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1
Liu, Ilon, Jiang Li, Daeun Jeong, Olivia A. Hack, McKenzie Shaw, Bernhard Englinger, Byron Avihai, et al. "EPCO-06. AGE- AND REGION-SPECIFIC MULTI-OMIC CHARACTERIZATION OF H3-K27M MUTANT DIFFUSE MIDLINE GLIOMA." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi2. http://dx.doi.org/10.1093/neuonc/noab196.005.
Анотація:
Abstract Diffuse midline gliomas driven by lysine27-to-methionine mutations in histone 3 (H3-K27M DMGs) are among the most fatal brain tumors. Molecular studies including single cell RNA-sequencing (scRNA-seq) of pediatric and predominantly pontine H3-K27M DMGs have shown that the H3-K27M oncohistone keeps glioma cells locked in a stem-like oligodendrocyte precursor cell (OPC) state that is capable of self-renewal and tumor-initiation. However, a comprehensive dissection of the cellular architecture of H3-K27M DMGs across different midline regions and age groups is required to better understand the cell-intrinsic and contextual regulation of H3-K27M DMG cell identities. In particular, the more recently described group of adult H3-K27M DMGs remains understudied. Here, we have collected and characterized 45 H3-K27M mutant patient tumors, spanning pontine (n=26), thalamic (n=17), and spinal (n=2) locations. Median age at surgery was 12 (2-68) years, encompassing 21 early childhood (0-10 years), 12 adolescent (11-20 years), and 12 adult (≥ 21 years) tumors. The majority of samples were obtained pre-treatment (n=28), as opposed to post-treatment or at autopsy (n=17). We profiled all 45 tumors by single cell/single nucleus RNA-seq and selected tumors were further characterized by the single cell assay for transposase-accessible chromatin (scATAC-seq). Our integrated analyses highlight the predominance of transcriptionally and epigenetically defined OPC-like tumor cells as the main cell population of H3-K27M DMGs across all age groups and locations. We further identify distinct age- and location-specific OPC-like cell subpopulations. Comparison of pediatric and adult tumors further demonstrates a significant increase of mesenchymal cell states in adult H3-K27M DMGs, which we link to differences in glioma-associated immune cell compartments between age groups. Together, this study sheds light on the effects of age- and region-dependent microenvironments in shaping cellular identities in H3-K27M DMGs.
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Liu, I., L. Jiang, E. Samuelsson, S. Marco Salas, O. Hack, D. Jeong, M. Shaw, et al. "JS04.6.A The landscape of tumor cell states and spatial organization in H3-K27M mutant diffuse midline glioma across age and location." Neuro-Oncology 24, Supplement_2 (September 1, 2022): ii7. http://dx.doi.org/10.1093/neuonc/noac174.021.
Анотація:
Abstract Background Histone 3 lysine27-to-methionine mutations (H3-K27M) frequently occur in childhood diffuse midline gliomas (DMGs) of the pons, thalamus and spinal cord, presumed to be driven by the specific spatiotemporal context of these midline locations during postnatal development. While most common in the pons and at mid-childhood ages, the same oncohistone mutation is recurrently detected in adult DMGs and throughout different midline regions. The potential heterogeneity of tumors at different ages and in different anatomical locations of the midline are vastly understudied. Material and Methods Through dissecting the transcriptomic, epigenomic and spatial architectures of a comprehensive cohort of patient H3-K27M DMGs - spanning the age range from 2-68 years and locations from spinal cord to thalamus - at single cell resolution, we delineate how age- and location-dependent contexts shape glioma cell-intrinsic and -extrinsic features in light of the shared driver mutation. Results We identify that oligodendrocyte precursor (OPC)-like cells constitute the stem-like compartment in H3-K27M DMGs across all clinico-anatomical groups, however, depending on location, display varying levels of maturity resembling less differentiated pre-OPCs or more mature OPCs further differentiated along the oligodendroglial lineage. We further demonstrate increased mesenchymal cell states in adult tumors, which we link to age-related differences in glioma-associated immune cell compartments. We for the first time resolve the spatial organization of H3-K27M DMG cell types in intact patient tissues, identifying a local niche of the oligodendroglial lineage. Conclusion Our study provides a powerful resource for rational modeling and therapeutic frameworks taking into account determinants of age and location in this lethal glioma group.
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Liu, Ilon, Li Jiang, Erik Samuelsson, Sergio Marco Salas, Alexander Beck, Olivia Hack, Daeun Jeong, et al. "DIPG-08. THE LANDSCAPE OF TUMOR CELL STATES AND SPATIAL ORGANIZATION IN H3-K27M MUTANT DIFFUSE MIDLINE GLIOMA ACROSS AGE AND LOCATION." Neuro-Oncology 25, Supplement_1 (June 1, 2023): i14. http://dx.doi.org/10.1093/neuonc/noad073.055.
Анотація:
Abstract Histone 3 lysine27-to-methionine mutations (H3-K27M) frequently occur in childhood diffuse midline gliomas (DMGs) of the pons, thalamus, and spinal cord, presumed to be driven by the specific spatiotemporal context of these midline locations during postnatal development. While most common in the pons and at mid-childhood ages, the same oncohistone mutation is recurrently detected in adult DMGs and throughout different midline regions. The potential heterogeneity of tumors at different ages and in different anatomical locations of the midline are vastly understudied. Through dissecting the transcriptomic, epigenomic and spatial architectures of a comprehensive cohort of patient H3-K27M DMGs - spanning the age range from 2-68 years and locations from spinal cord to thalamus - at single cell resolution, we delineate how age- and location-dependent contexts shape glioma cell-intrinsic and -extrinsic features in light of the shared driver mutation. We identify that oligodendrocyte precursor (OPC)-like cells constitute the stem-like compartment in H3-K27M DMGs across all clinico-anatomical groups, however, depending on location, display varying levels of maturity resembling less differentiated pre-OPCs or more mature OPCs further differentiated along the oligodendroglial lineage. We further demonstrate increased mesenchymal cell states in adult tumors, which we link to age-related differences in glioma-associated immune cell compartments, in particular an increase of macrophages in adult compared to pediatric tumors. Furthermore, we resolve the spatial organization of H3-K27M DMG cell types and states in intact patient tissues, identifying a local niche of the oligodendroglial lineage. Our study provides a powerful resource for rational modeling and therapeutic frameworks taking into account determinants of age and location in this lethal glioma group.
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Hübner, Jens-Martin, Torsten Müller, Dimitris N. Papageorgiou, Monika Mauermann, Jeroen Krijgsveld, Robert B. Russell, David W. Ellison, Stefan M. Pfister, Kristian W. Pajtler, and Marcel Kool. "EZHIP/CXorf67 mimics K27M mutated oncohistones and functions as an intrinsic inhibitor of PRC2 function in aggressive posterior fossa ependymoma." Neuro-Oncology 21, no. 7 (April 29, 2019): 878–89. http://dx.doi.org/10.1093/neuonc/noz058.
Анотація:
Abstract Background Posterior fossa A (PFA) ependymomas are one of 9 molecular groups of ependymoma. PFA tumors are mainly diagnosed in infants and young children, show a poor prognosis, and are characterized by a lack of the repressive histone H3 lysine 27 trimethylation (H3K27me3) mark. Recently, we reported overexpression of chromosome X open reading frame 67 (CXorf67) as a hallmark of PFA ependymoma and showed that CXorf67 can interact with enhancer of zeste homolog 2 (EZH2), thereby inhibiting polycomb repressive complex 2 (PRC2), but the mechanism of action remained unclear. Methods We performed mass spectrometry and peptide modeling analyses to identify the functional domain of CXorf67 responsible for binding and inhibition of EZH2. Our findings were validated by immunocytochemistry, western blot, and methyltransferase assays. Results We find that the inhibitory mechanism of CXorf67 is similar to diffuse midline gliomas harboring H3K27M mutations. A small, highly conserved peptide sequence located in the C-terminal region of CXorf67 mimics the sequence of K27M mutated histones and binds to the SET domain (Su(var)3-9/enhancer-of-zeste/trithorax) of EZH2. This interaction blocks EZH2 methyltransferase activity and inhibits PRC2 function, causing de-repression of PRC2 target genes, including genes involved in neurodevelopment. Conclusions Expression of CXorf67 is an oncogenic mechanism that drives H3K27 hypomethylation in PFA tumors by mimicking K27M mutated histones. Disrupting the interaction between CXorf67 and EZH2 may serve as a novel targeted therapy for PFA tumors but also for other tumors that overexpress CXorf67. Based on its function, we have renamed CXorf67 as “EZH Inhibitory Protein” (EZHIP).
