Journal articles on the topic 'Diffuse midline glioma (DMG)'
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1
Barron, Tara, Belgin Yalçın, Aaron Mochizuki, Evan Cantor, Kiarash Shamardani, Dana Tlais, Andrea Franson, et al. "CNSC-01. GABAERGIC NEURON-TO-GLIOMA SYNAPSES IN DIFFUSE MIDLINE GLIOMAS." Neuro-Oncology 25, Supplement_1 (June 1, 2023): i11. http://dx.doi.org/10.1093/neuonc/noad073.044.
Abstract:
Abstract High-grade gliomas include clinically and molecularly distinct subtypes that stratify by anatomical location into diffuse midline gliomas (DMG) such as diffuse intrinsic pontine glioma (DIPG) and hemispheric high-grade gliomas. Neuronal activity drives high-grade glioma progression both through paracrine signaling and direct neuron-to-glioma synapses. Glutamatergic, AMPA receptor-dependent synapses between neurons and malignant glioma cells have been demonstrated in both pediatric and adult high-grade gliomas, but neuron-to-glioma synapses mediated by other neurotransmitters remain largely unexplored. Using whole-cell patch clamp electrophysiology, in vivo optogenetics and patient-derived glioma xenograft models, we have now identified functional, tumor-promoting GABAergic neuron-to-glioma synapses mediated by GABAA receptors in DMGs. GABAergic input has a depolarizing effect on DMG cells due to NKCC1 expression and consequently elevated intracellular chloride concentration in DMG tumor cells. As membrane depolarization increases glioma proliferation, we find that the activity of GABAergic interneurons promotes DMG proliferation in vivo. Increasing GABA signaling with the benzodiazepine lorazepam – a positive allosteric modulator of GABAA receptors commonly administered to children with DMG for nausea or anxiety - increases GABAA receptor conductance and increases glioma proliferation in orthotopic xenograft models of DMG. Conversely, levetiracetam, an anti-epileptic drug that attenuates GABAergic neuron-to-glioma synaptic currents, reduces glioma proliferation in patient-derived DMG xenografts and extends survival of mice bearing DMG xenografts. Concordant with gene expression patterns of GABAA receptor subunit genes across subtypes of glioma, depolarizing GABAergic currents were not found in hemispheric high-grade gliomas. Accordingly, neither lorazepam nor levetiracetam influenced the growth rate of hemispheric high-grade glioma patient-derived xenograft models. Retrospective real-world clinical data are consistent with these conclusions and should be replicated in future prospective clinical studies. Taken together, these findings uncover GABAergic synaptic communication between GABAergic interneurons and DMG cells, underscoring a tumor subtype-specific mechanism of brain cancer neurophysiology with important potential implications for commonly used drugs in this disease context.
2
Al Sharie, Sarah, Dima Abu Laban, Jamil Nazzal, Shahad Iqneibi, Sura Ghnaimat, Abdallah Al-Ani, and Maysa Al-Hussaini. "Midline Gliomas: A Retrospective Study from a Cancer Center in the Middle East." Cancers 15, no. 18 (September 13, 2023): 4545. http://dx.doi.org/10.3390/cancers15184545.
Abstract:
Midline gliomas are tumors that occur in midline structures and can be circumscribed or diffuse. Classical midline structures include the thalamus, brainstem, and spinal cord. Other midline structures include the corpus callosum, basal ganglia, ventricles, paraventricular structures, and cerebellum. Diffuse midline glioma (DMG) is a diffuse glioma that occurs in the classical midline structures, characterized by a specific genetic alteration, and associated with grim outcome. This study was conducted at King Hussein Cancer Center and reviewed the medical records of 104 patients with circumscribed and diffuse gliomas involving midline structures that underwent biopsy between 2005 and 2022. We included a final cohort of 104 patients characterized by a median age of 23 years and a male-to-female ratio of 1.59-to-1. Diffuse high-grade glioma (DHGG) was the most common pathological variant (41.4%), followed by DMG (28.9%). GFAP was positive in most cases (71.2%). Common positive mutations/alterations detected by surrogate immunostains included H3 K27me3 (28.9%), p53 (25.0%), and H3 K27M (20.2%). Age group, type of treatment, and immunohistochemistry were significantly associated with both the location of the tumor and tumor variant (all; p < 0.05). DMGs were predominantly found in the thalamus, whereas circumscribed gliomas were most commonly observed in the spinal cord. None of the diffuse gliomas outside the classical location, or circumscribed gliomas harbored the defining DMG mutations. The median overall survival (OS) for the entire cohort was 10.6 months. Only the tumor variant (i.e., circumscribed gliomas) and radiotherapy were independent prognosticators on multivariate analysis.
3
Ibdah, Haleem, Shervin Pejhan, Lee Ang, Cynthia Hawkins, Barbara Fisher, Joseph Megyesi, and Maria MacDonald. "CEREBELLAR DIFFUSE MIDLINE GLIOMA, H3K27M ALTERED IN A FIFTY-FIVE-YEAR-OLD PATIENT." Neuro-Oncology Advances 5, Supplement_2 (July 1, 2023): i6. http://dx.doi.org/10.1093/noajnl/vdad071.026.
Abstract:
Abstract H3 K27M mutations were first identified in Pediatric Diffuse Intrinsic Pontine Glioma and are now recognized in gliomas occurring in other midline locations such as the thalamus, spinal cord and cerebellum. These gliomas were renamed to Diffuse Midline Glioma (DMG) H3 K27-altered in the 2021 WHO classification due to the discovery of alternate mechanisms of H3 K27 loss. These gliomas are more commonly found in children but also occur in adolescents and young adults. We present the case of a 55- year-old woman who presented with a 2.5-month history of nausea, vomiting and gait impairment. Imaging revealed a partially cystic, enhancing lesion in the midline of the cerebellum. She had a gross total resection with pathology revealing Diffuse Midline Glioma, H3K27 altered, subgroup DMG, H3 wildtype with EZHIP over-expression, WHO grade 4. The patient completed chemoradiation with temozolomide with plans to enroll in a clinical trial upon progression. However due to loss of ambulation and function she was admitted to hospice. The patient survived 24 months after her surgery, a period longer than the reported median overall survival in DMG with EZIP overexpression which is 16 months. This case illustrates the importance of considering DMG H3K27- altered glioma in adults older than 40 years who present with infiltrative IDH wildtype glioma in midline locations. Recognition of this diagnosis may allow enrollment in clinical trials and should prompt molecular testing for concurrent targetable alterations in the RAS-MAPK-pathway (e.g., mutations in BRAF V600E, FGFR1, NF1 and NTRK) and PI3K-mTOR pathway (e.g., PIK3CA mutation).
4
Choi, Seonah, In-Ho Jung, Jaejoon Lim, Ju Hyung Moon, Eui Hyun Kim, Se Hoon Kim, Seok-Gu Kang, and Jong Hee Chang. "PATH-06. SURVIVAL ANALYSIS FOR ADULT MIDLINE GLIOMA: DO ADULT MIDLINE GLIOMAS WITH THE H3 K27M MUTATION REALLY HAVE POOR PROGNOSIS?" Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii150—vii151. http://dx.doi.org/10.1093/neuonc/noac209.579.
Abstract:
Abstract PURPOSE Since it is known that midline located glioma with H3K27 mutation in children has a disastrous prognosis, in 2016 WHO classification, these tumors were defined as diffuse midline glioma (DMG) and classified as grade IV. A lot of papers about pediatric DMG have been published, but there are not many papers about adult DMG. In this study, we aimed to identify factors affecting the prognosis of adult midline glioma. This is the first paper to study the prognosis of adult DMG according to histological grade and is the largest study to investigate the survival of adult DMG. METHODS We reviewed the chart of adult patients diagnosed with midline glioma with H3K27M mutation after undergoing resection or biopsy among patients who visited our institution between January 2010 and December 2020. Survival analysis was performed according to tumor location, histological grading, Karnofsky Performance Scale (KPS), and age. RESULTS Among the 125 adult midline gliomas we identified, 45 (36.0%) had the H3K27M mutation. As a result of survival analysis performed on 125 adult midline gliomas, low histological grade, KPS ≥ 80, and age ≤ 60 showed significantly better survival. After adjusting for age, the difference in survival between H3K27M mutation and wildtype group was not significant. As a result of survival analysis performed on 45 DMG, low histological grade, KPS ≥ 80, total resection, and concurrent chemoradiation therapy group showed significantly better survival. CONCLUSION In adult midline glioma, disastrous prognosis due to H3K27M mutation was not observed as in children. The prognosis of adult midline gliomas is determined by histological grade, age, KPS, and extent of tumor resection. Therefore, the current WHO classification, which classifies all H3K27M mutant midline gliomas as grade IV regardless of histological diagnoses, is not suitable for adults.
5
Nakatogawa, Hirokazu, Hiroshi Kawaji, Nobuhide Hayashi, Junya Fukai, Noriyuki Kijima, Tomoko Shofuda, Ema Yoshioka, et al. "10184-BT-14 CLINICAL FEATURE OF HEMISPHERIC GLIOMA WITH H3F3A, PEDIATRIC-TYPE HIGH GRADE GLIOMA, H3 K27-ALTERED, NEC AND DIFFUSE HEMISPHERIC GLIOMA, H3 G34-MUTANT, CNS WHO GRADE 4." Neuro-Oncology Advances 5, Supplement_5 (December 1, 2023): v18—v19. http://dx.doi.org/10.1093/noajnl/vdad141.074.
Abstract:
Abstract INTRODUCTION Diffuse midline glioma (DMG), H3K27-altered, is a CNS WHO grade 4 glioma that usually located mainly in the brainstem, thalamus and spinal cord. However, DMG located in non-midline lesions are now described as pediatric-type high grade glioma, H3K27-altered, NEC (NDMG). On the other hand, diffuse hemispheric glioma, H3G34-mutant (DHG) located in the cerebral hemispheres, and is classified under the WHO 2021 classification. It is unknown that the differences in clinical characteristics of these hemispheric tumors with H3F3A mutations. In the present study, we report a comparative study of the clinical characteristics of two groups of NDMG and DHG. METHODS Among 4128 brain tumor samples collected in the Kansai Network for Molecular Diagnosis of Central Nervous System Tumors, 16 NDMG and 9 DHG cases were examined for comparison of clinical characteristics. RESULTS There were no differences in gender, tumor location, or pathology between NDMG and DHG. The median age was 47.3 years in NDMG and 26.2 years in DHG, and NDMG was significantly older than DHG (p=0.003). There was no significant difference in MGMT promoter methylation between NDMG and DHG (p=0.087). The Kaplan-Meier survival curve showed no significant difference, with a median survival of 495 days for NDMG and 587 days for DHG (p=0.765). There was no significant different survival rate between WHO grade 3 (n=15) and grade 4 (n=9) for pathological diagnosis. DISCUSSION AND CONCLUSION We compared the clinical characteristics of NDMG and DHG. There are some reports that NDMG and DHG gliomas located in non-midline lesion. Removing much tumor volume may improve the prognosis of non-midline glioma. We discuss the gliomas with H3F3A mutations located in a hemispheric lesions by literature review.
6
Morscio, Julie, Sandra Jacobs, and Frederik De Smet. "DIPG-55. DISSECTING THE ECOSYSTEM OF PEDIATRIC DIFFUSE MIDLINE GLIOMA." Neuro-Oncology 26, Supplement_4 (June 18, 2024): 0. http://dx.doi.org/10.1093/neuonc/noae064.108.
Abstract:
Abstract BACKGROUND Pediatric gliomas are heterogeneous tumors encompassing high grade (pHGG) and low grade (pLGG) subtypes. For tumors not amenable to surgery, in particular high grade H3K27 mutant diffuse midline glioma (DMG), no curative options exist. DMG is characterized by 1) extensive heterogeneity of tumor cells that can exist in different interchangeable cellular states mimicking normal development and 2) extensive heterogeneity of the tumor microenvironment (TME). A better understanding of the DMG ecosystem is needed for therapeutic target identification. METHODS Publicly available single cell RNA seq data of DMG (n=17, Jessa et al. Nat. Genet. 2022), high grade pediatric glioblastoma (GBM, n=16, scPCA) and low grade tumors (ganglioglioma, n=5; pilocytic astrocytoma, n=14, scPCA) were analyzed to define key molecular characteristics and differences between these pediatric brain tumors. Doublet cells were removed from each dataset and tumor and TME cells were discriminated based on marker gene expression and inferred CNVs. RESULTS In DMG, glioma cellular states and TME heterogeneity differed depending on the tumor location. DMG arising in the pons harbored a bigger fraction of astrocyte-like glioma cells whereas oligodendrocyte-like cells were more abundant in thalamic tumors. In line with this observation, Liana cellular communication analysis inferred more intratumoral (autocrine) signaling involving oligodendrocyte-like glioma cells in thalamic tumors (e.g. NCAM1-PTPRZ1, NLGN4X-NRXN1, NTN1-DSCAM) than in pons tumors. Notably, the TME of thalamic tumors contained a bigger fraction of immunotolerant macrophages expressing CD163 or VSIG4. In contrast, pons tumors harbored a unique cluster of VEGFA expressing astrocytes, not found in GBM or pLGG. Liana analysis inferred COPA/APP-CD74 interaction between VEGFA+ astrocytes and CD163/VSIG4+ macrophages and microglia, potentially contributing to an immunotolerant TME in pons DMG. CONCLUSIONS In DMG, patterns of tumor and TME composition associated with tumor location were uncovered. Furthermore, unique TME celltypes could contribute to the particularly aggressive nature of these tumors.
