseppe Giannini, Marella Maroder, Gianluca Canettieri, Angela Mastronuzzi, Daniele Guardavaccaro, Olivier Ayrault, Paola Infante, Francesca Bufalieri, Lucia Di Marcotullio
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Medulloblastoma (MB) is the most common malignant pediatric brain tumor arising from alterations in cerebellum development. The Sonic Hedgehog variant (SHH MB) is the best genetically characterized, however the molecular mechanisms responsible for its pathogenesis are not fully understood and therapeutic benefits are still limited. Mutations in key components of the SHH pathway and cytogenetic alterations (such as chromosome 17p deletion) lay the pathogenetic foundation for SHH MB subgroup. RENKCTD11 (here REN) is a tumor suppressor and substrate-receptor subunit of the Cullin3 Ring E3 ubiquitin ligase (CRL3) complex mapping on chromosome 17p and frequently deleted in SHH MB. We wished to expand the knowledge of CRL3REN activity to unveil molecular circuitries whose deregulation can contribute to SHH MB onset and to uncover novel therapeutic targets. METHODS Affinity purification coupled to mass spectrometry was performed to identify new REN interactors. Co-immunoprecipitation and ubiquitylation assays validated proteomic data. The proliferation of primary murine SHH MB cells and Patient Derived Xenografts (PDXs) models was evaluated in vitro by using the IncuCyte imaging system. Heterotopic and orthotopic allograft in vivo models of SHH MB were established in immunodeficient mice. RESULTS Proteomic analysis revealed that the pro-oncogenic stemness Spalt-like transcriptional factor 4 (SALL4) interacts with REN. We found that SALL4 is re-expressed in mouse SHH MB models and its high levels correlate with worse overall survival in SHH MB patients. We demonstrate that CRL3REN induces polyubiquitylation and degradation of wild type SALL4, but not of a SALL4 mutant lacking zinc finger cluster 1 domain (ΔZFC1). Interestingly, SALL4 binds GLI1 and cooperates with HDAC1 to potentiate GLI1 deacetylation and transcriptional activity. Notably, inhibition of SALL4 suppress SHH MB growth both in murine and PDX models. CONCLUSIONS Our findings identify SALL4 as a CRL3REN substrate and a promising therapeutic target in SHH-dependent cancers.
MDB-46. ARE RAB40 SMALL GTPASES DRIVERS OF MEDULLOBLASTOMA PATHOGENESIS?
Authors: Joseph Allen, Susannah Entwistle, Beth Coyle, Alistair N Hume
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Medulloblastoma is the most common solid paediatric neoplasm and is among the leading causes of cancer-related deaths in children. Patients associated with high-risk molecular subgroups convey poor outcomes due to frequent relapse and metastasis, with two thirds of survivors experiencing life-changing developmental deficits. Poor patient outcomes and significant co-morbidities highlight an urgent need for specific, molecularly targeted therapies. The RAB40 subfamily of atypical small GTPases regulate cytoskeletal structure and cell adhesion via their ubiquitin ligase activity. Although previous studies have linked the RAB40 subfamily with cell invasiveness, their role in paediatric brain cancer remains undefined. METHODS Patient methylation and survival data from Cavalli et. al (2017) was analysed via the R2 Genomics Analysis and Visualisation Platform. RAB40 gene and protein expression were determined in eight in vitro models of medulloblastoma via qRT-PCR and western blotting. Cells were transfected with EGFP-Cas9 mRNA and RAB40-targeted CRISPR sgRNA and seeded singly using fluorescence-activated cell sorting. RAB40 knockout clones were identified via western blot and Sanger sequencing. RESULTS Patient data demonstrated that higher RAB40 gene expression correlates with worse outcomes in group 3 and 4 medulloblastoma. RAB40 genes were also significantly more highly expressed in high-risk groups 3 and 4 compared to low-risk WNT group medulloblastoma. RAB40 mRNA was enriched in cell lines derived from high-risk group 3 and 4 medulloblastoma relative to SHH controls. RAB40 knockout models were subsequently generated in HD-MB03, an in vitro model of metastatic Group 3 medulloblastoma using CRISPR/Cas9. CONCLUSIONS Our data supports the hypothesis that RAB40 small GTPases are enriched in high-risk medulloblastoma subgroups, and that their expression correlates with worse patient outcomes. We have generated knockout models which will be used to characterise the impact of RAB40 GTPases on cell growth, adhesion, invasiveness, and chemotherapeutic tolerance.