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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.
Анотація:
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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Andrade, Augusto Faria, Danai Topouza, Michael McNicholas, Eduardo G. Gonzalez Santiago, Antonella De Cola, Arne Gehlhaar, Selin Jessa, et al. "TMIC-04. IMMUNE PROFILING OF PEDIATRIC ONCOHISTONE GLIOMAS REVEALS DIVERSE MYELOID POPULATIONS AND TUMOR-PROMOTING BEHAVIORS." Neuro-Oncology 25, Supplement_5 (November 1, 2023): v278. http://dx.doi.org/10.1093/neuonc/noad179.1070.
Анотація:
Abstract Pediatric high-grade gliomas pHGG are lethal and frequently bear missense mutations in histone H3, which drive tumorigenesis by altering the epigenome and cell fate/differentiation. While previous studies showed intrinsic contingencies associated with tumor development, limited information exists on the tumor microenvironment (TME) and immune cells for these tumors. To define the immune landscape of pediatric tumors at single-cell resolution, we profiled and compared 69 pediatric gliomas samples using the Chromium 10X technologies, H3.3 K27M (N=19) and G34R (N=16) mutant tumors, low-grade gliomas (N=11) and ependymomas (N=23). Additionally, to enable the spatial resolution of immune lineages, we performed Imaging Mass Cytometry (IMC) on H3-mutant samples (H3.3 K27M (N=7) and G34R (N=5)). We demonstrate that pediatric histone H3-mutant gliomas are highly infiltrated by myeloid cells, more specifically resident microglia, bone-marrow derived macrophages (BMDM) and monocytes, and are devoid of lymphoid infiltration. Different myeloid subsets were found to interact with H3-mutant cancer cells. Classical BMDM showed strong interactions with H3-mutant cancer cells while monocytes subsets showed tendency to interact only with G34R cells. We have generated a novel H3.3K27M glioma immunocompetent murine model, establishing a highly-penetrant and reliable tool. H3.3K27M murine tumors recapitulated the TME from human tumors, showing great myeloid infiltration. Using in vivo orthotopic serial engraftments, we observed that secondaries transplanted tumors had a significantly worse survival, possessing a less diverse immune infiltration compared to initial engraftments and a dominant presence of myeloid cells. Interestingly, in vivo myeloid depletion combined with PD-1 blockade extended overall mice survival. Our findings provide a valuable characterization of the biology of these tumors, reinforcing the several roles of myeloid cells in the context of pediatric brain tumours, providing a framework for understanding the H3.3K27M and G34R tumors, including other pediatric gliomas, and designing future immunotherapies.
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Budd, Kaitlin, Chang-Hyuk Kwon, Lawryn H. Kasper, Christopher Roberts, Jordan Roach, Jennifer Ocasio-Adorno, Jon D. Larson, and Suzanne J. Baker. "Abstract IA007: Transforming chromatin: Oncohistone mutations in pediatric high-grade glioma." Cancer Research 82, no. 23_Supplement_2 (December 1, 2022): IA007. http://dx.doi.org/10.1158/1538-7445.cancepi22-ia007.
Анотація:
Abstract Pediatric diffuse high-grade gliomas (HGGs) are a heterogeneous spectrum of disease with abysmal survival rates. Approximately half of diffuse high-grade gliomas in children arise in midline structures predominantly the brainstem, but also thalamus, cerebellum and spinal cord. Approximately 80% of these tumors harbor H3 K27M mutations, which result in dramatic depletion of the post-translational modification H3K27me3. Alternative mutations in diffuse midline gliomas can result in similar reduction of H3K27me3, leading to a redefined classification of this collection of tumors as diffuse midline glioma, H3 K27-altered. In contrast, distinct histone H3 mutations, H3.3 G34R/V, are found in approximately 30% of diffuse gliomas arising in the cerebral hemispheres of older adolescents and young adults, defining the tumor subgroup of diffuse hemispheric glioma, H3 G34-mutant. The striking spatiotemporal pattern of these histone mutations, termed oncohistones, indicates an intimate association between epigenetic dysregulation, brain development, and tumorigenesis. We will discuss use of genetically engineered and patient-derived models to investigate the contribution of oncohistone mutations to disrupted development, epigenetic dysregulation and gliomagenesis. Citation Format: Kaitlin Budd, Chang-Hyuk Kwon, Lawryn H. Kasper, Christopher Roberts, Jordan Roach, Jennifer Ocasio-Adorno, Jon D. Larson, Suzanne J. Baker. Transforming chromatin: Oncohistone mutations in pediatric high-grade glioma. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr IA007.
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Kida, Jun-ichiro, Takayuki Tsujioka, Shin-ichiro Suemori, Shuichiro Okamoto, Kanae Sakakibara, Takahiro Yamauchi, Akira Kitanaka, Yumi Tohyama, and Kaoru Tohyama. "Malignant Progression of an MDS-Derived Cell Line Serves As an in Vitro Model for the Leukemic Evolution of MDS." Blood 132, Supplement 1 (November 29, 2018): 5501. http://dx.doi.org/10.1182/blood-2018-99-110583.
Анотація:
Abstract Myelodysplastic syndromes (MDS) have a risk of progression to acute myeloid leukemia (AML), but the deterioration mechanisms of MDS and the alteration points still remain to be elucidated. We previously established a myelodysplastic cell line, MDS92 from the bone marrow of an MDS patient, and after a long-term interleukin(IL)-3-containing culture of MDS92, five blastic sublines including MDS-L were isolated. From MDS-L, we obtained two sublines, MDS-L-2007 and MDS-LGF after culture in the presence and absence of IL-3, respectively. To investigate the mechanism of leukemic evolution, we applied a next-generation sequencing (NGS) to the series of cell lines for comprehensive, comparative exome analyses, and searched for the origin of mutations by ultra-deep target sequencing of the original patient bone marrow. Whole exome sequencing and ultra-deep target sequencing demonstrated: (1) TP53 mutation was found in the patient bone marrow and this mutation was inherited by all subsequent cell lines; (2) CEBPA mutation was originally present in a small fraction of the bone marrow; (3) NRAS mutation emerged by chance during IL-3-containing culture; (4) HIST1H3C(K27M) mutation (Histone-H3-K27M) was newly detected at the generation of MDS-L from MDS92. H3-K27M mutation was detected in MDS-L-2007 but not in MDS-LGF. We focused on H3-K27M mutation because it is frequently found in pediatric brain stem tumors and recently found in a small population of AML cases (Lehnertz et al. Blood. 2017). MDS-L cells were a mixture of H3-K27M-mutant and wild-type clones. When MDS-L was cultured in the presence of IL-3, the proportion of H3-K27M-mutant fraction gradually increased. In contrast, when MDS-L was cultured without IL-3, the proportion of H3-K27M-mutant fraction gradually decreased. To investigate the implication of H3-K27M mutation, we tried single cell cloning from MDS-L and secured four wild-type clones and seven H3-K27M-mutant clones. In all H3-K27M-mutant clones, there was a marked reduction in H3-K27me3/2. Expression of a tumor-suppressor molecule p16 was reduced in six of the seven H3-K27M-mutant clones. H3-K27M-mutant clones showed rapid growth in the presence of IL-3, but cell proliferation was suppressed without IL-3. Competitive growth experiment by co-culture of H3-K27-wild-type and H3-K27M-mutant clones in the presence or absence of IL-3 showed that H3-K27M-mutant clones were predominant in the presence of IL-3, whereas wild-type clones were sustained comparatively in the absence of IL-3. Treatment with EPZ-6438, an inhibitor of H3-K27 methyltransferase EZH2, caused growth suppression of H3-K27M-mutant clones as well as wild-type clones and involved obvious recovery of p16 expression in H3-K27M-mutant clones, which provides a possibility that p16 might be a therapeutic target for H3-K27M mutant. Although GSK-J4, an inhibitor of H3-K27 demethylase JMJD3, was reported to inhibit H3-K27M-mutated pediatric brain stem tumors, GSK-J4 exerted only non-specific growth inhibitory effect on both H3-K27M-mutant and wild-type clones. Whole exome analyses indicated that the accumulation of oncogenic mutations seemed to have led to establishment of MDS cell lines. The finding that growth advantage of H3-K27M mutant was influenced by the presence or absence of IL-3 raised a possibility that even if neoplastic clones emerge, their expansion might be influenced not only by genetic/epigenetic status but by surrounding environmental factors including cytokines. This series of cell lines will be a useful tool as an in vitro model for leukemic evolution of MDS. Disclosures No relevant conflicts of interest to declare.
