Atrx loss as a promising screening tool for the identification of diffuse midline glioma subtype, H3K27/MAPKinase co-altered.
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SUBMITTER: Tauziede-Espariat A
PROVIDER: S-EPMC11209953 | biostudies-literature | 2024 Jun
REPOSITORIES: biostudies-literature
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Atrx loss as a promising screening tool for the identification of diffuse midline glioma subtype, H3K27/MAPKinase co-altered.
Tauziède-Espariat Arnault A Castel David D Ajlil Yassine Y Auffret Lucie L Appay Romain R Mariet Cassandra C Hasty Lauren L Métais Alice A Chrétien Fabrice F Grill Jacques J Varlet Pascale P
Acta neuropathologica communications 20240627 1
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Project description:Diffuse midline glioma with two components: classical glial and ependymal.
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Project description:BackgroundH3K27-altered diffuse midline glioma (DMG) is the deadliest pediatric brain tumor; despite intensive research efforts, every clinical trial to date has failed. Is this because we are choosing the wrong drugs? Or are drug delivery and other pharmacokinetic variables at play? We hypothesize that the answer is likely a combination, where optimization may result in a much needed novel therapeutic approach.MethodsWe used in vitro drug screening, patient samples, and shRNA knockdown models to identify an upregulated target in DMG. A single small molecule protein kinase inhibitor with translational potential was selected for systemic and direct, loco-regional delivery to patient-derived xenografts (PDX) and genetically engineered mouse models (GEMM). Pharmacokinetic studies were conducted in non-tumor bearing rats.ResultsAurora kinase (AK) inhibitors demonstrated strong antitumor effects in DMG drug screens. Additional in vitro studies corroborated the importance of AK to DMG survival. Systemic delivery of alisertib showed promise in subcutaneous PDX but not intracranial GEMM and PDX models. Repeated loco-regional drug administration into the tumor through convection-enhanced delivery (CED) was equally inefficacious, and pharmacokinetic studies revealed rapid clearance of alisertib from the brain. In an effort to increase the drug to tumor residence time, continuous CED over 7 days improved drug retention in the rodent brainstem and significantly extended survival in both orthotopic PDXs and GEMMs.ConclusionsThese studies provide evidence for increasing drug-tumor residence time of promising targeted therapies via extended CED as a valuable treatment strategy for DMG.
| S-EPMC10148679 | biostudies-literature
Project description:BackgroundDiffuse midline glioma with H3K27-altered (DMG-H3K27a) is a novel tumor entity of the pediatric-type diffuse high-grade tumor in the latest WHO CNS 5. It mostly affects children and is only rarely found in adults. The tumor has a high level of aggressiveness, with a rapid progression and bad prognosis. In adults, the spinal cord is the most common site of DMG-H3K27a. Rare adult cases of primary DMG-H3K27a in the spinal cord were reported in this study, together with clinico-histopathologico-radiographic data.MethodsFrom January 2016 to December 2020, we conducted a retrospective study of five adults with primary DMG-H3K27a in the spinal cord, analyzing their clinical, pathohistological, and radiographic datasets from the first diagnosis to follow-up.ResultsAll five patients were diagnosed for the first time and were given full treatment. In three of the five patients, post-operative follow-up revealed tumor recurrence. The longest survival of the five patients was 45 months at the time of report submission, while the longest progression-free survival (PFS) following surgery was 20 months. Immunohistochemical studies showed the tumors featured aggressive behavior (grade 4) and were positive for the H3K27M mutation. The radiographic appearances were varied, but they were all initially mistaken as benign. DMG-H3K27a in the spinal cord was characterized by isointense/hyperintense on T1WI and isointense/hyperintense on T2WI, as well as cystic necrosis and peripheral spinal cord edema, as well as central canal enlargement and other types of enhancement.ConclusionThis is the first case report focusing on adult DMG-H3K27a of the pediatric-type diffuses high-grade gliomas in the spinal cord. In our cases, we discovered the following: 1) adults had a better prognosis with a longer PFS compared with prior pediatric reports; 2) despite aggressive behavior under the microscope, radiographic appearances of the tumors were less aggressive; and 3) adjuvant treatment, including TCM, may have played a role in the prognosis.