7
Knowles, Truman, Shejuan An, Tina Huang, Jin Qi, and Amanda Saratsis. "DIPG-01. LIN28B EXPRESSION IN DIFFUSE MIDLINE GLIOMA." Neuro-Oncology 25, Supplement_1 (June 1, 2023): i12. http://dx.doi.org/10.1093/neuonc/noad073.048.
Abstract:
Abstract INTRODUCTION Diffuse midline glioma (DMG) is the most lethal of all childhood cancers. LIN28B is an RNA binding protein expressed in a variety of cancers, which suppresses the let-7 family of microRNAs, which in turn suppresses a plethora of oncogenes. However, the role of LIN28B in DMG has not yet been explored. Therefore, we sought to determine the pattern of expression and potential function of LIN28B in DMG using rare DMG cell lines. METHODS All studies were performed on DMG cell lines (n=6) and controls (normal human astrocytes n=1, human neural stem cells n=1). RNA-Seq was performed using single-read sequencing at 50bp on the Illumina NextSeq 500 Sequencing System. Cells were then treated with DMSO or the LIN28B inhibitor, LI71, and submitted to functional in vitro studies, as well as RNA-Seq and Western Blot analysis. Functional pathways analysis was subsequently performed on resulting gene expression values with Ingenuity Pathways Analysis (Qiagen). RESULTS Differential LIN28B expression was demonstrated across cell lines, with DMG cells expressing greater LIN28B gene and protein levels compared to controls. LIN28B inhibition with small molecule inhibitor LI71 resulted in decreased cell proliferation and migration, in vitro. A total of 946 differentially expressed genes were identified between treatment groups (FC>2 or <-2, p<0.05). Functional pathways analysis of differentially expressed genes implicated Cancer and Neurological Disease as the top disease processes, with Cellular Movement as the top molecular process in cell lines expressing LIN28B. Further, inactivation of Myc signaling was implicated in cells treated with LI71. CONCLUSIONS Our data demonstrates increased LIN28B expression in DMG cell lines compared with controls, with oncogenic effects on cell proliferation and migration. Further investigation of the LIN28B-let7 signaling axis is warranted in order to further explore LIN28B as a novel therapeutic target in DMG.
8
Knowles, Truman, Shejuan An, Tina Huang, Jin Qi, and Amanda Saratsis. "CSIG-11. LIN28B EXPRESSION IN DIFFUSE MIDLINE GLIOMA." Neuro-Oncology 25, Supplement_5 (November 1, 2023): v42. http://dx.doi.org/10.1093/neuonc/noad179.0167.
Abstract:
Abstract INTRODUCTION Diffuse midline glioma (DMG) is the most lethal of all childhood cancers. LIN28B is a RNA binding protein expressed in a variety of cancers, which suppresses the let-7 family of microRNAs, which in turn suppresses a plethora of oncogenes. However, the role of LIN28B in DMG has not yet been explored. Therefore, we sought to determine the pattern of expression and potential function of LIN28B in DMG using rare DMG cell lines. METHODS All studies were performed on DMG cell lines (n = 6) and controls (normal human astrocytes n = 1, human neural stem cells n = 1). RNA-Seq was performed using single-read sequencing at 50bp on the Illumina NextSeq 500 Sequencing System. Cells were then treated with DMSO or the LIN28B inhibitor, LI71, and submitted to functional in vitro studies, as well as RNA-Seq and Western Blot analysis. Functional pathways analysis was subsequently performed on resulting gene expression values with Ingenuity Pathways Analysis (Qiagen). RESULTS Differential LIN28B expression was demonstrated across cell lines, with DMG cells expressing greater LIN28B gene and protein levels compared to controls. LIN28B inhibition with small molecule inhibitor LI71 resulted in decreased cell proliferation and migration, in vitro. A total of 946 differentially expressed genes were identified between treatment groups (FC>2 or <-2, p< 0.05). Functional pathways analysis of differentially expressed genes implicated Cancer and Neurological Disease as the top disease processes, with Cellular Movement as the top molecular process in cell lines expressing LIN28B. Further, inactivation of Myc signaling was implicated in cells treated with LI71. CONCLUSIONS Our data demonstrates increased LIN28B expression in DMG cell lines compared with controls, with oncogenic effects on cell proliferation and migration. Further investigation of the LIN28B-let7 signaling axis is warranted in order to further explore LIN28B as a novel therapeutic target in DMG.
9
Knowles, Truman, Shejuan An, Tina Huang, Jin Qi, and Amanda Saratsis. "DIPG-02. LIN28B EXPRESSION IN DIFFUSE MIDLINE GLIOMA." Neuro-Oncology 26, Supplement_4 (June 18, 2024): 0. http://dx.doi.org/10.1093/neuonc/noae064.056.
Abstract:
Abstract BACKGROUND Diffuse midline glioma (DMG) is the most lethal of all childhood cancers. LIN28B is a RNA binding protein expressed in a variety of cancers, which suppresses the let-7 family of microRNAs, which in turn suppresses a plethora of oncogenes. However, the role of LIN28B in DMG has not yet been explored. Therefore, we sought to determine the pattern of expression and potential function of LIN28B in DMG using rare DMG cell lines. METHODS All studies were performed on DMG cell lines (n=6) and controls (normal human astrocytes n=1, human neural stem cells n=1). RNA-Seq was performed using single-read sequencing at 50bp on the Illumina NextSeq 500 Sequencing System. Cells were then treated with DMSO or the LIN28B inhibitor, LI71, and submitted to functional in vitro studies, as well as RNA-Seq and Western Blot analysis. Functional pathways analysis was subsequently performed on resulting gene expression values with Ingenuity Pathways Analysis (Qiagen). RESULTS Differential LIN28B expression was demonstrated across cell lines, with DMG cells expressing greater LIN28B gene and protein levels compared to controls. LIN28B inhibition with small molecule inhibitor LI71 resulted in decreased cell proliferation and migration, in vitro. A total of 946 differentially expressed genes were identified between treatment groups (FC>2 or <-2, p<0.05). Functional pathways analysis of differentially expressed genes implicated Cancer and Neurological Disease as the top disease processes, with Cellular Movement as the top molecular process in cell lines expressing LIN28B. Further, inactivation of Myc signaling was implicated in cells treated with LI71. CONCLUSIONS Our data demonstrates increased LIN28B expression in DMG cell lines compared with controls, with oncogenic effects on cell proliferation and migration. Further investigation of the LIN28B-let7 signaling axis is warranted in order to further explore LIN28B as a novel therapeutic target in DMG.
10
Larsen, Alexandra Giantini, Maricruz Rivera, David Pisapia, Sameer Farouk Sait, Matthias Karajannis, Jeffrey Greenfield, and Mark Souweidane. "DIPG-44. DIFFUSE MIDLINE GLIOMA WITH EXTRACRANIAL METASTASIS." Neuro-Oncology 25, Supplement_1 (June 1, 2023): i23. http://dx.doi.org/10.1093/neuonc/noad073.091.
Abstract:
Abstract Diffuse midline gliomas (DMGs) are malignant infiltrative gliomas enriched in the pediatric population and characterized by loss of the H3 K27me3 epigenetic marker, most frequently via mutation of the H3F3A gene. Few cases of extracranial DMG metastasis with redemonstrated H3F3A p.K28M (K27M) mutation in metastatic tissue are reported in the literature. Here, we report two such patients, both females (ages 12 and 15), with DMG and extracranial metastasis who died 5 years after initial diagnosis. The first patient with thalamic DMG underwent biopsy, radiation, chemotherapy, and subsequent decompression of spinal metastasis. Initial tumor biopsy demonstrated mutation in BRAF p.V600E, H3F3A K27M, and TERT promoter. The epidural spinal metastasis had mutations in BRAF p.V600E, H3F3A, TERT, and TP53. The second patient with brainstem DMG, diagnosed by radiographic appearance, underwent conventional external beam radiation therapy, chemotherapy including panobinostat and direct delivery of radioimmunotherapy, intra-arterial delivery of bevacizumab, and subsequent decompression of spinal metastasis. The histology and molecular profile for the spinal metastasis was consistent with DMG H3 K27M-mutant, with mutations in BRAF p.G464V, PTPN11 p.R498L, PDGFRA, and KIT. Bone marrow biopsy demonstrated atypical extrinsic cells with strong and diffuse immunolabeling for OLIG2. Autopsy revealed solid organ and osseous metastases. Both patients significantly exceeded the median life expectancy for DMG, raising the possibility that prolonged overall survival permitted progression to a rarely observed disseminated state of disease. There was absence of TP53/p53 modulating pathway mutation seen in classic DMG in the thalamic biopsy of the first patient, as well as the metastatic disease for the second patient, which may contribute to the prolonged survival observed. Molecular analysis of metastatic disease is important, as clinically and prognostically relevant alterations that vary from the primary site of disease may be detected, which shed light on clonal evolution patterns and further our understanding of disease biology.
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Butterfield, Hannah E., Juliana Hofstatter Azambuja, Lisa Maurer, Dong Hu, Andrea F. Cruz, Matthew E. Halbert, Taylor A. Gatesman, et al. "DIPG-85. MALT1 IN H3K27-ALTERED DIFFUSE MIDLINE GLIOMA." Neuro-Oncology 26, Supplement_4 (June 18, 2024): 0. http://dx.doi.org/10.1093/neuonc/noae064.138.
Abstract:
Abstract BACKGROUND H3K27-altered diffuse midline glioma (DMG) is a devastating pediatric brainstem tumor that affects 200-300 individuals in the US per year. Median survival is 9-11 months, and there are virtually no long-term survivors. Despite decades of clinical trials, radiation therapy remains standard of care, extending survival by 2-3 months. Elucidating the mechanisms that drive H3K27-altered DMG pathogenesis in order to uncover therapeutic vulnerabilities is of critical importance. Recent studies implicate MALT1 as a potential therapeutic target in gliomas. MALT1 is the effector molecule of the CARMA-BCL10-MALT1 (CBM) signalosome, a cytoplasmic protein complex that drives downstream pro-survival transcriptional activity. MALT1, which possesses scaffolding and protease functions, promotes cell viability, proliferation, and migration/invasion in multiple cancer types. We aim to evaluate the hypotheses that MALT1 promotes DMG cancer cell proliferation and migration and that MALT1 inhibition will abrogate tumor progression. METHODS/RESULTS We screened a panel of cells including astrocytes, neural stem cells, and DMG cell lines by Western blot and found that CBM complex members BCL10 and MALT1 are present in all cells tested. We next demonstrated that MALT1 is proteolytically active in DMG cell lines SF8628 and HSJD-DIPG-007. Specifically, we showed cleavage of the MALT1 protease substrate HOIL, which was abrogated by treatment with the MALT1 protease inhibitor MLT-748. We next generated multiple dox-inducible MALT1 shRNA DMG cell lines to assess the impact of MALT1 deficiency on DMG biology. Thus far, we find that shRNA knockdown of MALT1 does not impact SF8628 cell proliferation. CONCLUSIONS MALT1 is expressed and proteolytically active in DMG cells. Initial studies show that MALT1 knockdown does not affect proliferation of SF8628 cells. We will next evaluate the effect of MALT1 knockdown on proliferation of additional DMG cell lines, as well as the impact on other malignant features of DMG cells including migration/invasion.
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Miguel Llordes, Gloria, Víctor Manuel Medina Pérez, Beatriz Curto Simón, Irene Castells-Yus, Silvia Vázquez Sufuentes, and Alberto J. Schuhmacher. "Epidemiology, Diagnostic Strategies, and Therapeutic Advances in Diffuse Midline Glioma." Journal of Clinical Medicine 12, no. 16 (August 12, 2023): 5261. http://dx.doi.org/10.3390/jcm12165261.
Abstract:
Object: Diffuse midline glioma (DMG) is a highly aggressive and lethal brain tumor predominantly affecting children and young adults. Previously known as diffuse intrinsic pontine glioma (DIPG) or grade IV brain stem glioma, DMG has recently been reclassified as “diffuse midline glioma” according to the WHO CNS5 nomenclature, expanding the DMG demographic. Limited therapeutic options result in a poor prognosis, despite advances in diagnosis and treatment. Radiotherapy has historically been the primary treatment modality to improve patient survival. Methods: This systematic literature review aims to comprehensively compile information on the diagnosis and treatment of DMG from 1 January 2012 to 31 July 2023. The review followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement and utilized databases such as PubMed, Cochrane Library, and SciELO. Results: Currently, molecular classification of DMG plays an increasingly vital role in determining prognosis and treatment options. Emerging therapeutic avenues, including immunomodulatory agents, anti-GD2 CAR T-cell and anti-GD2 CAR-NK therapies, techniques to increase blood–brain barrier permeability, isocitrate dehydrogenase inhibitors, oncolytic and peptide vaccines, are being explored based on the tumor’s molecular composition. However, more clinical trials are required to establish solid guidelines for toxicity, dosage, and efficacy. Conclusions: The identification of the H3K27 genetic mutation has led to the reclassification of certain midline tumors, expanding the DMG demographic. The field of DMG research continues to evolve, with encouraging findings that underscore the importance of highly specific and tailored therapeutic strategies to achieve therapeutic success.