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Hohm, Annika, Michael Karremann, Gerrit H. Gielen, Torsten Pietsch, Monika Warmuth-Metz, Lindsey A. Vandergrift, Brigitte Bison, et al. "Magnetic Resonance Imaging Characteristics of Molecular Subgroups in Pediatric H3 K27M Mutant Diffuse Midline Glioma." Clinical Neuroradiology 32, no. 1 (December 17, 2021): 249–58. http://dx.doi.org/10.1007/s00062-021-01120-3.
Анотація:
Abstract Purpose Recent research identified histone H3 K27M mutations to be associated with a dismal prognosis in pediatric diffuse midline glioma (pDMG); however, data on detailed MRI characteristics with respect to H3 K27 mutation status and molecular subgroups (H3.1 and H3.3 K27M mutations) are limited. Methods Standardized magnetic resonance imaging (MRI) parameters and epidemiologic data of 68 pDMG patients (age <18 years) were retrospectively reviewed and compared in a) H3 K27M mutant versus H3 K27 wildtype (WT) tumors and b) H3.1 versus H3.3 K27M mutant tumors. Results Intracranial gliomas (n = 58) showed heterogeneous phenotypes with isointense to hyperintense signal in T2-weighted images and frequent contrast enhancement. Hemorrhage and necrosis may be present. Comparing H3 K27M mutant to WT tumors, there were significant differences in the following parameters: i) tumor localization (p = 0.001), ii) T2 signal intensity (p = 0.021), and iii) T1 signal homogeneity (p = 0.02). No significant imaging differences were found in any parameter between H3.1 and H3.3 K27M mutant tumors; however, H3.1 mutant tumors occurred at a younger age (p = 0.004). Considering spinal gliomas (n = 10) there were no significant imaging differences between the analyzed molecular groups. Conclusion With this study, we are the first to provide detailed MR imaging data on H3 K27M mutant pDMG with respect to molecular subgroup status in a large patient cohort. Our findings may support diagnosis and future targeted therapeutic trials of pDMG within the framework of the radiogenomics concept.
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Zhang, Peng, Tiantian Han, Yi Lu, Weijie Sun, Wanglong Deng, Guanghua Lu, Didi Guo, Xiaomin Li, and Fanfeng Bu. "Molecular characteristics of H3 K27M mutation gliomas in Chinese adults." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e14018-e14018. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e14018.
Анотація:
e14018 Background: Diffuse midline glioma H3 K27M–mutant is a specific entity added to the 2016 update of the WHO classification of CNS tumors. H3K27M-mutant gliomas are diagnosed primarily in children and adolescents with TP53 and/or ATRX mutations. However, the characteristics of H3 K27M-mutant gliomas in adults have not been explicitly described. Methods: We performed the 131-gene panel targeted sequencing on tumor samples from 33 adults H3 K27M-mutant gliomas( > 18 years) and 13 children and adolescents H3 K27M-mutant gliomas(≤18 years) in a CAP certified laboratory. Somatic mutations, copy number variations, and fusion genes were detected following the standard operating procedure (SOP). The MS-based assay measured MGMT promoter methylation. We calculated the tumor location and the median age in different cohorts. Results: In our adult cohort, 22/33（66.7%）had a midline location（spinal cord n = 2, thalamus n = 7, brainstem n = 6, cerebellum n = 3, pineal region n = 1, Basal ganglia region n = 3）, 6/33（18.1%）had a non-midline location (Lateral ventricle n = 2, Cerebral hemispheres n = 4). In the children and adolescents cohort, 11/13（84.6%）occurred in midline location, 1/13(7.7%) occurred in the Lateral ventricle. MGMT promoter methylation did not differ in adult and pediatric H3 K27M-mutant gliomas (12.1% vs. 0). H3 K27M-mutant adult gliomas significantly co-occurred with the NF1 mutation(P = 0.008937). The median age of H3 K27M-mutant adult gliomas with NF1 modification (13/33, 39.4%) is higher than the NF1 wild type (49 years vs. 38 years, P = 0.107), although the difference has no statistical significance. Conclusions: In Chinese adults, as in children, H3 K27M mutation gliomas are characterized by a constant midline location, low rate of MGMT promoter methylation. Inconsistently, H3 K27M mutant adult gliomas are featured by a higher rate of NF1 mutations. Our molecular profiling analysis revealed the H3 K27M mutation in adult gliomas. Our research suggests potential molecular pathogenesis of H3K27M mutant adult gliomas and identifies more therapeutic targets for precision medicine.
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Shema, Efrat. "Abstract PR006: Single-molecule and single-cell epigenetics: Decoding the epigenome for cancer research and diagnostics." Cancer Research 82, no. 23_Supplement_2 (December 1, 2022): PR006. http://dx.doi.org/10.1158/1538-7445.cancepi22-pr006.
Анотація:
Abstract Genes and genomic elements are packaged by chromatin structures that regulate their activity. We developed a novel high-throughput single-molecule imaging technology to decode combinatorial modifications on millions of individual nucleosomes. We apply this technology to image nucleosomes and delineate their combinatorial epigenetic patterns, and how these patterns are deregulated in cancer. In addition, we adapt single-cell technologies based on CyTOF to profile the global levels of multiple histone modifications in single cells, thus revealing epigenetic heterogeneity in cancer. Our research focuses on pediatric gliomas harboring lysine to methionine substitution of residue 27 on histone H3 (K27M). We provide evidence for widespread effects of the H3-K27M oncohistone on multiple core epigenetic pathways, and highlight the capability of single-molecule and single-cell tools to reveal mechanisms of chromatin deregulation and heterogeneity in cancer. We also harness the single-molecule technology as a novel liquid biopsy approach, by comprehensively profiling combinatorial epigenetic marks of plasma-isolated nucleosomes. Applying this analysis to a cohort of plasma samples detect colorectal cancer at high accuracy and sensitivity, even at early stages. Finally, combining this proteomic analysis with single-molecule DNA sequencing reveals the tissue-of-origin of the tumor. Citation Format: Efrat Shema. Single-molecule and single-cell epigenetics: Decoding the epigenome for cancer research and diagnostics. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr PR006.
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Morita, Shuhei, Masayuki Nitta, Yoshihiro Muragaki, Takashi Komori, Kenta Masui, Takashi Maruyama, Koichi Ichimura, et al. "Brainstem pilocytic astrocytoma with H3 K27M mutation: case report." Journal of Neurosurgery 129, no. 3 (September 2018): 593–97. http://dx.doi.org/10.3171/2017.4.jns162443.
Анотація:
In this report, the authors present the first case of adult brainstem pilocytic astrocytoma (PA) with the H3 K27M mutation. A 53-year-old man was incidentally found to have a 2.5-cm partially enhanced tumor in the tectum on MRI. The enhancement in the lesion increased over 3 years, and gross-total removal was performed via the occipital transtentorial approach. The resected tissue indicated PA, WHO Grade I, and genetic analysis revealed the H3 K27M mutation. However, although the radiological, surgical, and pathological findings all corresponded to PA, this entity can easily be misdiagnosed as diffuse midline glioma with the H3 K27M mutation, which is classified as a WHO Grade IV tumor according to the updated classification. This case highlights the phenotypic spectrum of PA, as well as the biology of the H3 K27M–mutated gliomas, and may prove to be an exception to the rule that diffuse midline gliomas with the H3 K27M mutation behave in an aggressive manner. Based on the findings of this case, the authors conclude that, in addition to detecting the existence of the H3 K27M mutation, an integrated approach in which a combination of clinical, pathological, and genetic information is used should be applied for accurate diagnosis and determination of the appropriate treatment for diffuse midline gliomas.
