tbuckley/cabot-search huggingface dataset:
DIPG-89. ENHANCEMENT OF BLOOD-BRAIN BARRIER PENETRATION AND TUMOR TARGETED DRUG DELIVERY FOR DMG USING A P-SELECTIN TARGETED NANOMEDICINE APPROACH
Authors: Bryan K Li, Jake Vaynshteyn, Daniel Tylawsky, Kristen Vogt, Raashed Raziuddin, Yi Ge, Daniel A Heller, Oren Becher, G Praveen Raju
Journal: Neuro-Oncology (2024)

Abstract The blood-brain barrier (BBB) is one of the greatest barriers for the effective treatment of brain tumors, including H3K27-altered diffuse midline glioma (DMG), a near universally fatal childhood brain cancer. The BBB typically requires drugs to be given at maximally tolerated doses that are limited by systemic toxicities, particularly in settings of combination therapy. We have developed a clinically compatible fucoidan nanoparticle (Fi-NP) that homes to P-selectin on tumor vasculature after low-dose radiation (RT) to breach the BBB through an active caveolin-1-dependent mechanism and deliver several classes of targeted therapies. In non-CNS cancer xenograft models and a transgenic mouse model of SHH-driven medulloblastoma with an intact BBB, this approach improved survival while eliminating on-target systemic toxicities. We have now applied this approach to both brainstem and non-brainstem RCAS-TVA mouse models of DMG with an intact BBB. Specifically, we have found that DMG tumor vasculature expresses P-selectin, and that a single low-dose 2 Gy fraction of ionizing radiation further enhances it in a time-dependent manner up to 24 hours post-treatment. Importantly, we have also found that this P-selectin targeted drug delivery approach facilitates DMG tumor localization of Fi-NP encapsulated EZH2 inhibitor tazemetostat (EPZ-6438) as well as larger macromolecules including the PROTAC BET degrader dBET6, two promising targeted therapies for DMG limited by extremely poor BBB-penetration, while sparing drug delivery to non-tumor healthy brain regions. Work to measure PK, biodistribution, survival benefit, and drug target inhibition is ongoing. Our findings will provide the foundation for this P-selectin targeted Fi-NP approach to be evaluated in clinical trials for children with this lethal cancer.
NFS-07. RESPONSE OF A CENTRAL NERVOUS SYSTEM (CNS) HEMANGIOBLASTOMA TO BELZUTIFAN IN A PEDIATRIC PATIENT WITH VON HIPPEL-LINDAU DISEASE (VHL)
Authors: Cierra M Brandt, Kristin N Zajo, Rebecca Ronsley, Aaron S McAllister, Eric A Sribnick, Ralph Salloum
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND VHL is a rare cancer predisposition syndrome which affects many organ systems, leading to renal clear cell carcinoma (RCC), pheochromocytoma, retinal angiomas and CNS hemangioblastomas. Surgical resection has traditionally been the mainstay of treatment of VHL-associated tumors. In 2021, belzutifan, a Hypoxia Inducible Factor 2-alpha inhibitor was approved by the Food and Drug Administration for the treatment of VHL-associated RCC based on efficacy in adults. There is a paucity of data in pediatric VHL patients with hemangioblastoma treated with this novel agent. Herein we present such a case. CASE A 15-year-old male, diagnosed with VHL caused by a de novo germline mutation at the age of 12, was found to have a left craniocervical junction lesion consistent with a hemangioblastoma on surveillance MRI. The lesion demonstrated growth upon serial imaging but remained asymptomatic. Due to location, the patient was started on medical treatment using once daily oral belzutifan (120mg) continuously, sperm banking was performed prior to initiation of therapy. Hematologic and metabolic laboratory values were monitored, in addition to regular physical examinations including blood oxygen saturation recordings. The first MRI on therapy (3 months after treatment started) demonstrated a major radiologic response using RANO criteria. Treatment has been overall very well tolerated with few treatment-related toxicities limited to CTCAE v5 grade 1 fatigue and grade 2 anemia. No dose reductions or interruptions were required. The patient remains on therapy and has completed 11 months of treatment with further reduction in the size of this target lesion. CONCLUSION Hemangioblastomas are preponderantly characterized by their highly vascular nature making surgical resection in some cases arduous depending on location. This unique pediatric case adds to the growing evidence that therapy with belzutifan may be a safe and efficacious option for VHL-associated CNS Hemangioblastomas. Prospective studies in children are needed.