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Klenner, Marbod, Pia Freidel, Mariella G. Filbin, and Alexander Beck. "DIPG-39. New preclinical models for Diffuse Midline Glioma." Neuro-Oncology 24, Supplement_1 (June 1, 2022): i27. http://dx.doi.org/10.1093/neuonc/noac079.096.
Abstract:
Abstract Malignant brain tumors are the leading cause of childhood death in Germany, with Diffuse Midline Glioma (DMG) being the most lethal of all paediatric brain tumors. Current treatment strategies are limited to irradiation which prolongs survival only by a few months. Preclinical studies have identified effective drug candidates, but translation into the clinic remains a major obstacle. It is known that interactions between tumor cells and components of the TME (tumor microenvironment), such as cell to cell contacts between malignant and non-malignant cells or secreted factors, can increase therapy resistance and progression of brain tumors. However, these important factors are not present in most conventional cell culture models for drug testing. Consequently, there is a need for more realistic DMG models to improve the relevance and translational potential of current drug screening. Therefore, the goal of this study was to develop a new DMG model for drug testing, consisting of induced pluripotent stem cell (iPSC) derived human brain cells and patient derived DMG cells to better mimic the complex tumor microenvironment. We co-cultured three-dimensional cerebral organoids with DMG tumor spheres resulting in the formation of DMG-Brain-Organoids (DBO). Preliminary results show that co-culture induces distinct tumor cell subpopulations corresponding to those detected in DMG tumors by single cell RNA sequencing (Filbin et al., 2018). These subpopulations mainly differ in their proliferative capacity and their differential response to clinical interventions may be critical for therapeutic success. DBOs subjected to drug treatments (single or combination) were sectioned and individual therapy effects on tumor cell subpopulations and proliferative capacity were monitored using multiplexed immunofluorescence imaging. By observing drug effects in a realistic setup, we hope to improve the predictive power of our preclinical drug screens and to find new combination therapies for DMG.
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Tanaka, Kazuhiro, Hiroaki Nagashima, Shunsuke Yamanishi, Hirofumi Iwahashi, Tomoo Itoh, and Takashi Sasayama. "MPC-16 CHARACTERISTICS AND PROGNOSTIC FACTORS OF H3K27M-MUTANT DIFFUSE MIDLINE GLIOMA." Neuro-Oncology Advances 4, Supplement_3 (December 1, 2022): iii15—iii16. http://dx.doi.org/10.1093/noajnl/vdac167.057.
Abstract:
Abstract H3 K27M-mutant diffuse midline gliomas (DMG) is a still challenging disease with no effective medical therapies. We analyzed the characteristics and prognostic factors of 64 patients with midline gliomas including 18 patients with H3 K27M-mutant DMG treated in Kobe University Hospital from 2006 to 2021. The median age at diagnosis in midline gliomas was 50.1 years (range: 14-82 y). All tumors were located in thalamus n=25, corpus callosum n=8, brainstem n=8, spinal cord n=6, cerebellum n=15, and pineal region n=2. Isocitrate dehydrogenase 1 (IDH1) and H3 K27 mutation was recognized in 6 and 18 patients, respectively, which was mutually exclusive. In all midline gliomas, the identification of an H3 K27M mutation was significantly a poor prognosis factor (median 19.8 months vs 27.9 months, p=0.042). Compared to midline gliomas without histone H3 and IDH1 mutations (IDH1/H3 wild type), however, H3 K27M-mutant DMG had no worse overall survival (median 19.8 months vs 15.9 months, p=0.51). H3 K27M-mutant DMG is considered as a distinct WHO Grade 4 regardless of histological features, but the biological properties of H3 K27M mutation is not yet defined in IDH1 wild-type midline gliomas.
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Tanaka, K., H. Nagashima, S. Yamanishi, T. Itoh, and T. Sasayama. "P10.11.A CHARACTERISTICS OF DIFFUSE MIDLINE GLIOMA WITH H3 K27M MUTATION IN ADULTS." Neuro-Oncology 25, Supplement_2 (September 1, 2023): ii64. http://dx.doi.org/10.1093/neuonc/noad137.209.
Abstract:
Abstract BACKGROUND H3 K27M-mutant diffuse midline gliomas (DMG) occur primarily in children but can also be encountered in adults. Adult H3 K27M-mutant DMG is a still challenging disease with no effective medical therapies. MATERIAL AND METHODS We retrospectively analyzed the characteristics and prognostic factors of 49 adult patients with intracranial midline gliomas treated in Kobe University Hospital from 2006 to 2022. RESULTS The median age at diagnosis in midline gliomas was 50.8 years (range: 17-83 y). All tumors were located in thalamus n=25, brainstem n=10, cerebellum n=14. Isocitrate dehydrogenase 1 (IDH1) and H3 K27M mutation was recognized in 6 and 16 patients, respectively, which was mutually exclusive. In all midline gliomas, the identification of H3 K27M mutation was significantly a poor prognosis factor (median 18.5 months vs 34.2 months, p=0.041). Among IDH1 wild-type midline gliomas, however, H3 K27M-mutant DMG had no worse overall survival (median 18.8 months vs 22.2 months, p=0.805). CONCLUSION H3 K27M-mutant DMG is considered as a distinct WHO Grade 4 regardless of histological features, but the biological properties of H3 K27M mutation is not yet defined in IDH1 wild-type midline gliomas in adults.
16
Nakatogawa, Hirokazu, Hiroshi Kawaji, Nobuhide Hayashi, Junya Fukai, Noriyuki Kijima, Tomoko Shofuda, Ema Yoshioka, et al. "MPC-15 CLINICAL FEATURE OF NON-MIDLINE GLIOMA WITH H3F3A GENE MUTATION." Neuro-Oncology Advances 4, Supplement_3 (December 1, 2022): iii15. http://dx.doi.org/10.1093/noajnl/vdac167.056.
Abstract:
Abstract Introduction Diffuse midline glioma (DMG), H3K27-altered, is a CNS WHO grade 4 glioma that usually occurs mainly in the brainstem region in children and also in the thalamus and spinal cord in older children and adults. On the other hand, glioma with histone H3 p. G34R/V mutations in the cerebral hemispheres are defined in a new classification of Diffuse hemispheric glioma, H3G34-mutant (DHG), in the WHO 2021 classification. However, there are some reports of H3K27-altered non-midline gliomas (NDMG) that are not located in the midline, but the differences between these hemispheric tumors with mutations in different regions of histone H3 are unknown. In this study, we report a comparative study of the clinical characteristics between two groups of glioma, H3K27-altered NDMGs and H3G34-mutant DHGs. Methods Among 4128 brain tumor specimens collected in the Kansai Network for Molecular Diagnosis of Central Nervous System Tumors, 25 NDMG cases, excluding 93 cases defined as DMG, were included out of 118 cases with mutations in the H3F3A gene. Both 16 H3K27-altered NDMG cases and 9 H3G34-mutant DHG cases were examined for comparison of clinical characteristics. Results There were no differences in gender, tumor location, or pathology between NDMG and DHG. The median age was 47.3 years in NDMG and 26.2 years in DHG, and NDMG was significantly older than DHG (p=0.003). The rate of MGMT promoter methylation is no significant difference between 4 cases (25%) in NDMG and 6 cases (66.7%) in DHG (p=0.087). The Kaplan-Meier survival curve showed no significant difference, with a median survival of 495 days for NDMG and 587 days for DHG (p=0.765). Discussion and Conclusion We reported on gliomas with H3F3A mutations that occur in the cerebral hemispheres. We compared the clinical characteristics of NDMG with H3K27-altered and DHG with H3G34-mutant, which have similar tumor locations of occurrence.
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Holliday, Holly, Anahid Ehteda, Aaminah Khan, Brian Krug, Jourdin R. C. Rouaen, Nisitha Jayatilleke, Chelsea Mayoh, et al. "DIPG-06. Uncovering the FACTs in Diffuse Midline Glioma (DMG)." Neuro-Oncology 24, Supplement_1 (June 1, 2022): i18. http://dx.doi.org/10.1093/neuonc/noac079.063.
Abstract:
Abstract Effective treatments are urgently needed for the incurable paediatric brainstem tumour Diffuse Midline Glioma (DMG). Most DMGs contain Histone H3 mutations (H3K27M), which produce extensive epigenetic dysregulation by inhibiting EZH2-mediated trimethylation of H3K27 (H3K27me3). Global depletion of the repressive H3K27me3 modification results in aberrantly open chromatin and is central to DMG tumorigenesis. Thus, targeting the epigenome is a promising avenue of treatment for DMG. We found that targeting the histone chaperone complex Facilitates Chromatin Transcription (FACT) with the curaxin drug CBL0137 to have potent pre-clinical efficacy against DMG, leading to a paediatric Phase I/II clinical trial for CBL0137 which includes a DMG/DIPG cohort (NCT04870944). In this project we aim to elucidate CBL0137’s molecular mechanism in DMG. FACT is critical for maintaining chromatin homeostasis during DNA replication, transcription, and repair. We therefore hypothesised that FACT maintains the aberrant epigenetic landscape resulting from H3K27M. Consistently, we found CBL0137 to be more cytotoxic against H3K27M-mutant, compared to H3-WT or isogenic DMG cells lacking the mutation. Furthermore, FACT directly interacts with H3K27M, and FACT inhibition increases both EZH2 catalytic activity and global H3K27me3 levels. We are now using ChIP-seq to discover the genome-wide distribution of FACT and H3K27M, and will interrogate the consequence of CBL0137 treatment on the epigenome and transcriptome. Preliminary results suggest that FACT is located at certain genes co-occupied by H3K27M, the active histone mark H3K27ac, and the BET protein BRD4. This implies that FACT is involved in maintaining open chromatin and perhaps transcription at these regions. Combining CBL0137 with other epigenetic drugs, such as BET inhibitors, could therefore represent a rational therapeutic opportunity for DMG. This work will ultimately inform mechanism-based targeted therapies to combine with CBL0137 to improve its efficacy and uncover valuable new insights into DMG epigenetics and pathobiology.
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Willimas, E. A., P. K. Brastianos, H. Wakimoto, S. Santagata, D. P. Cahill, and T. A. Juratli. "P04.04.A A comprehensive genomic study of 390 H3F3A-mutant pediatric-type diffuse high-grade gliomas WHO CNS grade 4." Neuro-Oncology 24, Supplement_2 (September 1, 2022): ii35—ii36. http://dx.doi.org/10.1093/neuonc/noac174.119.
Abstract:
Abstract Background Histone gene mutant malignant gliomas - H3K27-altered diffuse midline glioma (DMG) and diffuse hemispheric glioma (DHG) H3G34-mutant - occur in all age groups and can have significant variation in clinical outcomes. Here, we report comprehensive genomic profiling from one of the largest collections of H3F3A-mutant gliomas analyzed to date, identifying subsets defined by recurrently co-mutated genes. Material and Methods We identified 390 H3F3A-mutant diffuse gliomas WHO grade 4 (201 females and 189 males) that were profiled in the comprehensive genomic profiling program at Foundation Medicine between 2013-2020. Information from pathology reports, histopathology review, and patient clinical data was assessed Results Our cohort comprised 304 (77.9%) H3K27M-mutant DMG WHO grade 4 (156 females and 148 males) and 86 H3G34-mutant DHG (45 females and 41 males) with a median age of 20 years (1- 74 years). H3K27M-mutant DMG distributed equally between pediatric and adult patients, with 52% of the patients older than 20 years, 30% older than 30 years, and 18% older than 40 years at the time of first diagnosis. Clonal FGFR1 hotspot mutations were exclusively detected in K27M-mutant DMG (n = 64/304, 21%; p=0.0001), with a significant association with a higher age at first diagnosis (median 32.5 years), and with a wide tumor distribution across the diencephalon. Additional genes which were significantly more frequently altered in K27M-mutant compared to G34-mutant diffuse gliomas included NF1 (31% vs. 8.1%; p=0.0001) and PIK3CA/PIK3R1 (27.9% vs. 15.1%; p=0.016). Conversely, targetable alterations of the cell-cycle pathway (CDK4/6 amplifications and CDKN2A/B deletions) were enriched in H3G34-mutant DHG (26%) compared to H3K27M-mutant DMG (7%). Potentially targetable PDGFR alterations were present in 32.5% of H3G34-mutant DHG and in 18% of H3K27M-mutant DMG. Conclusion These data expand our understanding of the tumor-specific molecular features of pediatric-type high-grade gliomas, identifying cohort sub-structure by recurrent co-mutations, which can inform diagnosis and clinical trial design.
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Williams, Erik, Priscilla Brastianos, Hiroaki Wakimoto, Sandro Santagata, Daniel Cahill, and Tareq Juratli. "PATH-08. A COMPREHENSIVE GENOMIC STUDY OF 390 H3F3A-MUTANT PEDIATRIC-TYPE DIFFUSE HIGH-GRADE GLIOMAS WHO CNS GRADE 4." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii151. http://dx.doi.org/10.1093/neuonc/noac209.581.
