tbuckley/cabot-search huggingface dataset:
BIOM-11. TUMOUR SUPPRESSIVE ROLES OF MIR-206 AND MIR-383 VIA<i>CORO1C</i> AND<i>SV2B</i> IN AGGRESSIVE PAEDIATRIC AND ADULT BRAIN MALIGNANCIES
Authors: Denis Mustafov, George I Lambrou, Shoib S Siddiqui, Maria Braoudaki
Journal: Neuro-Oncology (2024)

Abstract Medulloblastoma (MB), the most prevalent brain malignancy in children, poses challenges in paediatric oncology due to its aggressiveness and potential for metastasis. Tailored treatment strategies are essential due to the impact of treatment-related toxicities and long-term side effects on children’s developing brains. This study aimed to identify therapeutic targets for paediatric MB and explore common biosignatures with glioblastoma multiforme (GBM), the most aggressive adult brain tumour. Total RNA and microRNAs (miRNAs) were extracted from eleven paediatric brain tissues (normal brain tissues, n=2; MB tumour tissue, n=8; pilocytic astrocytoma, n=1). High-throughput small-RNA sequencing (sRNA-seq) and transcriptomics were performed to identify the most deregulated miRNAs in paediatric MB tissue samples. Selected miRNAs, gene targets and encoded proteins were evaluated in vitro and ex vivo via real-time polymerase chain reaction (RT-qPCR), western blotting and immunohistochemistry (IHC). The sRNA-seq demonstrated that miR-383 and miR-206 were highly down regulated in MB samples suggesting their tumour suppressor properties. Bioinformatics analysis using miRSystem and TargetScan identified SV2B and CORO1C as their direct targets, respectively. Transcriptomics showed significant upregulation of SV2B and CORO1C in MB tissue samples. RT-qPCR analysis confirmed overexpression of SV2B and CORO1C within GBM cell lines and IHC depicted significant overexpression of SV2B and CORO1C proteins in paediatric MB and GBM patient cohorts (n=28) compared to their normal brain counterparts (n=32). Elevated CORO1C expression was also detected in adult MB (n=23) and GBM (n=73) tissue samples, when compared to normal brain tissue. Western blotting further verified the significant overexpression of CORO1C and SV2B within GBM cells, suggesting their role as potential oncoproteins. Collectively, our preliminary study proposes the clinical significance of miR-206 and miR-383 when overexpressed in the therapy of aggressive paediatric and adult brain malignancies.
HGG-15. SYNERGISTIC EFFECTS OF COMBINED MEK/CDK4/6 INHIBITOR TREATMENT ON BRAFV600E POSITIVE HIGH-GRADE GLIOMA
Authors: Lisa Mayr, Leah Mager, Lisa Gabler, Sibylle Madlener, Dominik Kirchhofer, Anna Lämmerer, Katharina Bruckner, Alexandra Lang, Romina Walter, Julia Schueler, Andreas Peyrl, Amedeo A Azizi, Christian Dorfer, Christine Haberler, Leonhard Müllauer, Walter Berger, Daniela Lötsch-Gojo, Johannes Gojo
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Pediatric high-grade glioma (pHGG) is associated with poor overall survival and standard care has remained unchanged for the past decade. BRAFV600E mutations occur in 5-10% and dabrafenib in combination with mekinist is approved in this subtype. Nevertheless, acquired resistance to targeted therapeutics is a common setback in highly aggressive tumors. Homozygous CDKN2A/B loss co-occurs in approximately 60% of this pHGG subtype. Taking advantage of those combined molecular alterations and exploiting acquired resistance mechanisms is of utmost importance to increase overall survival in these patients. METHODS Four HGG cell models with BRAFV600E mutation and homozygous CDKN2A/B loss were tested for the effects of CDK4/6 inhibitor monotherapy (palbociclib, ribociclib, abemaciclib) and/or combination treatment with trametinib on cell survival, cell cycle, apoptosis and senescence. RESULTS Abemaciclib showed the highest efficacy of CDK4/6 inhibitors comparable to trametinib monotherapy in our cell models. Abemaciclib led to a cell cycle arrest and combined treatment with trametinib induced distinctly increased levels of apoptosis in our tumor models when compared to monotherapy and a great proportion of surviving cells were senescent. One cell model was orthotopically implanted in mice and abemaciclib and combined treatment with trametinib showed a slightly increased response when compared to trametinib alone. CONCLUSIONS Summarizing, treatment with abemaciclib showed promising therapeutic effects in HGG cell models with BRAFV600E mutation and homozygous CDKN2A/B loss comparable to trametinib alone. Levels of apoptosis were distinctly higher with combinatorial abemaciclib and trametinib treatment when compared to monotherapy alone and senescence was induced in a great number of surviving cells. In vivo abemaciclib was more efficient when compared to trametinib alone. Currently we are working on in vivo experiments and the effect on sustained induction of senescence and mechanisms of tumor cell growth after discontinuation of therapy and in a combinatorial metronomic approach and in combination with radiotherapy.