QOL-48. NEUROPSYCHOLOGICAL INTERVENTION FOR PEDIATRIC BRAIN TUMOR PATIENTS AND SURVIVORS - A PRE-STUDY WITH A FOCUS ON PATIENT INVOLVEMENT
Authors: Ulrike Leiss, Carina Schneider, Hannah Gsell, Anna-Maria Maletzky, Anita Kienesberger, Claas Röhl, Albina Bocolli, Johannes Gojo, Rita Hansl, Anna Zettl, Liesa J Weiler-Wichtl
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Neuropsychological (i.e. cognitive, emotional and social) sequelae after pediatric brain tumors (PBT) can severely impair daily-life participation and consequently quality of life. Long-term access to appropriate interventions is therefore essential. Previous studies on effectiveness have recommended multi-component interventions tailored to the specific neuropsychological impairments and unique needs of the survivors. Hence, before conducting a new intervention study, we carried out a participative pre-study, in order to incorporate experienced needs of the group into a future concept. METHODS Known efficacy factors for neurocognitive interventions for PBT patients/survivors were analyzed in a systematic literature search (PubMed, PsychINFO and SCOPUS, 2000 -2024). In addition, a 3-part workshop (in total 4.5 days) was held with PBT survivors and carers (N=20) and Health-Care-Professionals (N=5). The “junior research academy” was designed to participatively run through the research process from the initial idea (how to improve interventions) to the study design. RESULTS After title and abstract screening only 27 studies remained for detailed analysis, with computerized/online cognitive training (mainly working memory), being the most frequently studied intervention, followed by exercise training. Single studies on the effect of medication, parent training, practice/strategy training and behavioral therapy, group training on social skills and neurofeedback were identified. Improvements in different domains have been shown, but recruitment often remains very difficult, as does the transfer to everyday life. Interestingly, the “junior research academy” developed in a slightly different direction: the winning projects (“family guide” or “everyday compass”) were primarily aimed at (1) providing quick and unbureaucratic information and support, (2) giving orientation in daily life, (3) helping to find appropriate interventions, and (4) providing emotional and organizational support. CONCLUSIONS A core group of the participating survivors and health-care-professionals will now finalize the development of an intervention with elements of both pillars and subsequently run a controlled trial.
QOL-46. EFFECTIVENESS OF A TELEREHABILITATION PROGRAM TO IMPROVE VISUAL PERCEPTION IN CHILDREN AND ADOLESCENTS WITH HEMIANOPIA CONSECUTIVE TO A BRAIN TUMOUR
Authors: Inci Yaman Bajin, Mariana Misawa, Bill Zhang, Monica Daibert-Nido, Danielle Tchao, Eduardo Garcia-Giler, Kyle Cheung, Lora Appel, Pi Nasir, Arun Reginald, Uri Tabori, Ute Bartels, Vijay Ramaswamy, Samuel N Markowitz, Eric Bouffet, Michael Reber
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Brain tumours in children often lead to visual impairment, which presents as a significant morbidity for long-term survivors. A recent Children Cancer Survivor Study showed that 22.5% of the patients with astroglial tumours had visual impairment five years after the diagnosis. In the pediatric population with hemianopia, there are no standardized protocols for managing vision loss. This study evaluated a 6-week home-based telerehabilitation program (home-based 3D-MOT-IVR) on visual perception in children with hemianopia consecutive to a brain tumour. METHODS This phase 2a, open-labelled, non-randomized, single-arm study included ten patients aged 12-18 years old with hemianopia consecutive to a pediatric brain tumour. Patients followed a 6-week home-based 3D-MOT-IVR with remote control of the device from the UHN laboratory. Visual assessments were performed at baseline, 2, 4, and 6 weeks, with follow-ups at 1 and 6 months to check the visual field, contrast sensitivity and reading speed. RESULTS The home-based 3D-MOT-IVR intervention proved feasible and safe, with no reported adverse events. All participants completed the prescribed stimulations, pre- and post-intervention assessment points, and 90% completed the follow-ups. Remarkably, the outcomes revealed significant improvements post-intervention: 50% of participants showed enhanced visual perception in their blind field, while 70% exhibited increased reading speed. Importantly, these positive effects were sustained at the 6-month follow-up. A robust correlation emerged between 3D-MOT-IVR performance and improved visual perception in the blind field, emphasizing the intervention’s effectiveness. CONCLUSION These promising results lay a strong foundation for a larger randomized controlled trial, offering hope for a meaningful breakthrough in visual rehabilitation for this vulnerable population. Further studies are being developed to confirm these results and identify the most appropriate schedules to optimize visual outcomes (such as duration and repetition of these programs).