Abstract:
Abstract OBJECTIVES Histone gene mutant malignant gliomas - H3K27-altered diffuse midline glioma (DMG) and diffuse hemispheric glioma (DHG) H3G34-mutant - occur in all age groups and can have significant variation in clinical outcomes. Here, we report comprehensive genomic profiling from one of the largest collections of H3F3A-mutant gliomas analyzed to date, identifying subsets defined by recurrently co-mutated genes. METHODS We identified 390 H3F3A-mutant diffuse gliomas WHO grade 4 (201 females and 189 males) that were profiled in the comprehensive genomic profiling program at Foundation Medicine between 2013-2020. Information from pathology reports, histopathology reviews, and clinical data was assessed. RESULTS Our cohort comprised 304 (77.9%) H3K27M-mutant DMG WHO grade 4 (156 females and 148 males) and 86 H3G34-mutant DHG (45 females and 41 males) with a median age of 20 years (1-74 years). H3K27M-mutant DMG distributed equally between pediatric and adult patients, with 52% of the patients older than 20 years, 30% older than 30 years, and 18% older than 40 years at the time of first diagnosis. Clonal FGFR1 hotspot mutations were exclusively detected in K27M-mutant DMG (n = 64/304, 21%; p=0.0001), with a significant association with a higher age at first diagnosis (median 32.5 years), and with a wide tumor distribution across the diencephalon. Additional genes which were significantly more frequently altered in K27M-mutant compared to G34-mutant diffuse gliomas included NF1 (31% vs. 8.1%; p=0.0001) and PIK3CA/PIK3R1 (27.9% vs. 15.1%; p=0.016). Conversely, targetable alterations of the cell-cycle pathway (CDK4/6 amplifications and CDKN2A/B deletions) were enriched in H3G34-mutant DHG (26%) compared to H3K27M-mutant DMG (7%). Potentially targetable PDGFR alterations were present in 32.5% of H3G34-mutant DHG and in 18% of H3K27M-mutant DMG. CONCLUSIONS These data expand our understanding of the tumor-specific molecular features of pediatric-type high-grade gliomas, identifying cohort sub-structure by recurrent co-mutations, which can inform diagnosis and clinical trial design.
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Uchida, Eita, Yukitomo Ishi, Jun Watanabe, Hiam Abdala-Valencia, Benjamin Singer, Samantha Gadd, and Rintaro Hashizume. "DIPG-82. RADIOSENSITIZATION WITH RAD52 INHIBITION IN DIFFUSE MIDLINE GLIOMA." Neuro-Oncology 26, Supplement_4 (June 18, 2024): 0. http://dx.doi.org/10.1093/neuonc/noae064.135.
Abstract:
Abstract BACKGROUND Diffuse midline glioma (DMG) is one of the most devastating childhood cancers that limited response to radiation therapy (RT). There is a critical need for new therapeutics that enhance the radiation effect. We, therefore, tested the hypothesis that targeting RAD52 activity sensitizes the radiation response of DMG. METHODS Genome-wide CRISPR/Cas9 screening was performed to identify the potential therapeutic target. RAD52 inhibition was used by shRNA-mediated RAD52 depletion and treatment with RAD52 inhibitor, D-I03. The protein expression, cell proliferation, DNA damage marker expression, DNA repair pathway, and transcriptional alteration were analyzed by western blotting, MTS assay, colony formation assay, immunocytochemistry, DNA repair pathway assay, and RNA sequencing. Mice with DMG patient-derived xenograft (PDX) models were treated with RAD52 inhibitor alone or combination with RT. RESULTS Genome-wide CRISPR/Cas9 screening identified RAD52 as a potential therapeutic target in DMG cells. RAD52 inhibition suppressed DMG cell proliferation. Importantly, RAD52 inhibition in combination with RT further increased the radiosensitivity of DMG cells. Immunocytochemistry of DNA double-strand breaks (DSB) marker γH2AX and repair marker 53BP1 showed that RAD52 inhibition sustained DNA damage with high levels of γH2AX at 24 hours following radiation while the level of 53BPI was decreased, thereby inhibiting DNA DSB repair. Western blotting also revealed that RAD52 inhibition causes a sustained level of phosphorylated Rad50 and γH2AX in irradiated DIPG cells over 24 hours. DNA repair assay showed that RAD52 inhibition suppressed homologous recombination DNA repair pathway. RNA sequencing showed that RAD52 inhibition downregulated genes associated with the DNA repair pathway. Finally, the combination therapy of RAD52 inhibitor and RT further suppressed tumor growth and increased survival of mice bearing DMG PDXs, outperforming either monotherapy. CONCLUSIONS these results highlight RAD52 inhibition as a potential radiosensitization and provide a rationale for developing combination therapy with radiation in the treatment of DMG.
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Liapodimitri, Athanasia, Kayleigh Lunsford, Ashley R. Tetens, Jordyn Craig-Schwartz, Farhad Vesuna, Venu Raman, and Michael A. Koldobskiy. "DIPG-64. UNRAVELING H3K27M INTERACTIONS IN DIFFUSE MIDLINE GLIOMA." Neuro-Oncology 26, Supplement_4 (June 18, 2024): 0. http://dx.doi.org/10.1093/neuonc/noae064.117.
Abstract:
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.
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Balakrishnan, Illango, Krishna Madhavan, Angela Pierce, Sujatha Venkataraman, and Rajeev Vibhakar. "EXTH-49. A NOVEL THERAPEUTIC ANTIBODY TARGETING DIFFUSE MIDLINE GLIOMA." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii220. http://dx.doi.org/10.1093/neuonc/noac209.847.
Abstract:
Abstract There is an unmet need to identify novel targeted therapies for H3K27M mutated Diffuse Midline Gliomas. (DMG) Using genetic overexpression and deletion of H3K27M in model cells we identified high expression of CD99 mRNA in H3K27M-mutant expressing DIPGs compared to other normal brain counterparts. A cell surface antigen screen confirmed that CD99 was highly expressed in DMG compared to normal tissues. We then developed a novel chimeric CD99 antibody based on a human IgG4 scaffold and tested the anti-tumor efficacy of this antibody in vitro and in vivo DMG xenografts. Our new CD99 antibody (10D1) significantly reduced DIPG tumor cell proliferation in vitro. In vivo intravenous administration of the antibody in orthotopic DMG tumor bearing mice showed complete clearance of tumor with prolonged animal survival establishing anti-tumor efficacy of 10D1 and demonstrating its ability in crossing the blood-brain-pons barrier. Loco-regional administration of 10D1, intratumorally or to the lateral ventricle, showed similar anti-tumor effects at reduced antibody concentrations while limiting systemic effects on normal T cells. 10D1 combined with radiation to further prolong the survival of orthotopic xenograft-bearing animals. In conclusion, we have identified a novel therapeutic for DMG which is now in further development.
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Boult, Jessica, Diana Carvalho, Ketty Kessler, Maria Vinci, Elisabet Fernandez, Lynn Bjerke, Mariama Fofana, et al. "IMG-09. Characterisation of a panel ofin vivo models of paediatric-type diffuse high-grade glioma (PDHGG) using magnetic resonance imaging." Neuro-Oncology 24, Supplement_1 (June 1, 2022): i78. http://dx.doi.org/10.1093/neuonc/noac079.285.
Abstract:
Abstract Novel therapies for paediatric-type diffuse high-grade glioma (PDHGG) are urgently required. Orthotopic models using patient-derived material are invaluable tools in preclinical drug development as they retain key genetic/epigenetic features, eg. histone H3G34 or H3K27 alterations. Their evaluation in situ is vital and requires sensitive imaging techniques such as MRI. 12 diffuse hemispheric glioma (DHG; 2 DHG-G34) and 21 diffuse midline glioma (DMG; 17 DMG-K27M) tumours have been characterised using MRI following site-specific orthotopic implantation of patient-derived cells directly from tumour material or after minimal expansion as stem cell cultures. Of the 62 models implanted; 3 DHG and 10 DMG samples were not tumourigenic and 13 DHG/3 DMG models are currently under MRI surveillance. Tumours identified on T2-weighted (T2w)-images varied from a diffuse hyperintense signal to well-defined high contrast masses. Tumour growth in 5 DMG models was too diffuse for longitudinal monitoring with T2w-MRI. Once established, diffusion-weighted, T1/T2 mapping and contrast-enhanced MRI were used to further assess tumour phenotype. Quantitative data from 15 DMG models demonstrated higher water diffusivity and T2 than 10 DHG tumours, which suggests less tightly packed tumour cells but may also reflect the closer proximity of tumours growing in the thalamus/pons/cerebellum to the ventricular system. Lack of contrast-agent enhancement in 11 DMG and 6/10 DHG models indicated an intact blood-brain barrier (BBB), with heterogeneous disruption observed in 4 DHGs; H3-G34 had no bearing on BBB integrity. Upon serial re-implantation survival was shortened in 3/4 DHG and 2/6 DMG models, while quantitative MRI parameters remained similar. Likewise, when 2 DHG and 2 DMG models grown in 2D/3D in vitro were implanted in parallel, poorer survival/improved penetrance was associated with 3D-cultured cells with no difference in imaging phenotype. The study highlights the potential of non-invasive MRI to accurately evaluate the efficacy of novel therapeutics in these PDHGG models.
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Gallitto, Matthew, Genesis Los De Santos, Hong-Jian Wei, Xu Zhang, Zhiguo Zhang, and Cheng-Chia Wu. "DIPG-41. CONVECTION ENHANCED DELIVERY-MEDIATED RADIOSENSITIZATION FOR DIFFUSE MIDLINE GLIOMA." Neuro-Oncology 26, Supplement_4 (June 18, 2024): 0. http://dx.doi.org/10.1093/neuonc/noae064.094.
Abstract:
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.
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Cartaxo, Rodrigo, Edwin Nieblas-Bedolla, Michael Niculcea, Madeline Miclea, Ruby `. Siada, Kallen Schwark, Sunjong Ji, et al. "HGG-52. MULTI-INTEGRIN TARGETING EFFECTIVELY SUPPRESSES DIFFUSE MIDLINE GLIOMA MIGRATION." Neuro-Oncology 26, Supplement_4 (June 18, 2024): 0. http://dx.doi.org/10.1093/neuonc/noae064.336.
Abstract:
Abstract Diffuse midline gliomas (DMGs) are aggressive tumors characterized by infiltration into normal midline brain tissue, hindering surgical resection and contributing to overall morbidity and mortality. We established a novel two-step pooled whole genome CRISPR-Migration screen by using serum-free conditions and laminin-dependent cell attachment, mimicking cell migration on brain vasculature scaffolds, a common feature in glioblastoma (GBM). Comparing DMG and GBM primary cell lines (n=5), genes involved in focal adhesion (ITGB1, CRKL, PARVA, PTK2, FERMT2) were identified as significantly restricting migration in all cell lines. Multi-institutional transcriptomic data revealed an association of expression of these focal adhesion genes with survival primarily in K27M-DMG and pediatric high-grade glioma compared to lower-grade brain tumors, and ITGB1 expression increased with glioma grade. Single-cell RNA-seq and spatial transcriptomic data demonstrated higher expression of ITGB1 in OPC-like/Mesenchymal cells associated with leading edge and microvasculature in both K27M-DMG and GBM tumors. Unexpectedly, knockout of ITGB1 (ITGB1-KO), primarily responsible for cell adhesion to laminin, led to the decreased expression of multiple mitochondrial NADH dehydrogenase genes, and reduced levels of glycolysis and oxidative phosphorylation (OXPHOS) activity. Preliminary mechanistic data linked this phenotype to impaired mitochondrial fusion. Orthotopic implantation of control and ITGB1-KO models of H3K27M-DMG and adult GBM in mouse brains revealed two distinct phenotypes: (1) ITGB1-KO reducing proliferation and significantly increasing survival; and (2) ITGB1-KO leading to upregulation of ITGB3 and ITGB5 in vivo without impacting survival. Cilengitide (αvβ3 and αvβ5 inhibitor) ablated migration of all ITGB1-KO models on vitronectin (secreted by pericytes surrounding blood vessels) in vitro. Ongoing combinatorial therapy with an experimental anti-Integrin Beta 1 antibody (AIIB2, CNS delivered) and Cilengitide is underway with promising early results. In summary, multi-integrin inhibition provides a feasible avenue to curb glioma spread in the brain through impaired focal adhesion as well as blunting mitochondrial glucose metabolism.
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Damodharan, Sudarshawn, Jeffrey Helgager, and Diane Puccetti. "INNV-13. INDOLENT H3 K27-ALTERED DIFFUSE MIDLINE GLIOMA." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii143. http://dx.doi.org/10.1093/neuonc/noac209.553.
Abstract:
Abstract INTRODUCTION H3 K27-altered diffuse midline glioma (DMG) is an aggressive central nervous system tumor that is universally fatal with a median survival of 8-12 months after diagnosis. Here we present a patient who was incidentally found to have a lesion within the right thalamus on brain magnetic resonance imaging (MRI). Twelve years later, she was found to have a brain mass within the same area with pathology consistent with an H3 K27-altered DMG. Case Description: A 14-year-old female presented with new onset left sided numbness and weakness, blurry vision and a right sided temporal headache. Her past medical history is significant for severe persistent asthma and anoxic brain injury secondary to a cardiopulmonary arrest at 2-years-of-age due to an asthma exacerbation. She has had multiple MRIs of her brain since her initial insult which initially showed the presence of a T2/FLAIR hyperintense lesion within the right medial thalamus in addition to chronic central nervous system changes. The right thalamic lesion was stable in size between images obtained at 2-years and 4-years of age. Her current physical exam is significant for decreased strength to her left upper and lower extremities. Brain MRI with and without contrast is obtained, demonstrating partial effacement of the third ventricle due to mass effect from an enlarging mass from the right thalamus. Biopsy of the lesion demonstrated an H3 K27-altered DMG, WHO grade 4. Our patient went on to receive palliative radiation therapy with 59.4 Gy over 33 fractions. DISCUSSION This case illustrates an unusual presentation of an H3 K27-altered DMG with an indolent course, diagnosed twelve years after the initial MRI finding. This proposes the possibility of multiple factors playing a role in the oncogenesis of these aggressive tumors and that further research is warranted.