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Odia, Yazmin, Ashley Love Sumrall, Timothy Francis Cloughesy, Phioanh Leia Leia Nghiemphu, Matthew David Hall, Doured Daghistani, Minesh P. Mehta, et al. "Single agent activity of ONC201 in non-midline H3 K27M-mutant diffuse gliomas." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e14037-e14037. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e14037.
Анотація:
e14037 Background: H3 K27M-mutant diffuse midline glioma is an invariably lethal form of brain cancer that disproportionately affects children and young adults and has no effective treatment following front-line radiation. The initial disease definition in the 2016 WHO Classification of Tumors of the Central Nervous System regarded the H3 K27M mutation as pathognomonic, though the definition was updated in 2018 restricting the diagnosis to histologically diffuse gliomas that involve midline CNS structures (cIMPACT-NOW update 2). ONC201 is an investigational anti-cancer small molecule, DRD2 antagonist and ClpP agonist that has induced durable tumor regressions by RANO-HGG criteria in a registration cohort of recurrent diffuse midline glioma, H3 K27M-mutant patients treated with single agent ONC201. Methods: We present 7 patients with H3 K27M-mutant diffuse gliomas were enrolled in ONC201 clinical studies, though excluded from the registration cohort due to involvement of non-midline CNS structures, all within the cerebral hemispheres (3 frontal, 1 temporal, 1 frontotemporal, 1 parietal, and 1 corona radiata). Results: Two of the 7 patients underwent objective responses by RANO-HGG criteria as assessed by investigator, which was associated with clinical benefit that included increased mobility and level of alertness. Conclusions: These results demonstrate that H3 K27M-mutant diffuse gliomas occur outside of midline CNS structures, and suggest that ONC201 has single agent activity in H3 K27M-mutant gliomas irrespective of CNS location.
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Odia, Yazmin, Ashley Sumrall, Timothy Cloughesy, Phioanh Nghiemphu, Matthew Hall, Doured Daghistani, Minesh Mehta, et al. "CTNI-27. SINGLE AGENT ACTIVITY OF ONC201 IN NON-MIDLINE H3 K27M-MUTANT DIFFUSE GLIOMAS." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi65. http://dx.doi.org/10.1093/neuonc/noab196.252.
Анотація:
Abstract BACKGROUND H3 K27M-mutant diffuse midline glioma is an invariably lethal form of brain cancer that disproportionately affects children and young adults and has no effective treatment following front-line radiation. The initial disease definition in the 2016 WHO Classification of Tumors of the Central Nervous System regarded the H3 K27M mutation as pathognomonic, though the definition was updated in 2018 restricting the diagnosis to histologically diffuse gliomas that involve midline CNS structures (cIMPACT-NOW update 2). ONC201 is an investigational anti- cancer small molecule, DRD2 antagonist and ClpP agonist that has induced durable tumor regressions by RANO-HGG criteria in a registration cohort of recurrent diffuse midline glioma, H3 K27M-mutant patients treated with single agent ONC201. METHODS We present 7 patients with H3 K27M-mutant diffuse gliomas were enrolled in ONC201 clinical studies, excluded from the registration cohort due to involvement of non-midline CNS structures, all within the cerebral hemispheres (3 frontal, 1 temporal, 1 frontotemporal, 1 parietal, and 1 corona radiata). RESULTS Two of the 7 patients underwent objective responses by RANO-HGG criteria as assessed by investigator, which was associated with clinical benefit that included increased mobility and level of alertness. CONCLUSIONS These results demonstrate that H3 K27M-mutant diffuse gliomas occur outside of midline CNS structures, and suggest that ONC201 has single agent activity in H3 K27M-mutant gliomas irrespective of CNS location.
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Gardner, Sharon L., Carl Johannes Koschmann, Rohinton Tarapore, Jeffrey C. Allen, Wafik Tharwat Zaky, Yazmin Odia, Matthew Hall, et al. "ONC201 in previously irradiated pediatric H3 K27M-mutant glioma or newly diagnosed DIPG." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 3619. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.3619.
Анотація:
3619 Background: ONC201 is a first-in-class DRD2 antagonist and ClpP agonist that has demonstrated promising activity in high-grade glioma preclinical models and radiographic regressions with single agent ONC201 in recurrent H3 K27M-mutant glioma patients . The recommended phase 2 dose (RP2D) of 625mg ONC201 orally once a week has been established in adult patients as well tolerated and biologically active. ONC201 efficacy has been shown in high-grade glioma preclinical models and radiographic regressions with single agent ONC201 have been reported in adult recurrent H3 K27M-mutant glioma patients. We report results from the first Phase I pediatric clinical trial of ONC201. Methods: This open-label, multi-center trial for pediatric H3 K27M-mutant glioma or non-biopsied DIPG employed a 3+3 dose-escalation and dose-expansion design with 6 arms. Arms A and E, which have completed accrual, determined the RP2D of ONC201 using oral capsule and liquid formulations in post-radiation pediatric H3 K27M-mutant glioma patients ONC201, respectively. Arm B aims to determine the RP2D for ONC201 in combination with radiotherapy in patients with newly diagnosed DIPG. Arms C and D aim to measure intratumoral ONC201 concentrations in midline glioma patients and the impact of ONC201 on H3 K27M DNA levels in CSF, respectively. Arm F was recently opened to study ONC201 as a single agent in patients with progressive H3 K27M-mutant tumors (excluding DIPG and spinal cord tumors) following radiotherapy. After determining the RP2D, a dose-expansion cohort will evaluate the safety, radiographic response, and activity of ONC201. Results: An RP2D of weekly 625mg ONC201 scaled by body weight as a capsule or in liquid formulation was established in the primary endpoints of arms A, B and E alone or in combination with radiation, without incidence of dose-limiting toxicity (DLT). Pharmacokinetic profiles were similar to those observed in adults (T1/2: 8.4h; Tmax: 2.1h; Cmax: 2.3ug/mL; AUC0-tlast: 16.4ug/mL), with similar exposure across body weights. Conclusions: ONC201 was well tolerated without DLTs at the same adult RP2D scaled by body weight as monotherapy or in combination with radiotherapy in pediatric H3 K27M-mutant glioma patients. Further investigation of ONC201 to treat H3 K27M-mutant glioma and DIPG is warranted. Clinical trial information: NCT03416530 .
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Kawakibi, Abed Rahman, Rohinton S. Tarapore, Sharon Gardner, Andrew Chi, Sylvia Kurz, Patrick Y. Wen, Isabel Arrillaga-Romany, et al. "HGG-18. CLINICAL EFFICACY OF ONC201 IN THALAMIC H3 K27M-MUTANT GLIOMA." Neuro-Oncology 22, Supplement_3 (December 1, 2020): iii347. http://dx.doi.org/10.1093/neuonc/noaa222.305.
Анотація:
Abstract ONC201, a bitopic DRD2 antagonist and allosteric ClpP agonist, has shown encouraging efficacy in H3 K27M-mutant glioma. Given that the thalamus has the highest extra-striatal expression of DRD2, we performed an integrated preclinical and clinical analysis of ONC201 in thalamic H3 K27M-mutant glioma. ONC201 was effective in mouse intra-uterine electroporation (IUE)-generated H3 K27M-mutant gliomas, with an in vitro IC50 of 500 nM and 50% prolongation of median survival in vivo (p=0.02, n=14). We analyzed thalamic H3 K27M-mutant glioma patients treated with ONC201 on active clinical trials as of 5/22/19 enrollment (n=19 recurrent and 10 post-radiation, non-recurrent; 5–70 years old). As of 12/18/2019, PFS6 and OS12 are 26.3% and 36.8%, respectively, in the recurrent group. For non-recurrent patients, with median follow up of 21.9 months (8.6–26.6) from diagnosis, median PFS or OS have not been reached. This surpasses historical OS of 13.5 months. Best response by RANO includes 1 CR, 3 PR, 4 SD, 8 PD for recurrent patients and 2 PR, 4 SD, 1 PD for non-recurrent patients (4 on-trial patients experienced regressions that are yet unconfirmed responses). Median duration of response for recurrent patients is 14.0 months (2.0–33.1). Furthermore, H3 K27M cell-free tumor DNA in plasma and CSF correlated with MRI response. In summary, single agent ONC201 administered at recurrence, or adjuvantly following radiation, demonstrates promising clinical efficacy in thalamic H3 K27M-mutant glioma patients who currently have no effective treatments following radiation. Investigations are ongoing to assess whether micro-environmental DRD2 expression explains the early exceptional responses in thalamic H3 K27M-mutant glioma.