QOL-51. FEASIBILITY AND EASE OF USE OF A REMOTE ONLINE COGNITIVE BATTERY AMONG PEDIATRIC BRAIN TUMOR SURVIVORS
Authors: Kristin M Lee, Joan Yu, Heather Stancel, M Fatih Okcu, Murali Chintagumpala, Lisa Kahalley, Kimberly P Raghubar
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Pediatric brain tumor survivors are at risk for cognitive deficits, including inattention, poor memory, and slow processing speed. Due to technology advances, computerized neuropsychological batteries were developed that can be completed via internet in the home. The primary aim of this study was to evaluate the rate of successful completion and ease of use of the Penn Computerized Neuropsychological Battery (CNB) among pediatric brain tumor survivors. METHODS Forty-eight pediatric brain tumor survivors completed the online remote administration version of the Penn CNB (10 subtests) assessing complex cognition, memory, executive control, processing speed, and motor speed. Participants were provided with an electronic link to the online cognitive battery as well as paper and electronic copies of an instruction guide and post-completion surveys to return via mail/email. RESULTS Patients (56.3% female) were diagnosed and treated for a brain tumor (54.2% received radiotherapy). All participants were at least 8 years of age (M=13.71, SD=3.82) and at least one-year post-diagnosis (M=4.76, SD=2.58 years). Eighty-eight percent of participants beginning the CNB completed all subtests. Sixty percent of participants completed and returned the post-assessment survey. Participants who returned post-assessment surveys were similar to those who did not on demographic and medical factors (all p-values &amp;gt;.05). Mean ratings suggest that survivors were “very interested” in the tasks and they were “somewhat easy” to complete. Younger children were more likely to have trouble understanding task instructions (r=.56, p &amp;lt;.01) and ask for help answering specific questions (r=.46, p &amp;lt;.05). CONCLUSIONS Remote administration of computerized batteries are feasible among pediatric brain tumor survivors and may assist with advancing both research and patient care. From a research standpoint, remote batteries may allow for participation and engagement in research with minimal survivor burden. Clinically, such batteries may offer alternatives for screening patients who will benefit from comprehensive services.
NFS-10. ROLE OF CDKN2A CO-DELETION IN DRIVING TUMOR INVASIVENESS IN NF1 MUTANT GLIOMA
Authors: Wai Chin Chong, Bavani Subramaniam, Federica Tomasso, Debasish Roy, Sridevi Yadavilli, Miriam Bornhorst, Roger Packer, Javad Nazarian
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Neurofibromatosis type 1, caused by mutations in the NF1 gene, is a common autosomal dominant genetic disorder associated with an increased risk of glioma tumor development. A high occurrence of CDKN2a codeletion in NF1-mutant high-grade gliomas (HGG) compared to low-grade gliomas (LGG) implies a potential role of CDKN2a loss in the transformation of NF1-mutant LGG to HGG. In our study, we aimed to elucidate the role of NF1 and CDKN2a in tumor transformation using a panel of glioma cell line models with varying NF1 and CDKN2a expression. METHOD A diverse panel of glioma cell lines, encompassing LGG (1667-ON, RES259, RES186, JHH-NF1-PA1) and HGG (GBM511, GBM110, SF8628, U87-MG, TM-31, 7316-2189, 7316-3058, 7316-4917), was cultured. Their growth rates and invasiveness were further evaluated using cell proliferation and Boyden chamber invasiveness assays. RESULTS LGG cell lines exhibited relatively lower growth rates and invasiveness compared to their high-grade counterparts. Intriguingly, RES259, a LGG cell line harboring both NF1 and CDKN2a variants, demonstrated the highest growth rate and invasiveness among LGG cell lines, surpassing even those with intact NF1 and CDKN2a, such as JHH-NF1-PA1 and RES186. To further elucidate the roles of NF1 and CDKN2a, CRISPR-Cas9 technology was employed to knockout these genes individually and in various combinations in RES186. Our findings unveiled that sole NF1 knockout had negligible impact on RES186. Conversely, CDKN2a knockout increased both growth rate and invasiveness. Strikingly, the codeletion of NF1 and CDKN2a in RES186 significantly exacerbated its growth rate and invasiveness. These results underscore the intricate interplay of NF1 and CDKN2a in governing the growth and invasiveness dynamics of glioma cells. CONCLUSION In conclusion, our preliminary study suggests that the concurrent loss of NF1 and CDKN2a promotes enhanced growth and invasiveness in gliomas, shedding light on the collaborative role of these genetic alterations in tumor transformation.