HGG-20. CANCER PREDISPOSITION SYNDROMES IN PEDIATRIC PATIENTS WITH HIGH-GRADE GLIOMAS
Authors: Giada Del Baldo, Selene Cipri, Luigi Boccuto, Emanuele Agolini, Antonio Novelli, Antonella Cacchione, Mariachiara Lodi, Maria Antonietta De Ioris, Sabina Barresi, Sabrina Rossi, Evelina Miele, Maria Vinci, Andrea Carai, Franco Locatelli, Angela Mastronuzzi
Journal: Neuro-Oncology (2024)

Abstract The association between pediatric high-grade gliomas (HGG) and cancer predisposition syndromes (CPS) remains inadequately elucidated in the existing literature, while next-generation sequencing (NGS) is increasingly utilized for diagnostic support. In this retrospective analysis, we evaluated a cohort of 95 consecutive pediatric patients with HGG reclassified according to the latest 2021 WHO classification, diagnosed and treated at the Bambino Gesù Children’s Hospital between 2011 and 2023. All patients underwent genetic germline testing with NGS technology to detect the presence of germline variants predisposing to cancer and were included in this study. Diagnosis of pHGG H3-IDH wild-type was performed in 23 patients (24.2%), diffuse midline glioma in 46 patients (48.4%), astrocytoma IDH-mutant in 7 patients (7.4%), anaplastic pleomorphic xanthoastrocytoma in 4 patients (4.2%), adult type HGG in 4 patients (4.2%), neuroepithelial tumor PATZ1 fusion-positive in 3 patients (3.2%), diffuse hemispheric glioma H3 G34-mutant in 2 patients (2.1%), infant-type hemisheric glioma in 2 patients (2.1%), other rare histologies in 4 patients (4.2%). Oncological family history was investigated up to the third generation for all patients and was positive in 43/95 (45.3%) cases. We identified a total of 65 variants in 95 patients, distributed as follows: 48 variants of uncertain significance (73.8%), 10 likely pathogenic (15.4%), and 7 pathogenic variants (10.8%). Notably, our findings reveal that pathogenic/likely pathogenic variants were detected in about 17% of the entire study population, higher than the 10% incidence reported in the existing literature. The high rate of mutations in CPS associated genes described in our work, leads to consider performing NGS even in the absence of clinical or anamnestic criteria suggestive of it. However, ethical and social issues are to be considered when we propose and investigate patients for CPS. Moreover, further research are needed to determine the role of variants of uncertain significance.
