tbuckley/cabot-search huggingface dataset:
DIPG-64. UNRAVELING H3K27M INTERACTIONS IN DIFFUSE MIDLINE GLIOMA
Authors: Athanasia Liapodimitri, Kayleigh Lunsford, Ashley R Tetens, Jordyn Craig-Schwartz, Farhad Vesuna, Venu Raman, Michael A Koldobskiy
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Diffuse midline glioma (DMG) harboring the histone H3 K27M mutation, also known as diffuse intrinsic pontine glioma when it occurs in the pons, is a uniformly fatal pediatric brain tumor. We sought to better understand protein-protein interactions of the mutant histone in DMG. METHODS To address this, we carried out endogenous co-immunoprecipitation of histone H3 K27M from patient-derived DMG neurosphere cell lines, followed by LC-MS/MS identification of binding partners, and validation of binding by Western Blot. Moving beyond identification, we investigated the functional consequences of these interactions. RESULTS We identified putative novel interactors of H3 K27M with notable binding partners including histone chaperones and RNA helicases of the DDX family. We then explored the disruption of downstream effects resulting from this interaction by pharmacologically inhibiting DDX3 using the small molecule inhibitor RK-33, and assessed impact on viability and radiation sensitivity. CONCLUSIONS Understanding the protein interactome of the mutant histone can inform alternative ways for targeting DMG, thus enriching the therapeutic toolbox against this aggressive tumor. Functional characterization of binding partners holds the potential to identify novel therapeutic targets that cooperate with H3 K27M. The use of inhibitors targeting these partners could specifically destabilize oncohistone-dependent homeostasis and survival pathways and increase sensitivity to radiation and other therapies.
IMMU-07. COMBINED PD1 AND LAG3 INHIBITION IN PRECLINICAL MODELS AND PATIENTS WITH DNA REPLICATION REPAIR DEFICIENT GLIOBLASTOMA (RRD-GBM): AN IRRDC STUDY
Authors: Anirban Das, Owen Crump, Olha Kos, Lucie Stengs, Amanda Li, Adrian Levine, Yoshiko Nakano, Alexander Stein, Gadi Abebe-Campino, Annika Eva Charlotte Bronsema, Vanessa Bianchi, Melissa Edwards, Stergios Zacharoulis, Birgit Ertl-Wagner, Daniel Morgenstern, Trevor J Pugh, Pamela S Ohashi, Eric Bouffet, Cynthia Hawkins, Peter Dirks, Uri Tabori
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND RRD-GBM harbour high tumor mutation burden (TMB) and respond to anti-PD1 immune checkpoint inhibition (ICI). However, the majority ultimately progress, highlighting the need for combinatorial therapies for sustained immune-surveillance. METHODS We performed transcriptomic analyses of human RRD-GBM specimens for immune checkpoint expression, and accordingly, tested combined ICI in immunocompetent murine models. Based on these preclinical data, we treated refractory patients using a combination of anti-PD1 and anti-LAG3 through single-patient trials/ compassionate access. Complimentary immuno-genomic biomarker analyses including circulating tumor DNA (ctDNA) were performed to study mechanisms and track responses. RESULTS Human RRD-GBM (n=80) demonstrated high LAG3 expression, providing a strong rationale for targeting. We tested combined anti-PD1 and anti-LAG3 inhibition in three immunocompetent RRD-GBM murine models. In the anti-PD1-responsive (Nestin-Cre-MSH2LoxP/LoxP-POLES459F/+) model, combined inhibition resulted in universal tumor response and survival. In the anti-PD1 resistant models (Mlh1-/-/Nestin-Cre+/Trp53LoxP/LoxP and therapy-induced hypermutant ENU/Trp53-/- gliomas), the combination improved survival despite a lack of response to anti-PD1 monotherapy. Biologically, high LAG3 expression and exhaustion was observed in CD8 T-cells after treatment with anti-PD1, which was subsequently ablated by the addition of anti-LAG3. Serially transplanted mice showed response and improved survival to the combination, suggesting that resistance to anti-PD1 could be abrogated by the combination. Four patients with RRD-GBM who had failed anti-PD1 treatment were treated using the combination, resulting in objective radiological responses and prolonged ongoing survival in patients with RRD-GBM and high LAG3 expression. Tolerability was better than a previous study of combined CTLA4 and PD1 inhibition for similar patients. Correlation with paired immuno-genomic tumor analyses, flow-cytometry, T-cell receptor clonotype and CSF ctDNA are ongoing prospectively. CONCLUSION LAG3 is an effective target in refractory RRD-GBM. Combined inhibition with anti-PD1 inhibition demonstrated radiological response, prolonged survival and manageable toxicities in patients, and will be tested in future clinical trials.