MDB-47. DEEP LEARNING DECODES NEW SITES OF RNA TRANSLATION IN MEDULLOBLASTOMA
Authors: Jim Clauwaert, Gerben Menschaert, John Prensner
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Medulloblastoma, a malignant brain cancer predominantly affecting children, possesses a high propensity for metastasis and is frequently fatal. Through studies on RNA translation, a core biological process, we aim to uncover the disease biology of cancer in order to design therapeutic targets. Yet, the exploration of canonical protein-coding genes has thus far yielded few viable targets in medulloblastoma, where non-canonical open reading frames (ORFs) are increasingly being investigated for their regulatory role. METHODS To address the significant challenge in delineating novel translated ORFs in individual cells or tissues, we have designed RIBO-former, a best-of-its-class machine learning model that leverages ribosome profiling data to detect translated open reading frames. Through RIBO-former, we expanded the proteome of healthy prenatal (n=30) and adult (n=42) samples, which are notoriously hard to process due to low read depth and noise, in addition to medulloblastoma cancer tissue (n=8) and cell line (n=15) data. RESULTS Across all medulloblastoma cell lines, we determine an initial selection of 3,638 non-canonical ORFs. Unsupervised clustering of the ribosome profiling read counts within these non-canonical ORF regions group samples according to the described subtypes of medulloblastoma cancer, hinting at the significant role these ncORFs play in protein homeostasis. Looking into distinct expression profiles between cell lines with high and low MYC expression, we revealed 201 non-canonical ORFs that are differentially expressed. We evaluate our data through various analyses including testing of which ORFs have a viable sequence context for translation, achieved through another in-house tool (TIS Transformer). CONCLUSIONS By taking advantage of advances in machine learning, we were able to uncover new sites of translation in medulloblastoma that can aid the future discovery of therapeutic targets. As such, we were able to find 22 highly promising non-canonical ORFs that show unique expression profiles in relation to MYC in medulloblastoma.
MDB-85. THE MIGRATORY ROLE OF BAIAP2 IN MEDULLOBLASTOMA
Authors: Luz C Ruiz, Nitish Jangde, Robert Suter, Anna Jermacowikz, Nagi Ayad
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Medulloblastoma is the most common malignant brain tumor in adolescents. There is still a dire need for a more effective treatment despite advances in technology. One challenge in treating medulloblastoma is its migratory and invasive properties. The underlying mechanisms that lead to these characteristics are still not understood. METHODS We sought to identify targets related to invasion and migration in medulloblastoma, first by mining single-cell RNA sequencing and microarray data. RESULTS We determined that BAIAP2 is differentially expressed in medulloblastoma compared to non-tumor brain cells and other brain cancers. In addition, there is a significant increase in BAIAP2 in metastatic medulloblastoma compared to non-metastatic. We found that CDC42 and RAC1, small GTPases, are protein-protein interactors with BAIAP2. In three medulloblastoma cell lines, we have demonstrated that these genes modulate each other’s expression. Furthermore, we show that the knockdown of BAIAP2, CDC42, and RAC1 decreases medulloblastoma cell migration and filopodia length. Using surface plasmon resonance, we identified compounds that target BAIAP2 protein. After characterizing these compounds, we have identified potential compound candidates that target these genes and impede their roles in migration and invasion in medulloblastoma. CONCLUSIONS These findings demonstrate a migratory role for BAIAP2 in medulloblastoma through the modulation of CDC42 and RAC1. We also demonstrate that BAIAP2 is a therapeutic target and have identified novel compounds that target it.