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Paul, Sonal, Nitin M. Gadgil, and Chetan Chaudhari. "Diffuse Midline Glioma (H3K27M mutant) in Adult: A Diagnostic Challenge." Annals of Pathology and Laboratory Medicine 7, no. 10 (October 29, 2020): C123–127. http://dx.doi.org/10.21276/apalm.2851.
Abstract:
Introduction: Diffuse midline glioma (DMG), H3K27M mutant is an infiltrative midline high grade glioma with predominantly astrocytic differentiation and K27M mutation in either H3F3A or HIST1H3B/C.
Case Report: A 45-year-old female presented with complaints of headache and memory loss for 3 months. MRI was suggestive of an infiltrative mass lesion in the quadrigeminal plate cistern suggestive of pineal neoplasm. Squash and histomorphology showed a low-grade astrocytic tumour with infiltrative growth pattern. Microvascular proliferation and necrosis were absent. Immunohistochemistry showed loss of ATRX protein, focal positivity for p53 proteinand IDH1R132H negativity. On molecular analysis, H3K27M mutation was noted and the case was labelled as DMG H3K27Mmutant (WHO IV)
Conclusion: DMG (H3K27M) is a newly added entity in the WHO 4th revised editionof 2016. It presents with a diagnostic challenge as it has varied histomorphology, not requiring atypia, mitosis, endothelial hyperplasia and necrosis for diagnosis as Grade IV.
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Tsoli, Maria, Caitlin Ung, Dannielle H. Upton, Pooja Venkat, Antonietta Salerno, Ruby Pandher, Chelsea Mayoh, Orazio Vittorio, and David S. Ziegler. "DIPG-35. OVERCOMING THE BLOOD-BRAIN BARRIER CHALLENGE IN DIFFUSE MIDLINE GLIOMA." Neuro-Oncology 26, Supplement_4 (June 18, 2024): 0. http://dx.doi.org/10.1093/neuonc/noae064.088.
Abstract:
Abstract Diffuse midline gliomas (DMGs) are aggressive paediatric brainstem tumours with no known cure. The development of effective treatments is greatly impeded by the failure of most anti-tumour agents to penetrate the blood-brain barrier (BBB). Our research, along with that of others, has revealed that the BBB remains intact in DMG. We employed DMG orthotopic models to explore potential region-specific variations in response to the therapeutic agent temsirolimus as well as confocal microscopy and single-cell RNA sequencing (scRNAseq) to elucidate the impact of DMGs on brain endothelial morphology and pathways governing BBB integrity. We first assessed the effectiveness of the mTOR inhibitor temsirolimus when administered in cortex-injected DMG models compared to brainstem-injected DMG. We found significantly increased survival rates, elevated temsirolimus levels, and reduced tumour cell proliferation in the cortex versus the brainstem. Confocal imaging analysis indicated no structural differences between DMG and Matrigel-injected animals. However, scRNAseq unveiled distinct transcriptomic changes: brainstem-injected DMG exhibited downregulation of genes related to inflammatory and apoptotic pathways, whereas cortex-injected DMG showed downregulation of interferon pathways. To overcome the tightened barrier in the brainstem, we explored three MCL1 inhibitors and SNGR-TNFa (targeting CD13) as potential blood-brain barrier modulators. These inhibitors significantly reduced transendothelial electrical resistance, increased tracer dye leakage in an in vitro DMG BBB model, and decreased the protein expression of claudin-5. Moreover, in vivo, we found that administration of a single dose of either SNGR-TNFa or the MCL1 inhibitor S63845 improved penetration of Texas-Red (3KDa) in DMG-engrafted animals, indicating the effective opening of the BBB. In summary, our study revealed that DMG directly affects BBB pathways in endothelial cells, tightening the barrier and reducing treatment efficacy. MCL1 inhibitors and SNGR-TNFa show promise in modulating the BBB and have the potential to enhance therapeutic activity.
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Nduom, Edjah K., John Glod, Desmond A. Brown, Margaret Fagan, Mahalia Dalmage, John Heiss, Seth M. Steinberg, Cody Peer, William D. Figg, and Sadhana Jackson. "Clinical protocol: Feasibility of evaluating abemaciclib neuropharmacokinetics of diffuse midline glioma using intratumoral microdialysis." PLOS ONE 18, no. 9 (September 8, 2023): e0291068. http://dx.doi.org/10.1371/journal.pone.0291068.
Abstract:
Diffuse midline gliomas (DMG) are the most aggressive brain tumors of childhood and young adults, with documented 2-year survival rates <10%. Treatment failure is due in part to the function of the BBB. Intratumoral microdialysis sampling is an effective tool to determine brain entry of varied agents and could help to provide a better understanding of the relationship of drug permeability to DMG treatment responsivity. This is a non-randomized, single-center, phase 1 clinical trial. Up to seven young adult (18–39 years) patients with recurrent high-grade or diffuse midline glioma will be enrolled with the goal of 5 patients completing the trial over an anticipated 24 months. All patients will take abemaciclib pre-operatively for 4.5 days at twice daily dosing. Patients will undergo resection or biopsy, placement of a microdialysis catheter, and 48 hours of dialysate sampling coupled with timed plasma collections. If intratumoral tumor or brain dialysate sampling concentrations are >10nmol/L, or tumor tissue studies demonstrate CDK inhibition, then restart of abemaciclib therapy along with temozolomide will be administered for maintenance therapy and discontinued with evidence of radiologic or clinical disease progression. The poor survival associated with diffuse midline gliomas underscore the need for improved means to evaluate efficacy of drug delivery to tumor and peritumoral tissue. The findings of this novel study, will provide real-time measurements of BBB function which have the potential to influence future prognostic and diagnostic decisions in such a lethal disease with limited treatment options. Trial registration: Clinicaltrials.gov, NCT05413304. Registered June 10, 2022, Abemaciclib Neuropharmacokinetics of Diffuse Midline Glioma Using Intratumoral Microdialysis.
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Ciani, Ludovica, Sandra Laternser, Bettina Kritzer, Kerstin Hasler, Justyna M. Przystal, Mohana R. Velagapudi, Marta M. Alonso, Marta Zalacain, Sabine Müller, and Javad Nazarian. "DIPG-22. TRIPTOLIDE AS A POTENTIALLY PROMISING THERAPY FOR DIFFUSE MIDLINE GLIOMA." Neuro-Oncology 25, Supplement_1 (June 1, 2023): i17. http://dx.doi.org/10.1093/neuonc/noad073.069.
Abstract:
Abstract Diffuse Midline Gliomas (DMG) are amongst the most lethal pediatric brain tumors. Children diagnosed with DMG face a grim prognosis of 9-11 months from diagnosis. Over 85% of DMG patients harbor mutation affecting histone-encoding genes (H3.1K27M, H3.3K27M) leading to genome hypomethylation and transcriptional disruption. Despite decades of clinical studies, the development of an effective therapy remains a challenge. Triptolide is a diterpenoid triepoxide compound inhibiting cell growth and exhibiting preclinical antitumor activity. A large drug screen conducted by the NCI using DMG cell lines identified triptolide as a candidate for reducing DMG cell viability. To further investigate triptolide and its potential for clinical intervention, we used DMG preclinical in vitro and in vivo models. In vitro viability assays with triptolide alone and in combination with other therapeutic drugs (ONC201 and ONC206), were carried out using seven DMG cell lines. Single treatment with triptolide resulted in a significant decrease in DMG cell viability and combination with both ONC201 and ONC206 showed additivity. Triptolide’s toxicity was assessed in vivo through direct injections into the yolk sac of zebrafish. Preliminary data demonstrated how triptolide has higher toxicity compared to un-injected and DMSO control groups. However, a major limitation of triptolide’s clinical utility is its low solubility. Therefore, for in vivo studies, we used minnelide, a water-soluble analog of triptolide, with potent antitumor properties. Studies were performed in eleven RAG2 female mice. PDX tumor-bearing mice were treated with minnelide and ONC201 for three weeks as single or in combination. Survival studies showed no significance in minnelide monotherapy. However, minnelide + ONC201 combination therapy resulted in significant (p=0.01) survival of PDX models. Our current studies investigate the efficacy of a higher dose of minnelide in vivo. Our goal is to establish minnelide potential as a combination strategy for the treatment of children diagnosed with DMG.
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Neyazi, Sina, Pruthvi Gowda, Stephen C. Frederico, Cuong M. Nguyen, Maria C. Trissal, Erika P. Portero, John-Paul Haley-Read, et al. "DIPG-14. METABOLIC REPROGRAMMING AS A RESISTANCE MECHANISM IN DIFFUSE MIDLINE GLIOMA." Neuro-Oncology 26, Supplement_4 (June 18, 2024): 0. http://dx.doi.org/10.1093/neuonc/noae064.067.
Abstract:
Abstract BACKGROUND Diffuse midline gliomas (DMG) are uniformly fatal pediatric brain cancers, refractory to current standards of care. Based on genomic and transcriptomic profiling data, we previously proposed that platelet-derived growth factor receptor alpha (PDGFRA) is crucial to the tumorigenic potential and maintenance of stem-like DMG cells and that targeting PDGFRA is an important therapeutic avenue in DMG. In comprehensive pre-clinical studies, we identified avapritinib, an FDA-approved PDGFRA inhibitor, to be highly effective in patient-derived xenograft (PDX) DMG models. We further reported the first clinical experience using avapritinib in recurrent DMG and demonstrated preliminary safety, tolerability, and efficacy of the drug in this population. While a subset of patients experienced a strong clinical response from avapritinib, tumor progression was eventually observed in all patients. METHODS Here, we investigated the molecular mechanisms that DMG cells upregulate following avapritinib treatment, with the aim to exploit them therapeutically. To uncover these mechanisms, we performed transcriptomic, metabolic and functional assays along with a combinatorial drug screening. RESULTS Transcriptional analysis of patient-derived DMG cell lines revealed an upregulation of genes associated with fatty acid metabolism and oxidative phosphorylation (OXPHOS) following treatment with avapritinib. Functional assays confirmed elevated OXPHOS in avapritinib-treated cells with significant (i) increase in mitochondrial energy transduction, (ii) increase in palmitate- (a product of fatty acid metabolism) driven oxygen consumption rate and (iii) greater incorporation of palmitate-derived carbons into the tricarboxylic acid cycle. To determine which therapies could target this dependency on OXPHOS and fatty acid metabolism, we performed a metabolic drug screening in patient-derived DMG cell lines and identified two metabolic drugs to have synergistic cytotoxic effects with avapritinib. CONCLUSION We revealed distinct metabolic reprogramming in avapritinib-treated DMG cells and showed that targeting these metabolic vulnerabilities might further increase the clinical benefit of PDGFRA inhibitor avapritinib.
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Damodharan, Sudarshawn, Peter Favreau, Connie Lebakken, and Mahua Dey. "BIOL-19. DIFFUSE MIDLINE GLIOMA CEREBRAL ORGANOID MODEL AND MULTIOMICS CHARACTERIZATION." Neuro-Oncology 25, Supplement_1 (June 1, 2023): i10. http://dx.doi.org/10.1093/neuonc/noad073.038.
Abstract:
Abstract Diffuse midline glioma (DMG) are highly aggressive malignancies of the central nervous system that primarily affect the pediatric population. These tumors are historically universally fatal with no curative treatment options available. There is a need to identify more targeted and optimal treatments for these patients. Current approaches to pre-clinical therapeutic testing have been limited by many obstacles to effectively translate theses to patients. It is known that the interactions between tumors and the other components of the tumor microenvironment (TME) can change the response to therapeutic interventions. This especially holds true for brain tumors and the complex neural network encompassed within their TME. Given this, it is crucial to develop more realistic DMG models that integrate this to conduct therapeutic testing rather than relying upon conventional cell culture models. The goal of our study was to develop a three-dimensional DMG cerebral organoid model derived from human induced pluripotent stem cells (iPSCs) co-cultured with three different DMG patient-derived xenograft (PDX) cell lines to better mimic the TME for therapeutic testing. We were able to successfully integrate our three cell lines into the cerebral organoids, capturing TME interactions along with performing multiomic profiling for better characterization. We next plan to perform therapeutic testing to further validate the model and improve preclinical drug screening for DMG.
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Knowles, Truman, Tina Huang, Shejuan An, Jin Qi, and Amanda Muhs Saratsis. "134 LIN28B as a Novel Therapeutic Target in Diffuse Midline Glioma." Neurosurgery 70, Supplement_1 (April 2024): 28–29. http://dx.doi.org/10.1227/neu.0000000000002809_134.