CP-14. VOLUMETRIC ANALYSIS OF PAEDIATRIC CRANIOPHARYNGIOMAS: CLINICAL-RADIOLOGICAL CORRELATION STUDY
Authors: Vitor Nagai Yamaki, Jai Sidpra, Bruno Santanna Peres, Flavia Massey, Catuto Domingos Alexandre Quianga, Guilherme Jose Costa da Borsatto, Joao Paulo Mota Telles, Inês Nobrega Silva, Juan Pedro Martinez-Barbera, Asthik Biswas, Kshitij Mankad, Hoong-Wei Gan, Hani J Marcus, Noor ul Owase Jeelani, Darren R Hargrave, Hamilton Matushita, Suely Kazue Nagahashi Marie, Kristian Aquilina
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Craniopharyngioma are heterogeneous hypothalamopituitary tumours with solid and cystic components which have a distinct natural history. Neuroimaging follow-up and the definition of progressive disease is challenging due to unpredictable growth of the inflammatory cystic component. METHODS This multicentre retrospective observational study aimed to describe the clinical-radiological correlation of craniopharyngiomas at two paediatric neurosurgery units (GOSH,UK and USP,Brazil). Craniopharyngiomas treated over a 20-year period were identified and standardized clinical outcomes recorded. Baseline MRIs were reviewed and volumetric T1-weighted images segmented by a board-certified paediatric neuroradiologist. RESULTS Of 123 patients, 92 baseline MRIs were available for image analysis (USP=32; GOSH=60). No differences between series were identified in either demography (mean age: USP=9.2±4.6; GOSH=8.2±4.1 years) or tumour characteristics, with tumours being predominantly cystic (USP=75%; GOSH=76%), localised to the sellar/suprasellar region (USP=84%; GOSH: 88%), and on pre-chiasmatic (USP=34%; GOSH=22%) or retro-chiasmatic (USP=59%; GOSH=67%) locations. Pre-chiasmatic tumours were associated with an increased prevalence of visual symptoms at presentation (p=0.006) and worse recovery of visual acuity at long-term follow-up (p=0.021). Regarding volumetric analysis, mean volumes were 16.6±25.1cm3 for the cystic component and 38.3±10cm3 for the solid component. Volumes of the solid and cystic components had no correlation with each other. Larger cystic tumour volumes were correlated with a greater prevalence of diabetes insipidus at presentation (p=0.06). Larger solid tumours were significantly related to younger ages (p=0.02) and had worse PFS in our series. In terms of long-term outcomes, high volume cystic tumours were related to worse hypothalamic outcomes. In multivariate analysis (n=92), Paris classification did not predict long-term outcomes. CONCLUSIONS Volumetric analysis of craniopharyngiomas showed significant correlation with the onset of diabetes insipidus and hypothalamic long-term outcomes. Larger cystic craniopharyngioma were more common in younger patients. The Paris classification did not predict long-term outcomes in multivariate analysis.