17
Kawakibi, Abed Rahman, Rohinton Tarapore, Sharon L. Gardner, Sylvia Christine Kurz, Patrick Y. Wen, Isabel Arrillaga-Romany, Tracy Batchelor, et al. "Clinical efficacy of ONC201 in thalamic H3 K27M-mutant glioma." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 3617. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.3617.
Анотація:
3617 Background: Diffuse midline gliomas, H3 K27M-mutant are associated with a poor prognosis compared to H3 wild-type gliomas and have no effective therapy following first-line radiation. ONC201 is a bitopic DRD2 antagonist and allosteric ClpP agonist that has shown encouraging single agent efficacy in recurrent H3 K27M-mutant gliomas located in various midline structures of the brain. In addition to tumor and immune cells, the pharmacodynamics of ONC201 extend to stromal cells that can mediate a bystander antitumor response in preclinical models. Given this observation and that the thalamus has the highest extrastriatal expression of DRD2, we report the clinical experience of ONC201 in a subgroup of H3 K27M-mutant glioma patients with primary tumors located in the thalamus. Methods: We analyzed 29 thalamic H3 K27M-mutant glioma patients treated with ONC201 in clinical trials enrolled as of 5/22/19. Nineteen enrolled with recurrent disease whereas 10 enrolled following radiation prior to recurrence. Twelve patients enrolled on NCT03295396, 10 NCT03416530, 4 NCT02525692, and 3 expanded access. Median age was 22 years old (range: 5-70) and baseline KPS was 80 (range: 60-90). Median time from radiation to start of ONC201 was 1.8 months (range: 0.2-8.7) for non-recurrent patients and 7.2 months (range: 1.4-102.0) for recurrent patients. Results: As of 12/18/2019, PFS6 and OS12 measured relative to initiation of ONC201 are 26.3% and 36.8%, respectively, in the recurrent group. For patients initiating ONC201 post-radiation prior to recurrence, median PFS or OS have not been reached with a median follow up of 21.9 months (8.6-26.6) from diagnosis, which surpass historical OS of 13.5 months. Best response for evaluable recurrent patients by RANO: 1 CR, 3 PR, 4 SD, 8 PD, 3 not reported; for non-recurrent patients: 2 PR, 4 SD, 1 PD, 3 not reported. Median duration of response for recurrent patients is 14.0 months (2.0-33.1). ONC201 was well tolerated and no dose-limiting toxicities or treatment discontinuations due to toxicity occurred. Furthermore, H3 K27M cell-free tumor DNA in plasma and CSF correlated with MRI response. Conclusions: In summary, single agent ONC201 administered at recurrence or following radiation, demonstrates promising clinical efficacy in thalamic H3 K27M-mutant glioma patients. Investigations are ongoing to assess whether micro-environmental DRD2 expression correlates with responses of thalamic H3 K27M-mutant glioma to ONC201. Clinical trial information: NCT03295396, NCT03416530, NCT02525692 .
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Hall, Matthew D., Yazmin Odia, Joshua E. Allen, Rohinton Tarapore, Ziad Khatib, Toba N. Niazi, Doured Daghistani, et al. "First clinical experience with DRD2/3 antagonist ONC201 in H3 K27M–mutant pediatric diffuse intrinsic pontine glioma: a case report." Journal of Neurosurgery: Pediatrics 23, no. 6 (June 2019): 719–25. http://dx.doi.org/10.3171/2019.2.peds18480.
Анотація:
Diffuse intrinsic pontine gliomas (DIPGs) frequently harbor the histone H3 K27M mutation. Gliomas with this mutation commonly overexpress dopamine receptor (DR) D2 and suppress DRD5, leading to enhanced sensitivity to DRD2 antagonism. This study reports the first clinical experience with the DRD2/3 antagonist ONC201 as a potential targeted therapy for H3 K27M–mutant DIPG. One pediatric patient (a 10-year-old girl) with H3 K27M–mutant DIPG was enrolled in an investigator-initiated, IRB-approved compassionate-use study and began single-agent ONC201 treatment 1 month after completing radiotherapy. The study endpoints were clinical and radiographic response (primary) and toxicities (secondary).The patient presented with House-Brackmann grade IV facial palsy and unilateral hearing loss. MRI demonstrated a 2.3 × 2.1 × 2.8–cm pontomedullary tumor. Stereotactic biopsy confirmed H3 K27M–mutated DIPG. The tumor was treated with radiotherapy, but 1 month after completion of that treatment, the tumor and neurological symptoms showed only minimal change, and ONC201 treatment was initiated as described above. The tumor volume sequentially decreased by 26%, 40%, and 44% over the next 6 months, and remained stable at 18 months. Ipsilateral hearing normalized and the facial palsy improved to House-Brackmann grade I by 4 months. After 1 year of ONC201 treatment, 2 new lesions were identified outside of the prior high-dose radiotherapy volume. The patient was treated with dexamethasone, bevacizumab, and additional focal radiotherapy to these new tumors. These tumors remained stable in size over the subsequent 6 months on MRI. To date, no adverse events have been observed or reported due to ONC201. The patient remains clinically improved as of the latest follow-up visit, 19 months after starting ONC201 and 22 months from diagnosis. This case supports further investigation of this novel agent targeting H3 K27M–mutated DIPG.
19
Schulte, Jessica, Robin Buerki, Sarah Lapointe, Annette Molinaro, Yalan Zhang, Javier Villanueva-Meyer, Arie Perry, et al. "PATH-30. CLINICAL AND GENETIC CHARACTERISTICS OF HISTONE H3 K27M-MUTANT DIFFUSE MIDLINE GLIOMAS IN ADULTS." Neuro-Oncology 22, Supplement_2 (November 2020): ii170—ii171. http://dx.doi.org/10.1093/neuonc/noaa215.711.
Анотація:
Abstract BACKGROUND “Diffuse midline glioma, H3 K27M-mutant” is a new tumor entity established in the 2016 WHO Classification of Tumors of the CNS that comprises a set of diffuse gliomas arising in midline structures that is molecularly defined by a recurrent K27M mutation in genes encoding the histone 3 variants H3.3 or H3.1. While this tumor entity is associated with poor prognosis in children, clinical experience in adults remains limited. Given the more frequent origin in the thalamus or spinal cord in adults versus the brainstem in children, gliomas with this mutation may encompass a heterogeneous population of tumor subtypes that vary based on patient age, anatomic site of origin, and concurrent genetic alterations. METHODS The 60 patients included were 18 years or older at initial diagnosis, during the period of 2014-2019 at UCSF. Cases were identified using immunohistochemistry with a H3 K27M-mutant specific antibody and/or next-generation sequencing of histone 3 genes H3F3A, HIST1H3B and HIST1H3C. Targeted NGS was performed on tumors from 21 patients, utilizing an UCSF institutional panel or a variety of commercial sources. RESULTS Patients presented primarily in the 3rd decade of life, and 57% of tumors were located in the thalamus. Genomic profiling revealed p.K27M mutations exclusively in H3F3A and an absence of mutations in HIST1H3B or HIST1H3C, which are present in approximately one-third of pediatric diffuse midline gliomas. Additionally, these adult H3 K27M-mutant diffuse midline gliomas are universally IDH-wildtype, and have frequent mutations in TP53, PPM1D, FGFR1, NF1, and ATRX. The overall survival of this adult cohort is longer than historical averages for both H3 K27M-mutant diffuse midline glioma in children and IDH-wildtype glioblastomas in adults. CONCLUSIONS Together, these findings indicate that H3 K27M-mutant diffuse midline glioma represents a heterogeneous disease with regard to outcomes, sites of origin, and molecular pathogenesis in children versus adults.