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Project description:IntroductionDespite much progress, the prognosis for H3K27-altered diffuse midline glioma (DMG), previously known as diffuse intrinsic pontine glioma when located in the brainstem, remains dark and dismal.Areas coveredA wealth of research over the past decade has revolutionized our understanding of the molecular basis of DMG, revealing potential targetable vulnerabilities for treatment of this lethal childhood cancer. However, obstacles to successful clinical implementation of novel therapies remain, including effective delivery across the blood-brain barrier (BBB) to the tumor site. Here, we review relevant literature and clinical trials and discuss direct drug delivery via convection-enhanced delivery (CED) as a promising treatment modality for DMG. We outline a comprehensive molecular, pharmacological, and procedural approach that may offer hope for afflicted patients and their families.Expert opinionChallenges remain in successful drug delivery to DMG. While CED and other techniques offer a chance to bypass the BBB, the variables influencing successful intratumoral targeting are numerous and complex. We discuss these variables and potential solutions that could lead to the successful clinical implementation of preclinically promising therapeutic agents.
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Project description:We previously identified VRK3 as a specific vulnerability in DMG-H3K27M cells in a synthetic lethality screen targeting the whole kinome. The aim of the present study was to elucidate the mechanisms by which VRK3 depletion impact DMG-H3K27M cell fitness. Gene expression studies after VRK3 knockdown emphasized the inhibition of genes involved in G1/S transition of the cell cycle resulting in growth arrest in G1. Additionally, a massive modulation of genes involved in chromosome segregation was observed, concomitantly with a reduction in the level of phosphorylation of serine 10 and serine 28 of histone H3 supporting the regulation of chromatin condensation during cell division. This last effect could be partly due to a concomitant decrease of the chromatin kinase VRK1 in DMG following VRK3 knockdown. Furthermore, a metabolic switch specific to VRK3 function was observed towards increased oxidative phosphorylation without change in mitochondria content, that we hypothesized would represent a cell rescue mechanism. This study further explored the vulnerability of DMG-H3K27M cells to VRK3 depletion suggesting potential therapeutic combinations, e.g. with the mitochondrial ClpP protease activator ONC201.
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Project description:Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPGs), are the most lethal of all childhood cancers. Palliative radiotherapy is the only proven life-prolonging treatment, with patient survival 9-11 months. ONC201 shows preclinical and emerging clinical efficacy in DIPG. Currently, little is known about the mechanisms of sensitivity/resistance of DIPGs to ONC201, or whether recurring genomic features influence response. Using a systems-biological approach, we show ONC201 elicits potent agonism of the mitochondrial protease, CLPP, driving proteolysis of electron transport chain (ETC) and tricarboxylic acid (TCA) cycle proteins. DIPGs harboring TP53-mutations show reduced sensitivity to ONC201. Molecular mechanisms identify metabolic adaptation and resistance to ONC201 regulated by redox-activated PI3K/Akt signaling, counteracted using the brain penetrant PI3K/Akt inhibitor, paxalisib, in both wt-TP53 and TP53-mutant DIPGs. The discoveries described within, coupled with the powerful anti-DIPG/DMG pharmacokinetic and pharmacodynamic properties of ONC201 and paxalisib inform the DIPG/DMG phase II combination clinical trial NCT05009992.