DIPG-41. CONVECTION ENHANCED DELIVERY-MEDIATED RADIOSENSITIZATION FOR DIFFUSE MIDLINE GLIOMA
Authors: Matthew Gallitto, Genesis Los De Santos, Hong-Jian Wei, Xu Zhang, Zhiguo Zhang, Cheng-Chia Wu
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Diffuse midline glioma (DMG) is the most aggressive primary brain tumor in children. The only approved standard of care is radiation therapy (RT). Studies examining the role of other systemic agents have failed to demonstrate a survival benefit, partially due to tumor extension to areas of the brain where the blood-brain barrier (BBB) remains intact. As our laboratory has recently determined active NAD(P)H Quinone Dehydrogenase 1 (NQO1) expression in patient-derived DMG tumor samples, we sought to investigate NQO1 bioactivatable agent Napabucasin to augment reactive oxygen species (ROS) production and overcome radioresistance in DMG. Furthermore, we explore the safety and feasibility of convection-enhanced deliver (CED) to overcome limitations of the BBB. METHODS Using two DMG cell lines, we performed clonogenic survival assays with increasing doses of RT with and without Napabucasin. We then created subcutaneous xenograft mouse models, treating with (1) vehicle control, (2) Napabucasin, (3) 2 Gy of RT daily, or (4) combination treatment with RT and Napabucasin. Using a syngeneic orthotopic DMG mouse model, we implanted 7-day osmotic infusion pumps containing either vehicle control or 80uM Napabucasin. Mice then underwent a second randomization with or without daily RT for 5 days. RESULTS We identified a robust radiosensitizing effect with Napabucasin using in vitro clonogenic survival assays. In subcutaneous flank models, combination treatment led to a statistically significant smaller tumor volume post-treatment completion when compared to any monotherapy. In our syngeneic orthotopic DMG mouse model, RT after CED pump implantation in the brainstem did not lead to significant morbidity or mortality. Combination RT and CED of Napabucasin led to a significant survival benefit when compared to monotherapy. CONCLUSIONS In this study, we show Napabucasin as a promising radiosensitizer in DMG. Furthermore, this is the first preclinical study showing safety/efficacy of CED with concurrent RT in DMG.
ATRT-17. INHIBITING THE MAP KINASE PATHWAY WITH MEK INHIBITOR MIRDAMETINIB SUPPRESSES CANCER GROWTH IN ATYPICAL TERATOID/RHABDOID TUMORS
Authors: Yiming Deng, Kristen Malebranche, Tyler Findlay, Anupa Geethadevi, Charles Eberhart, Jeffrey Rubens, Eric Raabe
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Atypical teratoid/rhabdoid tumors (ATRT) are poor-prognosis infantile brain tumors. Our prior studies examining ATRT primary tissues have shown an increased expression of phospho-ERK, a downstream effector of MEK in the mitogen-activated protein kinase (MAPK) pathway. The elevated MAPK pathway potentially contributes to drug resistance, aggressive cancer growth, and poor treatment outcomes. Mirdametinib is a highly specific MEK1/2 inhibitor reported to have superior blood-brain-barrier penetration compared to other MEK inhibitors. We hypothesized that mirdametinib can suppress ATRT tumor growth and improve overall survival. METHODS Mirdametinib effects were assessed through western blot for MAPK markers. Western blot analysis, Muse flow cytometer assays, and immunofluorescence were used for proliferation and apoptosis. Mirdametinib impact on survival was determined in orthotopic xenograft models of ATRT. RESULTS Mirdametinib decreased MAPK pathway activity in five ATRT cell lines (western blot: phospho-ERK). Cell lines treated with mirdametinib exhibited lower rates of proliferation (western blot: phospho-Rb; BrdU immunofluorescence staining: CHLA05 p=0.015, CHLA06 p&amp;lt;0.0001, BT37 p&amp;lt;0.0001 compared to DMSO control by t-test). Mirdametinib induced apoptosis in ATRT cells (western blot: cPARP; Muse Annexin V Assay: CHLA04, CHLA05, CHLA06, and BT37, p&amp;lt;0.0001, CHLA266, p&amp;lt;0.01 compared to DMSO control by t-test; cleaved caspase-3 immunofluorescence staining: CHLA05, CHLA06, and BT37, p&amp;lt;0.0001 compared to DMSO control by t-test). Daily oral delivery of mirdametinib treatment significantly extended the survival of mice bearing the very aggressive orthotopic CHLA06 tumors (17 to 24 days, log-rank test p=0.038 compared to vehicle control) and decreased the expression of phospho-ERK (western blot). Testing against additional ATRT orthotopic xenografts is currently underway. CONCLUSIONS Mirdametinib inhibits the MAPK pathway both in vitro and in vivo, suppressing proliferation and inducing apoptosis in ATRT. Our studies suggest that pharmacologically inhibiting the MAPK pathway with mirdametinib may be an effective strategy to target ATRT and help extend survival in this deadly disease.