DIPG-90. NON-INVASIVE METABOLIC IMAGING OF DIFFUSE MIDLINE GLIOMAS AND THEIR RESPONSE TO THERAPY
Authors: Pavithra Viswanath, Celine Taglang, Georgios Batsios, Anne Marie Gillespie, Sabine Mueller
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Diffuse midline gliomas (DMGs) harboring histone H3K27M mutations are devastating pediatric brain tumors. ONC201 is the first drug in decades to extend survival in DMG patients and is likely to be widely used for treatment of DMGs. However, magnetic resonance imaging (MRI), the gold standard for patient management, does not provide a reliable readout of response to therapy. The Warburg effect describes the propensity of tumor cells to increase glucose uptake and conversion to lactate. Deuterium metabolic imaging of the Warburg effect using [6,6’-2H]-glucose provides the unparalleled opportunity to obtain a biologically meaningful readout of treatment response. Therefore, the goal of this study was to assess the utility of [6,6’-2H]-glucose for DMG imaging. METHODS We performed expression profiling and deuterium metabolic imaging in patient-derived and syngeneic DMG models. RESULTS Our studies indicate that DMG cells upregulate key components of the Warburg effect, including SLC2A1, SLC2A3, HK2, PFKFB3, PGK1, and LDHA relative to normal astrocytes. Silencing the H3K27M mutation in DMG cells reduced glycolytic gene expression. Spatially resolved 2D chemical shift imaging at 3T showed that lactate produced from [6,6’-2H]-glucose was localized to tumor vs. normal brain in mice bearing intracranial tumors. ONC201 downregulated glycolytic gene expression in DMG cells, an effect that was accompanied by reduced lactate production from [6,6’-2H]-glucose. Importantly, lactate production from [6,6’-2H]-glucose was reduced following treatment with ONC201 in mice bearing intracranial tumors at 3T, at an early timepoint independent of MRI-detectable volumetric alterations and predictive of extended survival. CONCLUSIONS Our studies mechanistically link the H3K27M mutation with the Warburg effect. Importantly, they identify [6,6’-2H]-glucose as a novel contrast agent for visualizing the metabolic lesion and imaging early response to therapy in DMGs. Since [6,6’-2H]-glucose is a safe, orally administered agent, our studies have the potential to be rapidly translated to the clinic, where they will provide physicians with a much-needed tool to determine whether DMG patients are responding to therapy.
RADT-10. LITHIUM TREATMENT PROTECTS MICROGLIA AND NEWLY GENERATED NEURONAL POPULATIONS IN A MOUSE MODEL OF CRANIAL RADIOTHERAPY
Authors: Carlos F D Rodrigues, Efthalia Preka, Alejandro Lastra-Romero, Georgios Alkis Zisiadis, Yana Ruchiy, Adamantia Fragkopoulou, Klas Blomgren
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Radiotherapy remains a cornerstone of the treatment of high-grade brain tumors. However, while lifesaving, it results in long-term complications in 50-96 % of the treated individuals, where cognitive deficits are particularly debilitating. Currently, no treatments or preventive strategies are available to avert these deficits. Lithium (Li), long used to treat bipolar affective disorder, has been shown to reduce radiation-induced cognitive deficits in rodent models by preventing apoptosis of the neuronal stem and progenitor cells in the hippocampus and stimulating their proliferation. This work aimed to further elucidate the mechanisms behind the protective and pro-regenerative actions of Li in the irradiated young brain. METHODS Postnatal day (PD) 21, C57BL6/J mice were injected intraperitoneally with Li chloride (4 mmol/kg) and kept on a Li carbonate-containing diet for 4 weeks. Control animals were injected with saline and administered an equivalent control diet. On PD 25, the animals were administered a single-dose whole-brain radiation of 8 Gy and were subsequently sacrificed at different time points, spanning from 2 weeks to 1 year. At sacrifice, the hippocampi were harvested for single-cell RNA sequencing using a novel, 2-step protocol to harvest viable cells of all types, including neurons. RESULTS The results showed that radiation triggered the expression of senescence-related genes in the hippocampal microglia (e.g., Cdkn1a, Ccl12), which Li has prevented through the activation of the Bcl2 family of genes. Moreover, they corroborate the protective effect of Li on newly generated hippocampal neurons, which undergo remodeling over time, leading to the emergence of new subpopulations. CONCLUSIONS This work represents another advancement towards understanding the action of Li in the irradiated brain and confirms its potential to become the first pharmacological treatment for radiation-induced complications.