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Liu, Ilon, Li Jiang, Erik R. Samuelsson, Sergio Marco Salas, Alexander Beck, Olivia A. Hack, Daeun Jeong, et al. "The landscape of tumor cell states and spatial organization in H3-K27M mutant diffuse midline glioma across age and location." Nature Genetics 54, no. 12 (December 2022): 1881–94. http://dx.doi.org/10.1038/s41588-022-01236-3.
Анотація:
AbstractHistone 3 lysine27-to-methionine (H3-K27M) mutations most frequently occur in diffuse midline gliomas (DMGs) of the childhood pons but are also increasingly recognized in adults. Their potential heterogeneity at different ages and midline locations is vastly understudied. Here, through dissecting the single-cell transcriptomic, epigenomic and spatial architectures of a comprehensive cohort of patient H3-K27M DMGs, we delineate how age and anatomical location shape glioma cell-intrinsic and -extrinsic features in light of the shared driver mutation. We show that stem-like oligodendroglial precursor-like cells, present across all clinico-anatomical groups, display varying levels of maturation dependent on location. We reveal a previously underappreciated relationship between mesenchymal cancer cell states and age, linked to age-dependent differences in the immune microenvironment. Further, we resolve the spatial organization of H3-K27M DMG cell populations and identify a mitotic oligodendroglial-lineage niche. Collectively, our study provides a powerful framework for rational modeling and therapeutic interventions.
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Rahman Kawakibi, Abed, Sharon Gardner, Andrew Chi, Sylvia Kurz, Patrick Wen, Isabel Arrillaga-Romany, Tracy Batchelor, et al. "PDCT-12. CLINICAL EFFICACY OF ONC201 IN THALAMIC H3 K27M-MUTANT GLIOMA." Neuro-Oncology 21, Supplement_6 (November 2019): vi186. http://dx.doi.org/10.1093/neuonc/noz175.773.
Анотація:
Abstract ONC201, the first bitopic DRD2 antagonist for clinical oncology, has shown efficacy in H3 K27M-mutant glioma. We performed an integrated preclinical and clinical analysis of ONC201 in thalamic H3 K27M-mutant glioma. ONC201 was effective in mouse intra-uterine electroporation (IUE)-generated H3 K27M-mutant gliomas, with an in vitro IC50 of 500 nM and 50% prolongation of median survival in vivo (p=0.02, n=14). Elevated DRD2 expression was found in the thalamus of non-malignant brain tissue, leading to the hypothesis that thalamic tumors may be a particularly ONC201-sensitive sub-group. We analyzed thalamic H3 K27M-mutant glioma patients treated with ONC201 as of the 05/22/2019 cutoff date, which included patients who had recurrent disease prior to initiating ONC201 (n=20; 15–73 years old) and post-radiation non-recurrent patients (n=11; 5–19 years old). As of 5/22/2019, 10 of 20 recurrent patients and 9 of 11 non-recurrent patients remain on-treatment. Median PFS has not been reached for either cohort: median follow-up of 2.2 months (range: 0.6–37.9) for recurrent patients and 10.6 months (range: 4.3–20.5) from diagnosis for non-recurrent patients. Best response so far by RANO includes 1 CR, 2 PR, 7 SD, 9 PD, 1 NE for recurrent patients and 1 PR, 7 SD, 3 PD for non-recurrent patients. Additionally, 3 recurrent (-66%, -47%, -34%) and 2 non-recurrent (-40%, -10%) patients experienced regressions but are not yet confirmed PRs. For recurrent patients, median onset of response is 3.5 months (range: 2.2–3.8) and median duration of response has not been reached with a median follow-up of 12.5 months (range: 8.1–32.8). Preliminary analyses demonstrated a strong correlation of cell-free tumor DNA in plasma and CSF with MRI response. In summary, ONC201 demonstrates promising clinical efficacy in thalamic H3 K27M-mutant glioma patients, regardless of age. Micro-environmental DRD2 expression may enhance the overall ONC201 response and extend its therapeutic utility beyond H3 K27M-mutant glioma.
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Qiu, Tianming, Apisara Chanchotisatien, Zhiyong Qin, Jinsong Wu, Zunguo Du, Xialing Zhang, Fangyuan Gong, Zhenwei Yao, and Shuguang Chu. "Imaging characteristics of adult H3 K27M-mutant gliomas." Journal of Neurosurgery 133, no. 6 (December 2020): 1662–70. http://dx.doi.org/10.3171/2019.9.jns191920.
Анотація:
OBJECTIVEH3 K27M-mutant gliomas present heterogeneously in terms of pathology, imaging, and prognosis. This study aimed to summarize the imaging characteristics of adult H3 K27M-mutant gliomas.METHODSThe authors retrospectively identified all cases of glioma diagnosed using histopathological studies (n = 3300) that tested positive for histone H3 K27M mutations (n = 75) between January 2016 and December 2018 in a single hospital. Preoperative and follow-up MR images of 66 adult patients (age ≥ 18 years) were reviewed for anatomical location, degree of contrast enhancement, enhancement patterns, hemorrhage, edema, diffusion restriction, tumor dissemination, and tumor spread.RESULTSThe study included 66 cases (40 in men, 26 in women) of H3 K27M-mutant glioma in adult patients. Tumors were found in the following sites: thalamus (n = 38), brainstem (n = 6), brainstem with cerebellar or thalamic involvement (n = 4), whole brain (n = 8), corpus callosum (n = 3), hypothalamus (n = 1), hemispheres (n = 2), and spinal cord (n = 4). All pure brainstem lesions were located posteriorly, and all corpus callosal lesions were in the genu. Most spinal tumors were long-segment lesions. Hemispheric lesions mimicked gliomatosis cerebri in presentation, with the addition of traditional midline structure involvement. Most tumors were solid with relatively uniform signals on plain MRI. Of the 61 cases with contrast-enhanced MR images, 36 (59%) showed partial to no enhancement, whereas 25 (41%) showed diffuse or irregular peripheral enhancement. Hemorrhage and edema were rare. Most lesions were solid and showed mild diffusion restriction on diffusion-weighted imaging. Tumor dissemination to the leptomeninges (n = 8) and subependymal layer (n = 3) was observed.CONCLUSIONSThe authors described the MRI features of diffuse midline glioma with H3 K27M mutation in the largest study done to date in adult patients. Tumors were found in both midline and nonmidline structures, with the thalamus being the most common site. Although adult H3 K27M-mutant gliomas demonstrated highly variable presentations in this cohort of patients, the authors were able to observe shared characteristics within each location.
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Chen, Xueling, Ling Zhong, Jianwen Lin, and Jian Yu. "A rare case of adult diffuse midline glioma with H3 K27M mutant in the prepontine cistern." Journal of International Medical Research 49, no. 1 (January 2021): 030006052098126. http://dx.doi.org/10.1177/0300060520981266.
Анотація:
Diffuse midline glioma with the H3.3 histone A ( H3F3A) or H3 clustered histone 2/3 ( HIST1H3B/C) K27M mutation occurs primarily in children and less frequently in adults involving the midline structures of the central nervous system. This case report describes an adult patient with a diffuse midline glioma H3 K27M mutant in the prepontine cistern, which is an unusual site in clinical practice. The clinical, radiographic and histopathological data from the case are presented. Magnetic resonance imaging showed a progressively enlarged and enhanced nodule in the right prepontine cistern, with diffuse involvement of the meninges and communicating hydrocephalus. Analysis of the cerebrospinal fluid occasionally found suspiciously atypical cells with hyperchromatic nuclei and multiple nucleoli, as well as a severely elevated opening pressure and protein level, slightly elevated white cell count and decreased chloride level. Empirical antituberculosis treatment was administered but eventually proved to be ineffective. The definite diagnosis was made by histopathological analysis of the lesion based on the features of positive H3 K27M mutant protein and diffusely infiltrating growth. A diffuse midline glioma with the H3 K27M mutation may rarely present in an unusual site. A biopsy is recommended at an early stage for suspected cases to facilitate a definite diagnosis.