EPEN-13. PRE-IRRADIATION CHEMOTHERAPY EXPERIENCE FOR PEDIATRIC EPENDYMOMA POLISH PROTOCOL
Authors: Iwona Filipek, Mary Claire McGlynn, Monika Drogosiewicz, Magdalena Tarasińska, Marta Perek-Polnik, Paweł Kowalczyk, Ewa Święszkowska, Wiesława Grajkowska, Mohamed S Abdelbaki, Bożenna Dembowska-Bagińska, Joanna Trubicka
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Pediatric ependymomas are aggressive central nervous system malignancies arising from the ependymal linings of ventricles and spinal canal. Despite better understanding of tumor biology ependymomas remain therapeutic challenge in pediatric neurooncology. The role of chemotherapy remains controversial. Herein, we describe the outcomes of patients treated at the largest center in Poland who underwent surgery, pre-irradiation chemotherapy and irradiation regardless of extent of surgical resection. METHODS This retrospective review includes pediatric patients with ependymoma treated according to national protocol at the Children’s Memorial Health Institute. We reviewed histology, disease extent, treatment, and report on overall survival (OS) and progression free survival rates (PFS). Descriptive statistics were analyzed using SPSS software. RESULTS Forty-nine patients were included (median age: 84 months). Most patients (96%) had cranial ependymomas (43% supratentorial and 57% posterior fossa lesions). Disseminated disease was found in 16% of cases. Complete resection was achieved in 43%. All patients received pre-irradiation chemotherapy; 6.1% had progressive disease and 41% achieved complete response (CR). All patients, except one, underwent irradiation (67% focal, 2% focal/ventricular, 29% craniospinal, and 2% whole brain). Thirty-five percent of patients relapsed. Five-year PFS and OS were 69% and 80% respectively. Comparing posterior fossa to supratentorial lesions, there was no difference in response after surgery and pre-irradiation chemotherapy (CR 37% versus 50% (p=0.51)) or irradiation (CR 42% versus 55% (p=0.37)). However, relapse was more likely in posterior fossa ependymomas (OR 0.30 IQR (0.70, 1.29), p=0.03) with lower 5-year PFS (56% versus 85%, p=0.03) and 10-year PFS (52% versus 85%, p=0.02). The benefit of chemotherapy was marked in patients with Grade 3 (5-year OS 82% versus 69%) CONCLUSIONS We describe a large cohort of pediatric ependymoma patients who received pre-irradiation chemotherapy. This strategy did not negatively impact the incidence of progression before irradiation.