OTHR-30. THE CLINICAL AND BIOLOGICAL LANDSCAPE OF CNS CANCERS IN CONSTITUTIONAL MISMATCH REPAIR DEFICIENCY: AN IRRDC COHORT STUDY
Authors: Ayse Bahar Ercan, Melyssa Aronson, Nicholas R Fernandez, Yuan Chang, Zhihui Amy Liu, Logine Negm, Melissa Edwards, Vanessa Bianchi, Anita Villani, David Malkin, Cynthia Hawkins, Eric Bouffet, Anirban Das, Uri Tabori
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Constitutional mismatch repair deficiency (CMMRD) is an aggressive cancer predisposition syndrome. As a lack of data contributes to management challenges and inferior outcomes, especially in central nervous system (CNS) cancers, we aimed to determine the clinical spectrum, cancer biology, and impact of genetics on patient survival. METHODS To determine the cancer spectrum, biology, estimated incidence, and impact of genotype on cancer onset and survival, including following surveillance and immunotherapy, we collected cross-sectional, longitudinal, and genomic data on CMMRD patients and their cancers registered to an international consortium. RESULTS We report 201 patients enrolled between 2007-2022 (median follow-up: 7.2 years). Overall, 194 (97%) patients developed 339 cancers. Cumulative cancer and CNS tumor incidence were 93% and 82% by age 20, respectively. Median time between cancers was 2 years. Although neoplasms developed in 15 organs and included early-onset adult cancers, CNS tumors had the earliest median age of diagnosis (9.7 years), were the most common cancer type (51%), and the main cause of death (p&amp;lt;0.0001). All cancers exhibited high mutation and microsatellite burden, and pathognomonic mutational signatures. CNS cancers were enriched for mutations in POLE/POLD1, TP53, IDH1, and RAS/MAPK compared to hematopoietic and other cancers. These mutations determined response to therapy. Germline MLH1/MSH2 variants caused earlier cancer and CNS tumor onset than PMS2/MSH6, and inferior survival (survival at 15 years: PMS2: 63%, MSH6: 49%, MLH1: 19%, MSH2: 0%, p&amp;lt;0.0001). Strikingly, frameshift/truncating variants within the same gene caused earlier cancers and inferior outcomes (p&amp;lt;0.0001). The deleterious impact of MLH1/MSH2 persisted despite overall improvement in survival following surveillance and immunotherapy. CONCLUSION The extreme cancer burden and unique genomic landscape of CMMRD highlight the benefit of comprehensive assays in timely diagnosis focusing on specific genotypes to perform precision approaches toward surveillance and immunotherapy. These data will guide the management of children and emerging adult survivors of CMMRD.
OTHR-23. PATIENT DESIRE TO SHARE DATA AND PARTICIPATE IN RESEARCH IN THE DIPG/DMG COMMUNITY
Authors: Nicole Lyons, Lisa Ward
Journal: Neuro-Oncology (2024)

Abstract Direct and reciprocal communication between patient communities and their research and care teams is essential to building trust and ensuring that all essential information is shared. Patient participation in data collection of any sort is often challenging, as patients may be hesitant or unmotivated to share their information. The DIPG/DMG patient community faces the opposite challenge. Because of the frustration of the lack of treatment options and the established trust that exists between patient families and research professionals, DIPG/DMG patient families are both willing and eager to share any information they can. Patient families have seen how their knowledge has helped other families navigate impossible situations and care teams understand how to better support their patients. The information families eagerly provide is crucial to advancing treatment and research. Patient families have repeatedly expressed willingness to participate in quality of life assessments, repeated surveys during and after treatment, and provide their medical and biological information in the hopes that it can aid research. There is a need for a centralized manner for all of this data to be shared by the patient and accessed by care teams and researchers. Patient-led initiatives are addressing this by creating a network of resources. This network helps to guide other patient families through the data-sharing process, address concerns, and find ways to provide what is needed to push research and treatments ahead. There are many benefits to having a centralized data ecosystem for researchers and care teams, such as standardizing data collection and ease of analysis. In the future, this centralized hub could inform personalized care, making options such as n-of-1 trials and matching patients to optimal clinical trials possible in a manner that is effective and efficient.
MDB-107. MINNELIDE, A PROMISING COMPOUND FOR THE TREATMENT OF HIGH-RISK MEDULLOBLASTOMA
Authors: Jezabel Rodriguez Blanco, April Salvador, Pritika Sahani, Valentin Kliebe, Kendell Peterson, Maria Turos
Journal: Neuro-Oncology (2024)

Abstract Despite the overall good outcome of children with medulloblastoma (MB), a subset faces the challenge of highly aggressive metastatic tumors. The poor prognosis for these patients underscores the urgent need for advancing therapeutic approaches. Minnelide, an analog of the natural product triptolide, exhibits potent antitumor activity in preclinical and early clinical settings. Despite its efficacy and tolerable toxicity, Minnelide has not been assessed against MB. Using a bioinformatic dataset integrating cellular drug response and gene expression, we predicted sensitivity of Group 3 (G3) MB, characterized by a poor five-year survival, to triptolide/Minnelide. Subsequent experiments confirmed the ability of both triptolide and Minnelide to reduce the viability of G3 MB cells ex vivo. Transcriptomic analyses identified MYC signaling, a crucial driver of G3 MB, as a downstream target of these drugs. We validated the MYC dependency and demonstrated that triptolide affects both MYC transcription and protein stability. Notably, Minnelide acted in vivo on MYC, leading to reduced tumor growth and metastatic spread, resulting in improved survival in mouse and patient-derived G3 MB models. Furthermore, Minnelide enhanced the efficacy of adjuvant chemotherapy, suggesting its potential repurposing for treating MYC-driven G3 MB patients.