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Arrillaga-Romany, Isabel, Andrew Lassman, Susan McGovern, Sabine Mueller, L. Burt Nabors, Martin van den Bent, Michael Vogelbaum, et al. "RTID-01. ONC108: A RANDOMIZED PHASE 3 STUDY OF ONC201 IN PATIENTS WITH NEWLY DIAGNOSED H3 K27M-MUTANT DIFFUSE GLIOMA." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii249. http://dx.doi.org/10.1093/neuonc/noac209.961.
Анотація:
Abstract BACKGROUND H3 K27M-mutant diffuse midline glioma is a universally fatal malignancy primarily affecting children and young adults; while radiotherapy (RT) provides transient benefit, no effective systemic therapy is currently available. ONC201, a first-in-class imipridone, is an oral, blood-brain barrier penetrating, selective small molecule antagonist of dopamine receptor D2/3 (DRD2) and agonist of the mitochondrial protease ClpP. An integrated pooled analysis of objective response in ONC201-treated patients enrolled in one of five open-label trials has previously demonstrated efficacy in patients with recurrent disease. This phase 3 trial will be the first randomized, controlled study evaluating ONC201 in patients with H3 K27M-mutant disease. METHODS ONC108 is a randomized, double-blind, placebo-controlled, parallel-group, international Phase 3 study of ONC201 in patients with newly diagnosed H3 K27M-mutant diffuse glioma. Patients will be randomized to receive once-weekly ONC201 or placebo following standard frontline radiotherapy. Primary efficacy endpoints are overall survival (OS) and progression-free survival (PFS) in all participants; PFS will be assessed with the response assessment in neuro-oncology-high grade glioma by blind independent central review. Other objectives include assessments of safety, additional efficacy endpoints, clinical benefit, quality of life, pharmacokinetics, biomarkers, and healthcare resource utilization. Eligible patients will have histologically confirmed H3 K27M-mutant diffuse glioma, a Karnofsky/Lanksy performance status ≥ 70, and completed first-line radiotherapy. Eligibility will not be restricted based on age; however, patients must be ≥ 10 kg at time of randomization. Patients with a primary spinal tumor, diffuse intrinsic pontine glioma, leptomeningeal disease, or cerebrospinal fluid dissemination are not eligible.
25
Arrillaga-Romany, I., A. Lassman, S. L. McGovern, S. Mueller, L. B. Nabors, M. van den Bent, M. Vogelbaum, et al. "P11.46.A ACTION: A RANDOMIZED PHASE 3 STUDY OF DORDAVIPRONE (ONC201) IN PATIENTS WITH NEWLY DIAGNOSED H3 K27M-MUTANT DIFFUSE GLIOMA." Neuro-Oncology 25, Supplement_2 (September 1, 2023): ii84. http://dx.doi.org/10.1093/neuonc/noad137.280.
Анотація:
Abstract BACKGROUND H3 K27M-mutant diffuse midline glioma is a universally fatal malignancy primarily affecting children and young adults. While radiotherapy (RT) provides transient benefit, no effective systemic therapy is currently available and current standard of care is RT followed by monitoring. Dordaviprone (ONC201), a first-in-class imipridone, is an oral, blood-brain barrier penetrating, selective small molecule antagonist of dopamine receptor D2/3 (DRD2) and agonist of the mitochondrial protease ClpP. An integrated pooled analysis of five open-label trials previously demonstrated efficacy in dordaviprone-treated patients with recurrent disease. This phase 3 trial will be the first randomized, controlled study evaluating ONC201 in patients with H3 K27M-mutant disease. MATERIAL AND METHODS ACTION (NCT05580562) is a randomized, double-blind, placebo-controlled, parallel-group, international Phase 3 study of ONC201 in patients with newly diagnosed H3 K27M-mutant diffuse glioma. Patients who have completed standard frontline radiotherapy will be randomized 1:1:1 to receive placebo, once-weekly dordaviprone, or twice-weekly dordaviprone on two consecutive days. Primary efficacy endpoints are overall survival (OS) and progression-free survival (PFS) in all participants; PFS will be assessed by response assessment in neuro-oncology-high grade glioma by blind independent central review. Other objectives include assessments of safety, additional efficacy endpoints, clinical benefit, quality of life, pharmacokinetics, biomarkers, and healthcare resource utilization. Eligible patients will have histologically confirmed H3 K27M-mutant diffuse glioma, a Karnofsky/Lansky performance status ≥70, and completed first-line radiotherapy. Eligibility will not be restricted based on age; however, patients must be ≥10 kg at time of randomization. Patients with a primary spinal tumor, diffuse intrinsic pontine glioma, leptomeningeal disease, or cerebrospinal fluid dissemination are not eligible. ACTION is currently enrolling in the United States, with additional sites to be open internationally in 2023.
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Arrillaga-Romany, Isabel, Andrew Lassman, Susan McGovern, Sabine Mueller, Louis Burt Nabors, Martin van den Bent, Michael Vogelbaum, et al. "TIPS-08 ACTION: A RANDOMIZED PHASE 3 STUDY OF DORDAVIPRONE (ONC201) IN PATIENTS WITH NEWLY DIAGNOSED H3 K27M-MUTANT DIFFUSE GLIOMA." Neuro-Oncology Advances 5, Supplement_3 (August 1, 2023): iii35—iii36. http://dx.doi.org/10.1093/noajnl/vdad070.139.
Анотація:
Abstract BACKGROUND H3 K27M-mutant diffuse midline glioma is a universally fatal malignancy primarily affecting children and young adults. While radiotherapy (RT) provides transient benefit, no effective systemic therapy is currently available and current standard of care is RT followed by monitoring. Dordaviprone (ONC201), a first-in-class imipridone, is an oral, blood-brain barrier penetrating, selective small molecule antagonist of dopamine receptor D2/3 (DRD2) and agonist of the mitochondrial protease ClpP. An integrated pooled analysis of five open-label trials previously demonstrated efficacy in dordaviprone-treated patients with recurrent disease. This phase 3 trial will be the first randomized, controlled study evaluating ONC201 in patients with H3 K27M-mutant disease. METHODS ACTION (NCT05580562) is a randomized, double-blind, placebo-controlled, parallel-group, international Phase 3 study of ONC201 in patients with newly diagnosed H3 K27M-mutant diffuse glioma. Patients who have completed standard frontline radiotherapy will be randomized 1:1:1 to receive placebo, once-weekly dordaviprone, or twice-weekly dordaviprone on two consecutive days. Primary efficacy endpoints are overall survival (OS) and progression-free survival (PFS) in all participants; PFS will be assessed by response assessment in neuro-oncology-high grade glioma by blind independent central review. Other objectives include assessments of safety, additional efficacy endpoints, clinical benefit, quality of life, pharmacokinetics, biomarkers, and healthcare resource utilization. Eligible patients will have histologically confirmed H3 K27M-mutant diffuse glioma, a Karnofsky/Lansky performance status ≥70, and completed first-line radiotherapy. Eligibility will not be restricted based on age; however, patients must be ≥10 kg at time of randomization. Patients with a primary spinal tumor, diffuse intrinsic pontine glioma, leptomeningeal disease, or cerebrospinal fluid dissemination are not eligible. ACTION is currently enrolling in the United States, with international sites opening imminently.
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DeMasters, B. K., Samuel Guzman, and David Ormond. "PATH-18. MORE UNUSUAL FEATURES IN H3 K27M-MUTANT GLIOMAS." Neuro-Oncology 25, Supplement_5 (November 1, 2023): v171. http://dx.doi.org/10.1093/neuonc/noad179.0648.