MDB-48. A SINGLE INSTITUTION EXPERIENCE OF CIPN MEASURED BY THE PED-MTNS IN CHILDREN AND ADOLESCENTS WITH MEDULLOBLASTOMA TREATED ON A TRIAL USING SIMILAR DOSING OF VINCRISTINE AND CISPLATIN FOR ALL PATIENTS
Authors: Jill M Richards, Monica R Olsen, Anne E Bendel, Laura S Gilchrist, Lynn R Tanner
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Standard treatment for medulloblastoma in patients &amp;gt;3 years of age consists of tumor resection, radiation and chemotherapy using vincristine, cisplatin, cyclophosphamide +/- CCNU. Vincristine and Cisplatin are known to cause chemotherapy induced peripheral neuropathy (CIPN). The prevalence of CIPN in children with non-CNS cancers can be measured using the pediatric-modified Total Neuropathy Score (ped-mTNS). The purpose of this observational, retrospective pilot design is twofold: to investigate the prevalence of CIPN in children with medulloblastoma receiving neurotoxic chemotherapy, and to examine the feasibility of using the ped-mTNS as a measurement tool in this population. METHODS Data was manually extracted from medical records and entered into a REDCap database for analysis. The percent of patients successfully tested and clinical inferences made from ped-mTNS testing results were used to determine feasibility and barriers to use. A total of 33 medulloblastoma patients &amp;gt;3 years of age were treated from 6/2013 - 6/2021 at Children’s Minnesota. Of those, 18 received testing using the ped-mTNS during chemotherapy treatment. RESULTS During cancer treatment, 54.5% of the cohort of patients received ped-mTNS testing. The average age of children tested was 10.26 (4.39) years with a majority being male (79%), and non-Hispanic white race/ethnicity (89%). Of the tested participants, 61.1% had more than one measurement. For those patients tested at multiple timepoints, 72.7% demonstrated worsening ped-mTNS scores while on chemotherapy treatment. Therapists recorded inferences relating to neuropathy in 88.1% of testing occurrences with questions of accuracy recorded in 31.3% of testing occurrences. Barriers to use of results included confounding impairments that may occur as a result of the primary tumor, post-surgical changes, and radiation. CONCLUSIONS Using the ped-mTNS is feasible in children and adolescents with medulloblastoma. The ped-mTNS scores indicated that children with medulloblastoma, treated with Vincristine and Cisplatin, experience worsening neuropathy while undergoing chemotherapy treatment.
MDB-84. IDENTIFICATION AND CHARACTERIZATION OF NOVEL TRANSCRIBED ULTRA-CONSERVED REGIONS AS LONG NON-CODING RNAS IN MEDULLOBLASTOMA
Authors: Kadie Hudson, Ashley Vernon, Myron K Gibert Jr Ying Zhang, Shekhar Saha, Collin Dube, Yunan Sun
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Medulloblastoma is the most common malignant pediatric brain tumor. While medulloblastoma survival has improved with molecular subgrouping, children who undergo standard of care treatments frequently experience permanent neurological deficits and many still face poor prognoses. This work investigates the role of “Transcribed Ultra-Conserved Regions” (TUCRs) in medulloblastoma about which there is no published literature. TUCRs represent a distinct group of 481 putative lncRNAs that are 100% conserved across human, mouse, and rat genomes. These elements change 20 times slower than the average genomic region and are therefore under intense negative selection. Since their discovery, TUCRs have remained exceedingly underexamined within cancer research. We hypothesize that TUCRs play critical roles in the molecular basis of medulloblastoma which will lead to the development of targeted therapies for medulloblastoma of which there are none approved. METHODS We used RNA-sequencing and differential gene expression analysis of medulloblastoma tumors as compared to normal cerebellum samples to investigate TUCR dysregulation followed by Kaplan-Meier correlation to survival analysis. We generated a multifaceted scoring and prioritization system to rank TUCRs in medulloblastoma. Top ranked TUCRs were then investigated using in vitro functional experimentation in medulloblastoma cell lines. RESULTS Bioinformatics analysis of medulloblastoma tumors revealed significant TUCR dysregulation and identified numerous TUCRs whose expression correlated with overall survival. Application of the computational scoring system determined the top ten intergenic TUCRs in medulloblastoma. Analysis of medulloblastoma cell lines indicated significant dysregulation of these TUCRs and functional assays showed that uc.403 promoted cell proliferation. CONCLUSIONS We are continuing to investigate the functional effects and mechanisms of action of these select intergenic TUCRs in medulloblastoma. Altogether, our work investigates the oncogenic and tumor suppressive nature of TUCRs. It represents the first study of TUCRs in medulloblastoma that will significantly advance our basic understanding of this highly understudied class of molecules.