MDB-15. INHIBITING THE IRON-SULFUR CLUSTER TRANSPORTER ABCB7 CAN POTENTIATE CISPLATIN RESPONSE IN PEDIATRIC GROUP 3 MEDULLOBLASTOMAS BY TRIGGERING FERROPTOSIS
Authors: Sidharth Mahapatra, Ranjana K Kanchan, David Doss, Parvez Khan, Mohd Wasim Nasser, Surinder K Batra
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Medulloblastoma (MB) is the most common malignant pediatric brain tumor, with group 3 tumors (G3MB) being the most aggressive. Uniquely, their aggressiveness is inversely proportional to ferroptosis activation. Intracellularly, these tumors activate iron-sulfur (Fe-S) cluster export and upregulate the expression of glutathione peroxidase 4 (GPX4), the central regulator of ferroptosis. Our main objective was to investigate whether ferroptosis evasion was a targetable driver of aggressiveness in G3MBs that can be inhibited to potentiate classical chemotherapy. We hypothesized that inhibiting Fe-S cluster export would trigger ferroptosis and potentiate cisplatin cytotoxicity in G3MBs. METHODS We repressed ABCB7 expression (si-/sh-/KO) in classic G3MB cell lines (HDMB03 and D425) and studied its impact on cancer cell growth, ferroptosis activation, mitochondrial function, and cisplatin cytotoxicity. We further investigated the impact of artesunate, an FDA-approved anti-malarial agent capable of inhibiting ABCB7, on cisplatin action and tumor burden. To rescue cells from iron overload and ferroptosis, we used deferoxamine and ferrostatin-1, respectively. RESULTS Silencing ABCB7 resulted in cytoplasmic and mitochondrial iron overload, oxidative stress, and lipid ROS, culminating in ferroptosis and growth retardation. Seahorse studies revealed a switch from oxidative phosphorylation to glycolysis, and TMRM staining revealed loss of mitochondrial membrane potential in ABCB7-silenced cells. Notably, silencing ABCB7 abrogated GPX4 expression and reduced GSH levels. Moreover, ABCB7 silencing reduced the IC50 of cisplatin 2-fold, and ABCB7-silenced cells treated with cisplatin experienced a heightened index of ferroptosis. In vivo, silencing ABCB7 resulted in smaller tumors, dramatically prolonged survival, and potentiated cisplatin action. Artesunate recapitulated ABCB7 silencing by potentiating cisplatin action, reducing tumor burden, and prolonging survival in vivo. CONCLUSION The current study illustrates how targeting mitochondrial Fe-S cluster transport can trigger ferroptosis and potentiate cisplatin in G3MBs. Our study also provides evidence for using an FDA-approved drug with the same mechanism of action to treat G3MB tumors.
DIPG-84. PHASE 1 DOSE-ESCALATION STUDY OF ACT001 IN PEDIATRIC PATIENTS WITH ADVANCED BRAIN AND SOLID TUMORS SHOWS ACTIVITY IN DIFFUSE MIDLINE GLIOMA (DMG)
Authors: David S Ziegler, Tim Hassall, Santosh Valvi, Dongpo Cai
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND ACT001, an oral parthenolide derivative targeting STAT3 and NF-κB pathways, has shown activity in preclinical models of DMG. We evaluated safety, toxicity and activity of ACT001 in this recently completed, first-in-child study of DMG and other relapsed/refractory brain and solid tumors. METHODS Eligible patients ≥ 1 and ≤ 21 years old were enrolled with dose escalation following a rolling 6 design and tumor lesions evaluated every 8 weeks per RANO/ RECIST criteria. RESULTS A total of 29 patients were enrolled across 5 cohorts, including 19 with DMG (13 with Diffuse Intrinsic Pontine Glioma (DIPG)). Median age was 11 years for the whole cohort and 7 years (3-17) for DMG patients. Safety was evaluated in escalating doses in 188, 533, 700, 875 and 1100 mg/m2,BID cohorts. No DLT nor grade 3 and above TRAE was identified. One SUSAR was noted for a grade 1 pain in extremity event. Peak ACT001 concentration for each dose cohort were estimated based on limited PK sampling time (cycle 1 day 1 at pre-dose, 2 and 4 hours post dose; cycle 1 day 15 and cycle 2 day 1 both at pre-dose). ACT001 peak concentration plateaued at the highest dose levels, fluctuating in the range of 6360, 5430 and 5980 mg/m2 for 700, 875 and 1100 mg/m2 cohorts respectively. The half-life was approximately 3 hours. 8/14 DMG patients treated at ≥ 700 mg/m2 exhibited objective response or stable disease (SD), including one patient with SD for 14 months, another patient with confirmed Partial Response who remained on study for 11-months before disease progression and five other patients with different degrees of tumor burden reduction. CONCLUSION ACT001 was well tolerated and showed preliminary evidence of anti-tumor activity in DMG/DIPG patients dosed at the highest dose levels. A Phase 2 trial is planned using 875 mg/m2 as the RP2D.