2023-05-25 | PXD036245 | Pride
Project description: Not available
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Project description:H3K27M mutant (mut) diffuse midline glioma (DMG) is a lethal cancer with no effective cure. The glycosphingolipids (GSL) metabolism is altered in these tumors and could be exploited to develop new therapies. We tested the effect of the glucosylceramide synthase inhibitors (GSI) miglustat and eliglustat on cell proliferation, alone or in combination with temozolomide or ionizing radiation. Miglustat was included in the therapy protocol of two pediatric patients. The effect of H3.3K27 trimethylation on GSL composition was analyzed in ependymoma. GSI reduced the expression of the ganglioside GD2 in a concentration and time-dependent manner and increased the expression of ceramide, ceramide 1-phosphate, sphingosine, and sphingomyelin but not of sphingosine 1-phosphate. Miglustat significantly increased the efficacy of irradiation. Treatment with miglustat according to dose recommendations for patients with Niemann-Pick disease was well tolerated with manageable toxicities. One patient showed a mixed response. In ependymoma, a high concentration of GD2 was found only in the presence of the loss of H3.3K27 trimethylation. In conclusion, treatment with miglustat and, in general, targeting GSL metabolism may offer a new therapeutic opportunity and can be administered in close proximity to radiation therapy. Alterations in H3K27 could be useful to identify patients with a deregulated GSL metabolism.
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Project description:Diffuse midline gliomas (DMG) H3 K27-altered are incurable grade 4 gliomas and represent a major challenge in neuro-oncology. This tumour type is now classified in four subtypes by the 2021 edition of the WHO Classification of the Central Nervous System (CNS) tumours. However, the H3.3-K27M subgroup still appears clinically and molecularly heterogeneous. Recent publications reported that rare patients presenting a co-occurrence of H3.3K27M with BRAF or FGFR1 alterations tended to have a better prognosis. To better study the role of these co-driver alterations, we assembled a large paediatric and adult cohort of 29 tumours H3K27-altered with co-occurring activating mutation in BRAF or FGFR1 as well as 31 previous cases from the literature. We performed a comprehensive histological, radiological, genomic, transcriptomic and DNA methylation analysis. Interestingly, unsupervised t-distributed Stochastic Neighbour Embedding (tSNE) analysis of DNA methylation profiles regrouped BRAFV600E and all but one FGFR1MUT DMG in a unique methylation cluster, distinct from the other DMG subgroups and also from ganglioglioma (GG) or high-grade astrocytoma with piloid features (HGAP). This new DMG subtype harbours atypical radiological and histopathological profiles with calcification and/or a solid tumour component both for BRAFV600E and FGFR1MUT cases. The analyses of a H3.3-K27M BRAFV600E tumour at diagnosis and corresponding in vitro cellular model showed that mutation in H3-3A was the first event in the oncogenesis. Contrary to other DMG, these tumours occur more frequently in the thalamus (70% for BRAFV600E and 58% for FGFR1MUT) and patients have a longer overall survival with a median above three years. In conclusion, DMG, H3 K27 and BRAF/FGFR1 co-altered represent a new subtype of DMG with distinct genotype/phenotype characteristics, which deserve further attention with respect to trial interpretation and patient management.
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Project description:Diffuse midline glioma, H3 K27M-mutant is a lethal brain tumor located in the thalamus, brain stem, or spinal cord. H3 K27M encoded by the mutation of a histone H3 gene such as H3F3A plays a pivotal role in the tumorigenesis of this type of glioma. Although several studies have revealed comprehensive genetic and epigenetic profiling, the prognostic factors of these tumors have not been identified to date. In various cancers, oncogenic driver genes have been found to exhibit characteristic copy number alterations termed mutant allele specific imbalance (MASI). Here, we showed that several diffuse midline glioma, H3 K27M-mutant exhibited high variant allele frequency (VAF) of the mutated H3F3A gene using droplet digital polymerase chain reaction (ddPCR) assays. Whole-genome sequencing (WGS) revealed that these cases had various copy number alterations that affected the mutant and/or wild-type alleles of the H3F3A gene. We also found that these MASI cases showed a significantly higher Ki-67 index and poorer survival compared with those in the lower VAF cases (P < 0.05). Our results indicated that the MASI of the H3F3A K27M mutation was associated with the aggressive phenotype of the diffuse midline glioma, H3 K27M-mutant via upregulation of the H3 K27M mutant protein, resulting in downregulation of H3K27me3 modification.
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