OTHR-25. ANAPLASTIC TRANSFORMATION OF DIFFUSE LEPTOMENINGEAL GLIONEURONAL TUMORS: TWO PEDIATRIC CASES
Authors: Dolly Aguilera, Anna Janss, Matthew Schniederjan, Adam Goldman-Yassen, Jose Velazquez, Claire Mazewski, Rachel Gray, Tobey MacDonald, Jason Fangusaro, Robert Craig Castellino
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Diffuse Leptomeningeal Glioneuronal Tumors (DLGT) typically have a clinical course with slow progression; however, there have been cases of anaplastic transformation. We describe the clinical presentation, radiographic features, and molecular characteristics in 2 pediatric DLGT cases that underwent aggressive transformation. METHODS Patient 1: A 20 y/o male with DLGT with BRAF-KIAA1549 fusion and loss of 1p who was first diagnosed at 2.5 y/o. Over the course of 17 years, he was treated with numerous therapies due to multiple progressions, including temozolomide, carboplatin/vincristine, selumetinib, and vinblastine. At age 17, he developed significant growth of a posterior fossa mass with solid and cystic characteristics. Resection revealed new anaplastic pathologic features. Patient 2: He was diagnosed with DLGT at age 2 y/o. Imaging demonstrated intramedullary spinal nodules at T4 and T5 with abnormal thickening and enhancement over the cerebral leptomeningeal space. A biopsy revealed DLGT with a BRAF-KIAA1549 fusion, 1p loss and Ki67 5%. He received multiple therapies including carboplatin/vincristine, vinblastine, and selumetinib. RESULTS Patient 1: Molecular characterization revealed new ATRX mutation, and CDKN2A/B homozygous deletion. Over the following 2 years, he had multiple treatments, progressions, and surgeries. Final pathology revealed significant anaplasia with Ki67 90%, ATRX loss, and mutation of PPM1D and ARID1A. He rapidly declined. Patient 2: Approximately 2.5 years after diagnosis, he developed rapid progression in the 4th and lateral ventricles. Pathology confirmed recurrent DLGT, but with high-grade transformation, H3K27M (-), H3k27m3 loss, ATRX (+), Ki67 40%. He was treated with focal irradiation followed by temozolomide/CCNU. CONCLUSION In rare cases, DLGT can undergo anaplastic transformation. Once this occurs, it behaves clinically like a high-grade glioma. Understanding the molecular underpinnings and prognostic features that lead to this transformation are important for future study.
OTHR-22. SUCCESSFUL DEVELOPMENT OF RESOURCES FOR DMG/DIPG PATIENT FAMILIES THROUGH A NETWORK OF FAMILIES, RESEARCHERS, AND CARE TEAMS
Authors: Nicole Lyons, Lisa Ward
Journal: Neuro-Oncology (2024)

Abstract The DIPG community has been severely affected by a lack of resources and awareness due to the relative rarity of the disease. In recent years, this has led to a network of patient families, researchers, and clinicians who have worked together to develop resources that improve clinical care, research, and patient family support. These resources address issues in care equity such as access to clinical trials, accurate information, and consults with leading physicians in the field. These initiatives span across multiple institutions and are predominantly little to no cost for the families. This relationship is mutually beneficial; data from patient families inform researchers and clinicians. In turn, researchers and clinicians use these findings to support other families. Over the last five years, many of the resources developed and/or utilized by the DIPG community have been successful. Since May 2021, 42% of post-mortem tissue donations through Gift From a Child have been DIPG or DMG. Data from this tissue is shared openly through the Children’s Brain Tumor Network, ensuring that a diverse patient population is represented in future research projects. DIPG One-link helps patient families navigate vetted resources for care at any point after diagnosis. Resources include patient navigators, information about research and clinical trials, emotional and grief support, places to safely share their data, and referrals to the DIPG/DMG National Tumor Board. All of these resources have shown an overall increase in use since implementation. There has also been an increase in access by patient populations and care teams that previously would have been unable to access such important resources. The direct involvement of patient families ensures that patient voices are represented and valued. These resources are essential to removing institutional, financial, geographic, and health literacy barriers, and ensuring all future patients have equitable access to care.