Abstract:
INTRODUCTION: Diffuse midline glioma (DMG) is the most lethal of all childhood cancers. LIN28B is a RNA binding protein expressed in a variety of cancers, which suppresses the let-7 family of microRNAs, which in turn suppresses a plethora of oncogenes. However, the role of LIN28B in DMG has not yet been explored. METHODS: All studies were performed on DMG cell lines (n = 6) and controls (normal human astrocytes n = 1, human neural stem cells n = 1). RNA-Seq was performed using single-read sequencing at 50bp on the Illumina NextSeq 500 Sequencing System. Cells were then treated with DMSO or the LIN28B inhibitor, LI71, and submitted to functional in vitro studies, as well as RNA-Seq and Western Blot analysis. Functional pathways analysis was subsequently performed on resulting gene expression values with Ingenuity Pathways Analysis (Qiagen). RESULTS: Differential LIN28B expression was demonstrated across cell lines, with DMG cells expressing greater LIN28B gene and protein levels compared to controls. LIN28B inhibition with small molecule inhibitor LI71 resulted in decreased cell proliferation and migration, in vitro. A total of 946 differentially expressed genes were identified between treatment groups (FC >2 or <-2, p < 0.05). Functional pathways analysis of differentially expressed genes implicated Cancer and Neurological Disease as the top disease processes, with Cellular Movement as the top molecular process in cell lines expressing LIN28B. Further, inactivation of Myc signaling was implicated in cells treated with LI71. CONCLUSIONS: Our data demonstrates increased LIN28B expression in DMG cell lines compared with controls, with oncogenic effects on cell proliferation and migration. Further investigation of the LIN28B-let7 signaling axis is warranted in order to further explore LIN28B as a novel therapeutic target in DMG.
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Mobark, Nahla Ali, Musa Alharbi, Yasser S. Bayoumi, Aymn Albanyan, Ali Abdullah O. Balbaid, Wael abdel Rahman Aljabarat, and Malak Abedalthagafi. "DIPG-35. Personalized treatment for molecularly heterogeneous Diffuse midline glioma, H3 k27-altered Paediatric case." Neuro-Oncology 24, Supplement_1 (June 1, 2022): i26. http://dx.doi.org/10.1093/neuonc/noac079.092.
Abstract:
Abstract Diffuse midline glioma, H3 k27-altered (DMG) is a type of Paediatric- type diffuse high grade gliomas according to the 2021 WHO CNS tumors Classification. Diffuse intrinsic pontine glioma (DIPG) is another acceptable related term when it located in the pons with fatal prognosis. The combination of H3K27M with BRAF V600 mutations rarely reported in DMG although more commonly in Paediatric-type low grade gliomas (Diffuse low-grade glioma, MAPK pathway-altered). We present a twenty-month-old boy, previously healthy, presented with 2 weeks history of unsteady gait, drooling, cranial nerves palsy MRI imaging showed diffuse pontine mass with classic radiological features of DIPG. 2.6 x 1.6 x 3.2 (AP x TV x CC) with no evidence for spinal metastases. Patient underwent right retro sigmoid approach and open biopsy of lesion he received focal Radiation Therapy 54GY/30fx as stander of care of DIPG with mild neurogical improvement Pathological & molecular Diagnosis was Diffuse midline glioma, H3 k27-altered with Co-occurrence BRAF V600E mutation. Two months after end of radiation, he presented with vomiting, and neurological deterioration with new right-side hemiplegia. Imaging studies showed interval increase in the pontine lesion with increased edema causing narrowing of the fourth ventricle, no active hydrocephalus. He was started on combination therapy BRAF inhibitor Dabrafenib and MEK Inhibitor Trametinib as maintenance therapy the patient gradually showed Marked neurological and clinical improvement. A 6-month MRI after start of targeted therapy showed favorable treatment response with complete resolution of the previous diffusion restriction, reduced tumor volume on MR perfusion ,reduced perilesional edema otherwise almost stabilization of nonenhancing pontine lesion. The poor prognosis of recurrent DIPG is well known but our patient is clinically and radiologically stable with excellent quality of life and well tolerating the therapy . Our case show that personalized treatment approach that address molecular heterogeneity of H3K27M glioma are safe and feasible
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Tzaridis, Theophilos, Tanja Eisemann, Augusto Faria Andrade, Jennifer L. Hope, Oren Becher, Nada Jabado, Linda M. Bradley, Peter Adams, and Robert Wechsler-Reya. "Abstract 2648: CD155 regulates cell growth and immune evasion in diffuse midline glioma." Cancer Research 84, no. 6_Supplement (March 22, 2024): 2648. http://dx.doi.org/10.1158/1538-7445.am2024-2648.
Abstract:
Abstract There is an unmet need for effective treatment strategies for diffuse midline glioma (DMG), a devastating brain tumour arising in children and young adults. While immunotherapy is emerging as a powerful approach for treatment of other cancers, clinical trials with immune checkpoint inhibitors have failed to show a survival benefit for DMG patients. In this study, we analysed the expression of known immune checkpoint molecules on the surface of human and murine DMG cells by flow cytometry and identified CD155 and B7-H3 as the most highly expressed checkpoint molecules, with minimal expression of others, including PD-L1 and PD-L2. These findings were confirmed in primary patient samples from pediatric brain tumours (gliomas, medulloblastomas and ependymomas). To test whether CD155 regulates susceptibility to CD8+ T cell killing, we cultured murine DMG cells expressing ovalbumin (OVA) with CD8+ T cells from OT-I mice, which express T cell receptors specific for OVA. shRNA mediated silencing of CD155 led to a strong increase in T cell-mediated killing. In vivo, adoptive transfer of OT-I T cells into OVA-positive DMG-bearing immuno-compromised mice resulted in delayed tumour growth, and this effect was enhanced when tumours lacked CD155. Strikingly, CD155-deficient DMG cells failed to grow at all in immuno-competent mice, and depletion of CD8 T cells allowed these tumours to grow, highlighting a role for CD8 T cells in rejection of CD155-deficient cells. In addition to its effects on susceptibility to T cells, CD155 also exerted cell-autonomous effects on tumour cells: silencing of CD155 led to induction of apoptosis of DMG cells in vitro and to delayed tumour growth in vivo, even in immune-compromised mice. These studies demonstrate that CD155 functions as an immune checkpoint and as a regulator of tumour cell survival in DMG, and suggest that targeting CD155 could be a valuable double-pronged therapeutic strategy for this devastating disease. Citation Format: Theophilos Tzaridis, Tanja Eisemann, Augusto Faria Andrade, Jennifer L. Hope, Oren Becher, Nada Jabado, Linda M. Bradley, Peter Adams, Robert Wechsler-Reya. CD155 regulates cell growth and immune evasion in diffuse midline glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2648.
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Jackson, Sadhana, John Glod, Cody Peer, William Figg, Mahalia Dalmage, and Desmond Brown. "TRLS-02. FEASIBILITY OF EVALUATING ABEMACICLIB NEUROPHARMACOKINETICS OF DIFFUSE MIDLINE GLIOMA USING INTRATUMORAL MICRODIALYSIS." Neuro-Oncology 25, Supplement_1 (June 1, 2023): i79. http://dx.doi.org/10.1093/neuonc/noad073.305.
Abstract:
Abstract BACKGROUND Diffuse midline gliomas (DMG) are the most aggressive brain tumors of childhood and young adults, with documented 2-year survival rates <10%. Treatment failure is due in part to the function of the BBB. Intratumoral microdialysis sampling is an effective tool to determine brain entry of varied agents and could help to provide a better understanding of the relationship of drug permeability to DMG treatment response. METHODS This is a non-randomized, single-center, phase 1 clinical trial. Up to seven young adult (18-39 years) patients with recurrent high-grade or diffuse midline glioma will be enrolled with the goal of 5 patients completing the trial over an anticipated 24 months. All patients will take abemaciclib pre-operatively for 4.5 days at twice daily dosing. Patients will undergo resection or biopsy, placement of a microdialysis catheter, and 48 hours of dialysate sampling coupled with timed plasma collections. If intratumoral tumor or brain dialysate sampling concentrations are >10nmol/L, or tumor tissue studies demonstrate CDK inhibition, then restart of abemaciclib therapy along with temozolomide will be administered for maintenance therapy and discontinued with evidence of radiologic or clinical disease progression. DISCUSSION The poor survival associated with diffuse midline gliomas underscore the need for improved means to evaluate efficacy of drug delivery to tumor and peritumoral tissue. The findings of this novel study, will provide real-time measurements of BBB function which have the potential to influence future prognostic and diagnostic decisions in such a lethal disease with limited treatment options. TRIAL REGISTRATION: Clinicaltrials.gov, NCT05413304. Registered June 10, 2022, Abemaciclib Neuropharmacokinetics of Diffuse Midline Glioma Using Intratumoral Microdialysis; https://clinicaltrials.gov/ct2/show/NCT05413304?term=22c0003&draw=2&rank=1
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Messinger, Dana, Micah Harris, Jessica Cummings, Chase Thomas, Tao Yang, Stefan Sweha, Rinette Woo, et al. "CSIG-09. THERAPEUTIC TARGETING OF PRENATAL PONTINE ID1 SIGNALING IN DIFFUSE MIDLINE GLIOMA." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii40. http://dx.doi.org/10.1093/neuonc/noac209.158.
Abstract:
Abstract Diffuse midline gliomas (DMG) are highly invasive brain tumors with rare survival beyond two years past diagnosis. The mechanism behind tumor invasion is currently not well understood. Previous reports demonstrate upregulation of the protein ID1 with H3K27M and ACVR1 mutations in DMG, but this has not been confirmed in human tumors or therapeutically targeted. Whole exome, RNA, and ChIP-sequencing were performed on the ID1 locus in DMG tissue. Scratch-assay migration and transwell invasion assays of cultured cells were performed following shRNA-mediated ID1-knockdown. In vitro and in vivo genetic and pharmacologic [cannabidiol (CBD)] inhibition of ID1 on DMG tumor growth was assessed. Additional in vitro experiments were performed to determine a potential mechanism of action for CBD-mediated effects. Self-reported CBD dosing information was collected from DMG patients. We found that increased ID1 expression in human DMG and in utero electroporation (IUE) murine tumors is associated with H3K27M mutation and brainstem location. ChIP-sequencing indicates a similar epigenetically active state at ID1 regulatory regions in human H3K27M-DMG tumors and prenatal pontine cells. Higher ID1-expressing astrocyte-like DMG cells share a transcriptional program with oligo/astrocyte-precursor cells (OAPCs) from the developing human brain and demonstrate upregulation of the migration regulatory protein SPARCL1. Genetic and pharmacologic (CBD) suppression of ID1 decreases tumor cell migration, tumor growth, and to a lesser extent invasion in both murine IUE and multiple patient-derived in vivo DMG models, improving mouse survival. ID1 knockdown significantly decreases the effect of CBD on migration, tumor growth, and invasion. CBD increases reactive oxygen species production, which also affects DMG cell proliferation in a non-ID1 mediated manner. Overall, we find that H3K27M-mediated reactivation of ID1 in DMG results in a SPARCL1+ migratory transcriptional program that is therapeutically targetable with CBD.
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Tanaka, Shota, Shunsaku Takayanagi, Yuki Shinya, Mariko Kawashima, Masahiro Shin, Hirofumi Nakatomi, and Nobuhito Saito. "DIPG-17. BIOPSY-PROVEN DIFFUSE MIDLINE GLIOMA IN ADOLESCENTS AND YOUNG ADULTS." Neuro-Oncology 22, Supplement_3 (December 1, 2020): iii290. http://dx.doi.org/10.1093/neuonc/noaa222.067.
Abstract:
Abstract INTRODUCTION Diffuse midline glioma (DMG) mostly affects young children. The newly-introduced disease entity DMG, H3K27M-mutant uniformly portends poor prognosis, and therefore that in the pons is usually treated based upon radiological diagnosis without histological confirmation. DMG is rarer in adolescents and young adults (AYA), and remains poorly characterized. In this study, we sought to investigate the clinical, pathological, and molecular profiles of DMG in AYA generation. METHODS Patients of age between 16 and 39 undergoing biopsy at the University of Tokyo Hospital between 2003 and 2019 were included in the study. Clinical data and images were retrospectively reviewed. Genetic analyses were performed in cases with abundant tissues. RESULTS Ten patients included 8 brainstem and 2 thalamic DMG. The median age was 25 years (range, 19–38). Pathological diagnosis was DMG, H3K27M-mutant in 3 patients, glioblastoma, IDH-mutant in 1, anaplastic astrocytoma, IDH-wildtype in 4, diffuse astrocytoma, IDH-mutant in 1, and diffuse astrocytoma, IDH-wildtype in 1. Genetic analyses detected H3F3A-K27M mutation in 2, HIST1H3B-K27M mutation in 1, IDH1-R132H mutation in 1, and IDH1-R132S mutation in 1. With a median follow-up of 23 months (range, 2–61), only 3 patients died 29–61 months after diagnosis, and the remaining 7 patients survived for 2–59 months. Neither IDH1 mutation nor H3K27M mutation was associated with survival in this series. CONCLUSION Survival of AYA patients with DMG was seemingly variable with some long survivors. H3K27M mutation was present in a subset of patients. A further study is warranted to correlate molecular profile with clinical pictures including patient survival.