RADT-12. CLINICAL RELEVANCE OF RADIATION-INDUCED CAVERNOUS MALFORMATIONS
Authors: Lauren A Burnett, Corey Cavannaugh, Mariko Sato
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Radiation-induced cavernous malformations (RICMs) are delayed complications of brain irradiation during childhood. The prevalence of cavernomas in the general population was found to be 0.5% in a large prospective study. However, the exact incidence of RICM in children and the mechanisms of the development of RICM remain largely unknown since the cumulative incidence of RICM is underreported. Recent systemic review revealed 113 children with RICM after treatment of brain tumors and leukemias. 67% were asymptomatic and 21% showed signs of hemorrhage. In this review, the average dose of radiation was 50Gy and the mean time to detection was 9.2 years. METHODS We conducted a retrospective review of RICM in children who underwent total body irradiation (TBI) for bone marrow transplant. Our study goals were to better understand the incidence and patterns of RICMs and to develop a risk stratification for monitoring. Between 9/2000-1/2023, 161 patients underwent TBI. Of 47 patients who had post-transplant brain MR imaging done, 15 patients had MRIs available for review. RESULTS Of 15 reviewed MRIs, 11 (73.3%) had RICMs identified. 6 cases had &amp;gt;5 small (&amp;lt;3mm) RICMs. Most RICMs were in the frontal lobes. MRIs were obtained an average of 64 months from TBI. Radiation doses ranged from 200-2760cGy with an average of 1144cGy. There was 1 case of microhemorrhage due to RICM. None of our patients deceased as a result of their RICM. CONCLUSIONS Our cohort showed a high incidence (73.3%) of RICM despite low doses of radiation. Due to their typically small size and lack of clinical symptoms, RICM is often underreported. Although the outcome of cavernous malformation is favorable, it is important to understand the incidence and risk of adverse neurologic outcomes posed by RICMs. By performing regular surveillance, complications related to RICMs may be intervened with preventative procedures such as microsurgery.
ETMR-22. IDENTIFICATION OF 5-FLUROURACIL AS A SELECTIVE THERAPY IN A NOVEL EP300::BCOR FUSION GLIOMA TUMOR MODEL
Authors: Andrew M Donson, Vladimir Amani, Andrea M Griesinger, Annaliese Calzadilla, Enrique Grimaldo, Nicholas Willard, Nicholas K Foreman, Jean Mulcahy-Levy
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION BCL6 corepressor gene (BCOR)-altered glioma brain tumors are a newly identified entity which include cases involving a gene fusion with histone acetyltransferase EP300. Treatment strategies for BCOR-fusion gliomas have not yet been established, largely due to their rarity. In this study we utilize a newly established EP300::BCOR fusion cell line to identify effective FDA-approved oncology compounds in vitro. METHODS EP300::BCOR fusion cell line MAF-1211, established from autopsy material, was molecularly defined to confirm the fusion and fidelity with patient samples. The treatment effect of FDA-approved oncology drugs (n=97) in MAF-1211 was compared to other pediatric brain tumor types to identify clinically available compounds with BCOR-fusion glioma selective potency. RESULTS RNAseq analysis of MAF-1211 cell line identified a fusion breakpoint between EP300 exon 31 and BCOR intron 6, which matched both patient presentation and autopsy samples. MAF-1211 also showed molecular fidelity with patient tumors, showing transcriptomic clustering with the patient tumor from which it was established, and matching most strongly with CNS BCOR-altered tumors by DNA methylation classifier analysis. FDA-approved oncology drug screening showed a relatively high sensitivity of MAF-1211 to fluorinated pyrimidines 5-fluorouracil (5-FU), carmofur, and floxuridine compared to other pediatric brain tumor cell lines (HGG, medulloblastoma, ependymoma, ATRT). Discussion: Identification of 5-FU and related drugs identified by our study have the potential to inform design of upcoming clinical studies in BCOR-fusion gliomas. Given the rarity of these tumors it may be more feasible to combine BCOR-fusion gliomas with a potential upcoming clinical trial of 5-FU in posterior fossa A ependymoma.