IMMU-11. CLINICAL EXPERIENCE WITH THE CONCEPT OF MULTIPHASE COMBINED TREATMENT FOR ADULTS WITH GBM
Authors: Stefaan W Van Gool, Jennifer Kosmal, Peter Van de Vliet, Linde F C Kampers, Wilfried Stuecker
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND We published survival data of 50 adults with GBM treated with individualized multimodal immunotherapy (IMI) as part of a multiphase combined treatment (Van Gool et al, https://doi:org/10.1016/bs.mcb.2023.06.001). Analysis was repeated with new observation data. METHODS Patient definition for retrospective analysis: start IMI between 27/05/2015 and 31/10/2023, &amp;gt;18y, newly diagnosed, IDH1 wild-type, MGMT promoter-methylation status documented, survival known, no second malignancy. RESULTS Forty (14 female, 26 male) GBM patients were MGMT-promoter-unmethylated (unmeth), while 31 (15 female, 16 male) were MGMT-promoter-methylated (meth). Comparing the molecular subgroups, both respective median age; 48 years (range 18-65) and 54 years (range 26-72), and respective Karnofsky performance index; 70 (range 50-100) and 80 (range 60-100), were equal. Patient distribution (&amp;lt; complete resection, complete resection, not documented) was equal: 17/15/8 (unmeth) versus 17/11/3 (meth). Both groups were treated similarly: in median 37 (range 0-147) sessions of modulated electrohyperthermia, in median 37 (range 5-147) bolus injections of Newcastle Disease Virus, in median 2 (range 0-6) IO-Vac® vaccines with a median total number of 30.7x10e6 DCs (range 0-158x10e6). The median overall survival (mOS) for the total group was 27 months. The 2-year overall survival (OS) was 57.9 % and the 3-year OS 37.1 %. The mOS for unmeth patients was 22.1 month, with a 2-year OS of 42.7%. The mOS for meth patients was 37.7 months, with a 2-year OS of 75.5%. Sampling five control arms of contemporary RCTs as external control arm (Liau et al, JAMA Oncol 2023) showed for unmeth and meth patients a mOS of 14.6 resp. 21.3 months with a 2-year OS of 21% resp. 42%, which reflects the current prognosis for these patients. CONCLUSIONS Our analysis confirms that the integration of IMI during and after standard of care improves the OS. Similar multiphase combined treatment strategy, including IMI, should be considered to treat childhood GBM.
HGG-21. DISTRIBUTION AND MUTATIONAL PATTERNS OF TP53 ALTERATIONS ACROSS SUBTYPES OF PEDIATRIC HIGH-GRADE GLIOMAS
Authors: Mirjam Blattner-Johnson, Dominik Sturm, Steffen Hirsch, Barbara Jones, Kathrin Schramm, Gnana Prakash Balasubramanian, Martin Sill, Robert Autry, Christopher Previti, Cornelis M van Tilburg, Till Milde, Kristian W Pajtler, Felix Sahm, Christof M Kramm, Olaf Witt, Stefan M Pfister, David T W Jones
Journal: Neuro-Oncology (2024)

Abstract Inactivating alterations of tumor suppressor gene TP53 are a hallmark of tumor progression in various cancer entities. Unfortunately, TP53 inactivation has not yet provided an actionable vulnerability. To investigate distribution, mutational pattern and impact of TP53 alterations in pediatric high-grade gliomas (pedHGG), we investigated TP53 alterations in 407 pedHGG by analyzing genomic sequencing and survival data collected through the INFORM and MNP molecular diagnostic pipelines. Nearly half of pedHGG (47%) showed signs of genomic TP53 inactivation. A second hit suggesting complete loss of function was observed in 84% of tumors, with loss of heterozygosity as the most common mechanism (70%). The frequency of TP53 alterations ranged from 97% in H3 G34-mutated tumors, 70% in IDH-mutated tumors and 61% in H3 K27-mutated tumors down to 40% in H3-/IDH-wildtype subtypes and none in infant-type hemispheric gliomas. Alterations in TP53 were associated with significantly shorter mean overall survival of 11 vs. 15 months in patients diagnosed with H3 K27-mutated tumors. Previously described TP53 hotspot mutations, such as amino acid substitutions at position 17, 248, 273, 282 and 342 were also prominent in the studied cohort (NM_000546). Mutations at position 342 were enriched in H3 G34-mutated tumors, with one-third carrying a stopgain mutation at this position rarely seen in other pedHGG. G34-mutated tumors also showed an abundance of nonsense, splicing or frameshift mutations in contrast to the predominance of missense mutations in other subtypes. The functional impact of these differences is currently under investigation. Lastly, we observed potential evidence for a genotype-phenotype link with Li-Fraumeni syndrome (LFS)-associated (constitutional) TP53 mutations in pedHGG, including an absence of the R248 hotspot mutation in 15 LFS-associated tumors.