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Tomita, Yusuke, Nozomu Takata, and Oren Becher. "10084-TB-2 IN VITRO CHARACTERIZATION OF COMBINATION THERAPY IN GENETICALLY-ENGINEERED MURINE DIFFUSE MIDLINE GLIOMA MODELS." Neuro-Oncology Advances 5, Supplement_5 (December 1, 2023): v10. http://dx.doi.org/10.1093/noajnl/vdad141.038.
Abstract:
Abstract BACKGROUND Diffuse midline glioma (DMG) is an incurable pediatric brain cancer without a FDA-approved drug that prolongs survival. Recent molecular analyses have suggested the potential efficacy of CDK4/6 inhibitors and MEK inhibitors. We recently established a genetically engineered murine DMG model that could capitulate the characteristics of human DMG. Here, we evaluated the features of DMG cells and the efficacy of the CDK4/6 inhibitor ribociclib and the MEK inhibitor trametinib in vitro. METHODS We used the RCAS/Tv-a avian retroviral system to generate DMG in Nestin-expressing progenitors in the neonatal mouse brainstem. We dissociated the DMG tissue to single cells and conducted the spheroid culture. We incubated the DMG cells with a hindbrain organoid to evaluate invasiveness. We treated the DMG cells with CDK4/6 inhibitor ribociclib and MEK inhibitor trametinib to evaluate the synergistic effect. RESULTS Induction of PDGF-A overexpression, H3.3K27M mutation, and p53 deletion resulted in gliomas in murine brainstem. Median survival of the murine DMG model was 62.5 days. From the DMG tissue, we successfully established the DMG cell line with spheroid culture. By incubating with the organoid, DMG cells could invade into the organoid. There was a mild synergistic effect with ribociclib and trametinib both in the cytotoxicity assay and the TUNEL apoptosis assay. CONCLUSIONS We could establish the DMG cell line that maintained the proliferative capability and invasiveness.
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Knowles, Truman, Tina Huang, Jin Qi, Shejuan An, Noah Burket, Scott Cooper, Javad Nazarian, and Amanda M. Saratsis. "LIN28B and Let-7 in Diffuse Midline Glioma: A Review." Cancers 15, no. 12 (June 19, 2023): 3241. http://dx.doi.org/10.3390/cancers15123241.
Abstract:
Diffuse midline glioma (DMG) is the most lethal of all childhood cancers. DMGs are driven by histone-tail-mutation-mediated epigenetic dysregulation and partner mutations in genes controlling proliferation and migration. One result of this epigenetic and genetic landscape is the overexpression of LIN28B RNA binding protein. In other systems, LIN28B has been shown to prevent let-7 microRNA biogenesis; however, let-7, when available, faithfully suppresses tumorigenic pathways and induces cellular maturation by preventing the translation of numerous oncogenes. Here, we review the current literature on LIN28A/B and the let-7 family and describe their role in gliomagenesis. Future research is then recommended, with a focus on the mechanisms of LIN28B overexpression and localization in DMG.
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Pal, Sharmistha, Jakub P. Kaplan, Sylwia A. Stopka, Michael S. Regan, Bradley R. Hunsel, Benjamin H. Kann, Nathalie Y. R. Agar, et al. "DDRE-32. THERAPEUTIC TARGETING OF A NOVEL METABOLIC ADDICTION IN DIFFUSE MIDLINE GLIOMA." Neuro-Oncology Advances 3, Supplement_1 (March 1, 2021): i13. http://dx.doi.org/10.1093/noajnl/vdab024.054.
Abstract:
Abstract Diffuse midline glioma (DMG) is a uniformly fatal pediatric cancer that is in need of urgent “outside the box” therapeutic approaches. Recent studies show that tumor cells adapt to stresses created by oncogenic mutations and these oncogene-induced adaptations create vulnerabilities that can be exploited to therapeutic ends. To uncover these oncogene-induced vulnerabilities in DMGs we conducted a genome-wide CRIPSR knockout screen in three DMG lines. The top common DMG dependency pathway that we discovered is de novo pyrimidine biosynthesis. Under normal conditions pyrimidine nucleotide needs are met through the salvage pathway. However, in DMG tumorigenesis, pyrimidine nucleotide synthesis is rewired such that the cells become dependent on the de novo biosynthesis pathway. De novo pyrimidine synthesis is catalyzed by CAD, DHODH and UMPS; all three genes are identified as dependencies in our screen and have been validated using shRNA mediated gene knockdown. Interestingly, DMG cells did not exhibit a dependency on the de novo purine biosynthesis pathway. Using a small molecule inhibitor of DHODH, BAY2402234 [currently studied in phase I trial for myeloid malignancies (NCT03404726)], we have demonstrated and validated, (i) efficacy and specificity of de novo pyrimidine synthesis inhibition in vitro in DMG cells; (ii) de novo pyrimidine addiction is not attributable to cell proliferation; (iii) DHODH inhibition induces apoptosis by hindering replication and inciting DNA damage; (iv) DHODH and ATR inhibition act synergistically to induce DMG cell death; and (v) critical in vivo efficacy. The in vivo experiment documents that BAY2402234 crosses the blood-brain barrier, is present in the brain at therapeutically relevant concentrations, suppresses de novo pyrimidine biosynthesis in intracranial DMG tumors in mice, and prolongs survival of orthotopic DMG tumor bearing mice. Taken together, our studies have identified a novel metabolic vulnerability that can be translated for the treatment of DMG patients.
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Findlay, Izac J., Geoffry N. De Iuliis, Ryan J. Duchatel, Evangeline R. Jackson, Nicholas A. Vitanza, Jason E. Cain, Sebastian M. Waszak, and Matthew D. Dun. "Pharmaco-proteogenomic profiling of pediatric diffuse midline glioma to inform future treatment strategies." Oncogene 41, no. 4 (November 10, 2021): 461–75. http://dx.doi.org/10.1038/s41388-021-02102-y.
Abstract:
AbstractDiffuse midline glioma (DMG) is a deadly pediatric and adolescent central nervous system (CNS) tumor localized along the midline structures of the brain atop the spinal cord. With a median overall survival (OS) of just 9–11-months, DMG is characterized by global hypomethylation of histone H3 at lysine 27 (H3K27me3), driven by recurring somatic mutations in H3 genes including, HIST1H3B/C (H3.1K27M) or H3F3A (H3.3K27M), or through overexpression of EZHIP in patients harboring wildtype H3. The recent World Health Organization’s 5th Classification of CNS Tumors now designates DMG as, ‘H3 K27-altered’, suggesting that global H3K27me3 hypomethylation is a ubiquitous feature of DMG and drives devastating transcriptional programs for which there are no treatments. H3-alterations co-segregate with various other somatic driver mutations, highlighting the high-level of intertumoral heterogeneity of DMG. Furthermore, DMG is also characterized by very high-level intratumoral diversity with tumors harboring multiple subclones within each primary tumor. Each subclone contains their own combinations of driver and passenger lesions that continually evolve, making precision-based medicine challenging to successful execute. Whilst the intertumoral heterogeneity of DMG has been extensively investigated, this is yet to translate to an increase in patient survival. Conversely, our understanding of the non-genomic factors that drive the rapid growth and fatal nature of DMG, including endogenous and exogenous microenvironmental influences, neurological cues, and the posttranscriptional and posttranslational architecture of DMG remains enigmatic or at best, immature. However, these factors are likely to play a significant role in the complex biological sequelae that drives the disease. Here we summarize the heterogeneity of DMG and emphasize how analysis of the posttranslational architecture may improve treatment paradigms. We describe factors that contribute to treatment response and disease progression, as well as highlight the potential for pharmaco-proteogenomics (i.e., the integration of genomics, proteomics and pharmacology) in the management of this uniformly fatal cancer.
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Oza, Viral, Shilpa Sampathi, Yelena Chernyavskava, Kenan Flores, and Jessica Blackburn. "Abstract 1126: Extracellular vesicle mediated radioresistance in H3K27M-diffuse midline glioma." Cancer Research 84, no. 6_Supplement (March 22, 2024): 1126. http://dx.doi.org/10.1158/1538-7445.am2024-1126.
Abstract:
Abstract H3K27M-Diffuse Midline Gliomas (DMGs) are a subset of uncurable malignant pediatric gliomas and the deadliest form of brain tumors in children worldwide. Radiation therapy, the current standard of care, is initially effective but all tumors become resistant within 4-6 months. H3K27M-DMGs are heterogenous, comprised of an average of 6 genetically distinct subclones. Some subclones harbor mutations in genes previously linked to radiation resistance, such as TP53. We have found subclones are also functionally distinct, with some clones harboring intrinsic radiation resistance. Extracellular signaling between clones is linked with therapy resistance and tumor progression in other tumors, and we hypothesized that radioresistant H3K27M-DMG release small extracellular vesicles (sEVs) that impact the radiosensitivity of neighboring tumor cells. We found that all patient-derived H3K27M-DMG samples examined (n=6) produced sEVs (< 220nm), indicating this is a common feature in this tumor type. We isolated sEVs from a radioresistant (RR) patient-derived H3K27M-DMG cell line and used them to treat radiosensitive (RS) DMG cells. Using flow cytometry to profile sEV uptake dynamics, we found that RR-sEVs are internalized by RS cells within 2 hours of exposure and are retained at 18 hours (p<0.001, compared to control). This uptake can be significantly abrogated by proteinase K treatment of the sEVs, (p<0.001), indicating that uptake involves sEV surface proteins. We then applied a biosensor approach to assess single-cell phenotypic changes in RS DMG after RR-sEV treatment on radiation-induced cell death, DNA damage, and cell senescence, three dynamic processes. Using a genetically encoded death indicator (GEDI), we found that RR-sEVs significantly enhanced the survival of RS cells after acute radiation exposure (p<0.001). This was due to enhanced DNA damage repair as measured by 53BP1 foci (p<0.01). Small RNA sequencing of sEV cargo demonstrated that RR-sEVs express multiple miRNAs that are involved in oncogenic signaling such as the miR-7 family, miR-1246, and miR-1290 at several log fold higher than RS-sEVs. Overall, this data reveals the first functional role for sEVs in the context of radiation induced tumor transformation in DMG. We plan to further investigate the primary route of sEV uptake and define the mechanism through which sEV cargo alters radiosensitivity. This study provides new insight into the impact of heterogeneity and sEVs in mediating radioresistance in H3K27M-DMG and may lead to the development of novel radiosensitizers, which are critically needed for all patients. Citation Format: Viral Oza, Shilpa Sampathi, Yelena Chernyavskava, Kenan Flores, Jessica Blackburn. Extracellular vesicle mediated radioresistance in H3K27M-diffuse midline glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1126.
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Patel, Palak, Bharti Kukreja, Brian Kalish, Sanja Pajovic, and Cynthia Hawkins. "TMIC-77. UNVEILING THE DEPTHS: EXPLORING DIFFUSE MIDLINE GLIOMA, TUMORIGENESIS, AND RADIATION RESISTANCE." Neuro-Oncology 25, Supplement_5 (November 1, 2023): v295—v296. http://dx.doi.org/10.1093/neuonc/noad179.1142.
Abstract:
Abstract Diffuse Midline Glioma (DMG) is a highly aggressive form of brainstem cancer that primarily affects children, leading to a grim prognosis and limited treatment options. Despite extensive research efforts, many crucial aspects of DMG development and progression remain poorly understood. One significant knowledge gap lies in comprehending the invasive nature of DMG cells, which enables their escape from the primary tumor site and dissemination to other regions of the brain. Additionally, understanding the molecular basis that drives this invasive behavior is essential but remains largely unexplored, necessitating further investigation. To address these critical knowledge gaps, we have generated one of the largest single-cell multi-omic datasets ( >300,000 cells) specifically focusing on pons development in humans and its relation to DMG. This dataset provides a valuable resource for investigating the intricacies of tumorigenesis and the development of resistance to radiation therapy. Comprehensive analyses of this dataset shed light on the molecular events driving DMG progression and radiation resistance, ultimately paving the way for the discovery of novel therapeutic targets and the development of innovative strategies to combat this devastating pediatric cancer. In summary, our study aims to deepen our understanding of DMG by elucidating the mechanisms associated with histone mutations, unraveling the invasive behavior of DMG cells, and exploring the factors contributing to radiation resistance. Through these endeavors, we hope to make significant advancements in the field and improve the outcomes for patients affected by DMG.
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du Chatinier, Aimée, Michaël H. Meel, Arvid I. Das, Dennis S. Metselaar, Piotr Waranecki, Marianna Bugiani, Marjolein Breur, et al. "MODL-16. Generation of immunocompetent syngeneic allograft mouse models for pediatric diffuse midline glioma." Neuro-Oncology 24, Supplement_1 (June 1, 2022): i172. http://dx.doi.org/10.1093/neuonc/noac079.639.