DIPG-05. CHARACTERIZATION OF THE EFFECTS OF H3K27M VARIANTS ON THE DNA-DAMAGE RESPONSE AND TUMOR EVOLUTION IN DIFFUSE MIDLINE GLIOMA
Authors: Nicolas Poux, Adam F Kebede, Rameen Beroukhim, Pratiti Bandopadhayay
Journal: Neuro-Oncology (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.
ATRT-20. ATYPICAL TERATOID RHABDOID TUMOR: ASSOCIATION OF CLINICAL, HISTOLOGICAL, RADIOLOGICAL, MOLECULAR, AND THERAPEUTIC DATA WITH THE SURVIVAL OF PATIENTS ATTENDED AT IOP/GRAACC/UNIFESP
Authors: Jéssica Benigno Rodrigues, Andrea Maria Cappellano, Frederico Adolfo Benevides da Silva, Sergio Cavalheiro, Patricia Dastoli, Marcos Devanir Silva da Costa, Maria Teresa Seixas de Alves, Silvia Regina Caminada de Toledo, Francine Tesser-Gamba, Nasjla Saba Silva Saba da da Silva
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND In childhood, Atypical Rhabdoid Teratoid Tumor accounts for 2% of cases of brain tumors. There is no consensus for the treatment, resulting in multiple protocols. METHODS Retrospective study at the Institute of Pediatric Oncology-IOP/GRAACC/UNIFESP, from January 2000 to December 2022. There were 31 patients admitted during this period. The classification of the histological type into rhabdoid/classic, small round and blue cells, epithelial, and mesenchymal was carried out by the same pathologist, and a 50% cutoff characterized the predominant pattern. A neuro-radiologist reviewed the radiological data. Molecular analysis was performed using NGS. RESULTS In patients &amp;lt;3yo, 74.9% of patients died. Overall survival (OS) at 3 years was 24.5%, and progression-free survival (PFS) at 3 years was 13.8%. In patients &amp;lt;3yo, the absence of metastases was associated with a higher OS and PFS (3y-OS 35.6% and 3y-PFS 23.7%, vs 3y-OS 10% and 3y-PFS 0% in patients with M+). The OS was higher in patients who received radiotherapy at the first treatment (3y-OS of 66.6% vs 7.8% in the non-irradiated group). The classic histological pattern had a lower PFS than the epithelial and small cell groups (p=0.021). In patients&amp;gt;3 yo, 57.1% of patients died. The 3y-OS was 38.1% and the 3y-PFS was 53.5%. In this age group, there was no difference in OS and PFS considering metastases, location, histological pattern, and tumor volume. For post-surgical status, only PFS was significantly higher in patients with complete resection (3y-PFS of 75%, p=0.008). The mean survival time in patients &amp;lt;3 yo was 1.9 years, and the mean survival time in patients &amp;gt;3 yo was 2.5 years. The genetic alterations found were SMARCB1, NOTCH1, and KMT2D. CONCLUSION Patients &amp;gt;3yo seem to have a higher OS and PFS than those &amp;lt;3 yo. Early diagnosis of ATRT may corroborate to a better outcome. The radiotherapy in the first treatment can improve the outcome of patients under 3 years of age. The classic histological pattern was associated with worse PFS.