Abstract:
Abstract Diffuse midline gliomas (DMG) are highly aggressive pediatric brain tumors with a grim prognosis. A lack of effective treatment options highlights the critical need to investigate new therapeutic strategies. This includes the use of immunotherapy, which has shown promise in other hard-to-treat tumors. To facilitate immunotherapeutic research in this field, and to complement the existing immunodeficient patient-derived DMG models, we developed three distinct immunocompetent mouse models representing different DMG subtypes, i.e., histone 3 wildtype and histone 3 K27M mutant DMG (H3.3K27M or H3.1K27M), that can be used for preclinical testing of new therapies. We first established primary tumor cell cultures from murine DMG tumors that were generated by brainstem-targeted intra-uterine electroporation (IUE). This method enabled the introduction of DMG-associated mutations within the intact developing brainstem, thereby generating DMG tumors in a spatially and temporally defined manner, while maintaining a genetically identical (isogenic) background. We then created allograft DMG mouse models by orthotopically implanting the established primary cell cultures into syngeneic (C57BL/6) mice. Herewith, we provide an allograft tool that is better suitable for large-scale therapeutic studies and more accessible to the scientific community. Importantly, we demonstrated that these allograft models recapitulate the histopathologic phenotype of human DMG, including their diffuse infiltrative growth and expression of DMG-associated antigens. Furthermore, CyTOF mass cytometry analysis indicated that these murine pontine tumors exhibit a tumor immune microenvironment (TIME) similar to human DMG, characterized by considerable myeloid cell infiltration and a paucity of T-lymphocytes and NK cells. As such, we provide a representative model to further delineate the immune landscape in DMG and to preclinically investigate novel (immuno)therapies. Currently, we are using these immunocompetent models to study the interaction between DMG cells and microglia, and we are investigating how we can modify the immune microenvironment to improve checkpoint inhibition in DMG.
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Moloney, Sam, Vickyanne Carruthers, Melissa J. Davis, Dharmesh D. Bhuva, Cristina Mignone, Susan Singh, Rebecca E. Gardiner, Santosh Valvi, David D. Eisenstat, and Jordan R. Hansford. "DIPG-54. PREDICTING EARLY DEATH IN DIFFUSE MIDLINE GLIOMA." Neuro-Oncology 26, Supplement_4 (June 18, 2024): 0. http://dx.doi.org/10.1093/neuonc/noae064.107.
Abstract:
Abstract BACKGROUND Diffuse midline glioma (DMG) is an invariably fatal diagnosis with a median survival of 9-11 months. While early death is uncommon, such cases do exist. Identification of children at risk of short-term survival can support clinicians to provide informed counselling to families regarding important treatment decisions. METHODS We identified patients with a radiological diagnosis of DMG at the Royal Children’s Hospital (Melbourne) and the Women’s and Children’s Hospital (Adelaide) between 2001-2023. Clinical, imaging, and histopathological data were abstracted and compared between short-term survivors (STSs) and longer survivors (LSs). RESULTS Among 89 patients included, 21 (24%) had an overall survival (OS) of < 6 months of which 7 (8%) had an OS < 3 months. 5 of these cases had dramatic early death with < 1 month since diagnosis. While neither the pattern nor presence of contrast enhancement were predictive of poor survival, STSs were found to have a larger volume of contrast enhancement on T1-weighted imaging compared to LSs (1.3 cm3 vs 0.2 cm3, p < 0.01). Evaluation of the presence and extent of intratumoural susceptibility signals (ITSS) on susceptibility weighted imaging (SWI) demonstrated higher grades of ITSS (> 5 foci) were strongly associated with poor survival (p = 0.01, median OS = 5.5 months). Furthermore, 50% (6/12) of STSs had ≥ 11 dot-like or fine linear ITSSs in a maximum tumour cross section. From a treatment standpoint, as expected, patients who did not receive upfront radiotherapy experienced significantly worse OS (3.4 months vs 10.4 months, p < 0.01). Notably, a number of STSs did not receive palliative therapy in the context of their rapid and unforeseen disease progression. CONCLUSIONS The preliminary findings from this multi-centre study provide the foundation for future exploratory analysis alongside international collaborators at the DMG/DIPG registry to improve prognostication for patients with high-risk features of early death.
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Frederico, Stephen C., Sina Neyazi, Pruthvi Gowda, Cuong Nguyen, Maria Trissal, Erika P. Portero, John-Paul Haley-Read, et al. "Revealing and targeting metabolic drivers contributing to treatment escape in diffuse midline glioma." Journal of Clinical Oncology 42, no. 16_suppl (June 1, 2024): 10038. http://dx.doi.org/10.1200/jco.2024.42.16_suppl.10038.
Abstract:
10038 Background: Diffuse midline glioma (DMG) is an aggressive pediatric brain tumor that predominately affects children, with a median survival of 9-11 months. DMGs are driven by self-renewing, stem-like glioma cells that have been stalled in an oligodendrocyte precursor cell (OPC)-like state and that highly express PDGFRA. This overexpression of PDGFRA has been shown to be pivotal in DMG development. Thus, targeting PDGFRA may serve as a viable treatment approach for DMG. In our previous studies, we revealed that avapritinib, a next generation tyrosine kinase inhibitor of PDGFRA, is highly effective in DMG cells. While a subset of patients receiving treatment with avapritinib experienced a promising clinical response, all patients eventually experienced tumor progression due to treatment escape. In this study, we investigated which mechanisms DMG cells use to escape avapritinib treatment, and how we can therapeutically exploit these resistance mechanisms. Methods: Transcriptomic profiling and functional assays were performed on patient-derived DMG cell lines. A combinatorial drug screening identified drug candidates evaluated in this study. Results: Bulk RNA sequencing analysis of two patient derived DMG cell lines revealed an upregulation of genes associated with both fatty acid metabolism and oxidative phosphorylation (OXPHOS) following avapritinib treatment. Functional assays confirmed elevated OXPHOS in avapritinib-treated cells with significant increases in mitochondrial energy transduction, palmitate- (a product of fatty acid metabolism) driven oxygen consumption rates, and incorporation of palmitate-derived carbons into the tricarboxylic acid (TCA) cycle. CRISPR-Cas9-mediated knockout of PDGFRAin one DMG cell line confirmed the metabolic changes observed following avapritinib treatment. Analysis of bulk RNA sequencing data revealed an upregulation of key fatty acid- related transcription factors in avapritinib-treated DMG cells. Specifically, Peroxisome Proliferator-Activated Receptor alpha (PPAR-alpha), Sterol Regulatory Binding Element Binding Transcription Factors 1 and 2, and Fatty Acid Synthase (FASN) were most prominently upregulated. To determine which therapies could target the dependency of avapritinib-treated cells on fatty acid metabolism, we performed a combinatorial drug screening and found three lipid pathway inhibitors that have synergistic cytotoxic effects with avapritinib. Specifically, a FASN inhibitor, cholesterol pathway inhibitor, and PPAR-alpha inhibitor. Conclusions: In this study, we revealed metabolic drivers that may contribute to avapritinib resistance in DMG cells, and identified compounds capable of inhibiting these drivers that demonstrate synergy with avapritinib. We now intend on testing these combination therapies in vivo as we aim to provide a long-term clinical benefit to DMG patients receiving avapritinib.
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Di Ruscio, Valentina, Giada Del Baldo, Francesco Fabozzi, Maria Vinci, Antonella Cacchione, Emmanuel de Billy, Giacomina Megaro, Andrea Carai, and Angela Mastronuzzi. "Pediatric Diffuse Midline Gliomas: An Unfinished Puzzle." Diagnostics 12, no. 9 (August 25, 2022): 2064. http://dx.doi.org/10.3390/diagnostics12092064.
Abstract:
Diffuse midline glioma (DMG) is a heterogeneous group of aggressive pediatric brain tumors with a fatal prognosis. The biological hallmark in the major part of the cases is H3K27 alteration. Prognosis remains poor, with median survival ranging from 9 to 12 months from diagnosis. Clinical and radiological prognostic factors only partially change the progression-free survival but they do not improve the overall survival. Despite efforts, there is currently no curative therapy for DMG. Radiotherapy remains the standard treatment with only transitory benefits. No chemotherapeutic regimens were found to significantly improve the prognosis. In the new era of a deeper integration between histological and molecular findings, potential new approaches are currently under investigation. The entire international scientific community is trying to target DMG on different aspects. The therapeutic strategies involve targeting epigenetic alterations, such as methylation and acetylation status, as well as identifying new molecular pathways that regulate oncogenic proliferation; immunotherapy approaches too are an interesting point of research in the oncology field, and the possibility of driving the immune system against tumor cells has currently been evaluated in several clinical trials, with promising preliminary results. Moreover, thanks to nanotechnology amelioration, the development of innovative delivery approaches to overcross a hostile tumor microenvironment and an almost intact blood–brain barrier could potentially change tumor responses to different treatments. In this review, we provide a comprehensive overview of available and potential new treatments that are worldwide under investigation, with the intent that patient- and tumor-specific treatment could change the biological inauspicious history of this disease.
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Parthasarathy, Akhila, Marc Garcia-Moure, Jiasen He, Dong Ho Shin, Andrew G. Gillard, Andres Lopez-Rivas, Lethan A. Hampton, et al. "DIPG-45. TARGETING HYPERACETYLATION IN PEDIATRIC DIFFUSE MIDLINE GLIOMAS USING ONCOLYTIC ADENOVIRUSES." Neuro-Oncology 26, Supplement_4 (June 18, 2024): 0. http://dx.doi.org/10.1093/neuonc/noae064.098.
Abstract:
Abstract BACKGROUND H3K27-altered pediatric diffuse midline glioma (DMG) is a highly aggressive type of brain tumor with a 5-year survival rate of less than 2%. Conventional treatments are restricted to palliative radiation therapy. Therefore, effective treatments are urgently needed. Results from a recent phase I clinical trial for Diffuse Intrinsic Pontine Glioma showed that intratumoral administration of Delta-24-RGD oncolytic adenovirus in combination with radiation improves survival without unwanted toxicity. Based on the rationale that, during infection, the early viral protein E1A binds P300, we hypothesize that combining oncolytic adenoviruses with p300 inhibitors will induce a robust modification of the post-translational landscape of DMGs and increase the anti-cancer effect of the oncolytic virus. METHODS Studies on Delta-24-RGD infectivity and replication were performed in a panel of clinically significant DMG cells. Modification of the acetylation levels of acid-extracted histones after Delta-24-RGD was analyzed using Western blot. Cell Titer Blue was utilized to measure cell viability, and ZIP-synergy scores were calculated using SynergyFinder. RESULTS We observed a time-dependent reduction in H3K27ac in human DMG cells following Delta-24-RGD infection with an 89% reduction in H3K27ac at 48h post-infection. Delta-24-RGD treatment of DMG cells resulted in optimum viral infectivity and replication. Combining Delta-24-RGD with the p300 inhibitor C646 resulted in enhanced cell death in vitro. Using a panel of oncolytic viruses that induce differential enzymatic and binding functions of P300, we showed that Delta-24-RGD mediated alteration of P300 activity is required for hypoacetylation in DMGs. We characterized the in vivo dynamics of K27M-H3.1 and K27M-H3.3 DMG-derived tumors in the brain stem of syngeneic animal models. In vivo experiments are in progress to examine the combinatorial anti-glioma effect of Delta-24-RGD and P300 inhibitors. CONCLUSION Collectively, our studies provide a strong mechanistic rationale for combining oncolytic adenoviruses and p300 inhibitors and should propel the eventual clinical testing of this approach in DMG patients.
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Gestrich, Catherine, Kristina Grieco, Hart Lidov, Keith Ligon, Sandro Santagata, Kee Kiat Yeo, Sanda Alexandrescu, and David Meredith. "DIPG-44. H3K27-altered diffuse midline gliomas with secondary driver molecular alterations." Neuro-Oncology 24, Supplement_1 (June 1, 2022): i28. http://dx.doi.org/10.1093/neuonc/noac079.101.
Abstract:
Abstract INTRODUCTION: Large-scale sequencing led to the identification of driver molecular alterations such as FGFR1 and BRAF in occasional diffuse midline gliomas (DMGs) H3K27-altered, but their significance is not completely explored. We evaluated these associations in our institutional cohorts. MATERIALS AND METHODS: We searched our sequencing data base (2013-2020) for H3K27M-mutant gliomas and analyzed the co-occurring genetic alterations. The demographics, clinical information, and pathology were reviewed. Copy number profiles were evaluated using BioDiscovery's Nexus Copy Number software package. Oncoplots and Kaplan-Meier survival curves were generated with the maftools R package. RESULTS: We identified 77 patients (age range 2-68, median 26). The diagnosis was DMG (n=55), anaplastic astrocytoma/glioblastoma (n=19), low-grade glioma (n=1), low-grade glioneuronal tumor (n=1), and ganglioglioma (n=1). Recurrent alterations were seen in TP53 (n=42), ATRX (n=17), NF1 (n=15), PDGFRA (n = 4). Five cases had BRAF V600E (1 ganglioglioma; 4 DMG); twelve had FGFR1 mutations (9 DMG; 3 anaplastic astrocytoma/glioblastoma). The most common location in the BRAF group was the brainstem and in the FGFR1 was the thalamus. Survival ranged from 0 to 97 months, median 12.9 months (28.8 months for FGFR1 and 22.8 for the BRAF V600E). This was not significantly different from OS reported in the literature for DMG.The BRAF V600E ganglioglioma patient is alive 37 months after diagnosis. CONCLUSION: There was no significant difference in outcomes for patients with secondary molecular drivers when compared with conventional H3K27M DMG. The outcome of the BRAF V600E tumors seemed to correlate with the histology. These findings and the possibility of targeted therapy argue for comprehensive sequencing of H3K27-altered gliomas.