Анотація:
Abstract Diffuse midline glioma, H3 K27M-altered, WHO grade 4 is an infiltrating midline glioma; however, H3 K27M mutation can also be seen in midline circumscribed, non-infiltrating gliomas and rarely in non-midline tumors. We report 2 unusual examples. A 37-year-old female developed a right posterior frontal infiltrating glioma; resection showed infiltrative tumor with brisk mitotic activity, elevated MIB-1 (20%), negative p53 expression, ATRX retention, but no necrosis or microvascular proliferation. Molecular workup showed neither IDH1/2/TERT promoter mutations or co-deletion 1p, 19q; further testing showed gain of whole chromosome 7 + loss of whole chromosome 10, meeting molecular criteria for glioblastoma. Recurrent tumor 2 years later in the same area prompted re-resection again of infiltrating tumor devoid of necrosis or microvascular proliferation; molecular testing now revealed a H3F3A (p.K28M) mutation. Both tumors showed protein expression by H3 K27M IHC+. She succumbed post-therapy at 3 ½ years. A 30-year-old woman developed a circumscribed, non-enhancing third ventricular mass; resection demonstrated circumscribed, non-infiltrating glioneuronal tumor with monotonous rounded tumor nuclei, synaptophysin IHC+, negative GFAP, H3 K27M IHC+, and low MIB-1. Molecular testing identified alterations in H3F3A p. K28M and FGFR1 p.N546K. She was treated, but lost to follow-up, until she re-presented 5 years later with hemorrhagic left frontal lobe tumor contiguous with the midline, with dorsal midbrain and 4th ventricular involvement. After resection, tumor now showed infiltrative features, necrosis and microvascular proliferation, diffuse GFAP IHC+, retention of nuclear ATRX, p53 (20%), MIB-1 (22%), and H3 K27M IHC+. New tumor had no FGFR1 alteration or PDGFRA amplification to suggest radiation-induced tumor, instead manifesting PTPRZ1-MET fusion. She survives at 5 years. These cases offer new insights into survival of a non-midline example and transformation of a circumscribed, non-infiltrating tumor to secondary infiltrating H3 K27-altered tumor with new molecular alterations, possibly representing second independent tumor development.
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Arrillaga-Romany, Isabel, Andrew Lassman, Susan L. McGovern, Sabine Mueller, Louis B. Nabors, Martin van den Bent, Michael Vogelbaum, et al. "Abstract CT060: ACTION: A randomized phase 3 study of dordaviprone (ONC201) in patients with newly diagnosed H3 K27M-mutant diffuse glioma." Cancer Research 83, no. 8_Supplement (April 14, 2023): CT060. http://dx.doi.org/10.1158/1538-7445.am2023-ct060.
Анотація:
Abstract Background: H3 K27M-mutant diffuse midline glioma is a universally fatal malignancy primarily affecting children and young adults. While radiotherapy (RT) provides transient benefit, no effective systemic therapy is currently available and current standard of care is RT followed by monitoring. Dordaviprone (ONC201), a first-in-class imipridone, is an oral, blood-brain barrier penetrating, selective small molecule antagonist of dopamine receptor D2/3 (DRD2) and agonist of the mitochondrial protease ClpP. An integrated pooled analysis of five open-label trials previously demonstrated efficacy in dordaviprone-treated patients with recurrent disease. This phase 3 trial will be the first randomized, controlled study evaluating dordaviprone in patients with H3 K27M-mutant disease. Methods: ACTION (NCT05580562) is a randomized, double-blind, placebo-controlled, parallel-group, international Phase 3 study of dordaviprone in patients with newly diagnosed H3 K27M-mutant diffuse glioma. Patients who have completed standard frontline radiotherapy will be randomized 1:1:1 to receive placebo, once-weekly dordaviprone, or twice-weekly dordaviprone on two consecutive days. Primary efficacy endpoints are overall survival (OS) and progression-free survival (PFS) in all participants; PFS will be assessed by response assessment in neuro-oncology-high grade glioma by blind independent central review. Other objectives include assessments of safety, additional efficacy endpoints, clinical benefit, quality of life, pharmacokinetics, biomarkers, and healthcare resource utilization. Eligible patients will have histologically confirmed H3 K27M-mutant diffuse glioma, a Karnofsky/Lansky performance status ≥70, and completed first-line radiotherapy. Eligibility will not be restricted based on age; however, patients must be ≥10 kg at time of randomization. Patients with a primary spinal tumor, diffuse intrinsic pontine glioma, leptomeningeal disease, or cerebrospinal fluid dissemination are not eligible. ACTION is currently enrolling in the United States, with additional sites to be open internationally in 2023. Citation Format: Isabel Arrillaga-Romany, Andrew Lassman, Susan L. McGovern, Sabine Mueller, Louis B. Nabors, Martin van den Bent, Michael Vogelbaum, Joshua E. Allen, Allen S. Melemed, Rohinton S. Tarapore, Dewen Yang, Patrick Wen, Timothy Cloughsey. ACTION: A randomized phase 3 study of dordaviprone (ONC201) in patients with newly diagnosed H3 K27M-mutant diffuse glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT060.
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Gardner, Sharon, Rohinton Tarapore, Jeffrey Allen, Wafik Zaky, Yazmin Odia, Matthew Hall, Doured Daghistani, et al. "DIPG-52. PHASE I CLINICAL TRIAL OF ONC201 IN PEDIATRIC H3 K27M-MUTANT GLIOMA OR NEWLY DIAGNOSED DIPG." Neuro-Oncology 22, Supplement_3 (December 1, 2020): iii297. http://dx.doi.org/10.1093/neuonc/noaa222.097.
Анотація:
Abstract H3 K27M-mutant gliomas often manifest as midline gliomas, have a dismal prognosis, and have no effective treatments. ONC201 efficacy has been shown in high-grade glioma preclinical models and durable responses with single agent ONC201 have been reported in adults with recurrent H3 K27M-mutant gliomas. These observations led to a Phase I pediatric clinical trial of ONC201 dosed by body weight. This multi-center, open-label, 3 + 3 dose-escalation and dose-expansion clinical trial (NCT03416530) for H3 K27M-mutant glioma or non-biopsied DIPG has 6 arms: arms A and E determine the RP2D in pediatric post-radiation (recurrent or not-recurrent) H3 K27M-mutant glioma patients with ONC201 administered as an oral capsule as well as a liquid formulation, respectively. Both arms have completed accrual. The study is currently enrolling newly diagnosed DIPG patients to determine the RP2D for ONC201 in combination with radiation (arm B). Dedicated assessment of intratumoral ONC201 concentrations in midline gliomas patients (arm C) and the effects of ONC201 in H3K27M DNA levels in circulating CSF (arm D) are currently enrolling patients. ONC201 as a single agent in patients with progressive H3K27M mutant tumors following irradiation (excluding DIPG/spinal cord tumors) was recently opened (arm F). Once the RP2D is confirmed, there is a dose-expansion cohort to confirm the safety, radiographic efficacy and survival with ONC201. The primary endpoints of arms A, B, and E have been established with the RP2D of 625mg scaled by body weight as a capsule or liquid formulation administered alone or in combination with radiation without incidence of dose-limiting toxicity.
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Gardner, Sharon L., Jeffrey C. Allen, Wafik Tharwat Zaky, Yazmin Odia, Doured Daghistani, Ziad Khatib, Carl Johannes Koschmann, et al. "ONC201 in previously-irradiated pediatric H3 K27M-mutant glioma." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 10046. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.10046.
Анотація:
10046 Background: ONC201 is the first DRD2 antagonist for clinical oncology. The recommended phase 2 dose (RP2D) of 625mg ONC201 orally once a week has been established in adult patients. ONC201 efficacy has been shown in high-grade glioma preclinical models and radiographic regressions with single agent ONC201 have been reported in adult recurrent H3 K27M-mutant glioma patients. We report results from the first Phase I pediatric clinical trial of ONC201. Methods: This multicenter, open-label, dose-escalation and dose-expansion clinical trial (NCT03416530) determined the RP2D of ONC201 in pediatric H3 K27M-mutant glioma patients as a single agent. ONC201 was orally administered once a week and scaled by body weight. Dose escalation was performed by a 3 + 3 design beginning with one 125mg capsule less than the adult RP2D equivalent. Three patients were treated at the starting dose and 19 were treated at the adult RP2D equivalent. Results: The primary endpoint was achieved by establishing the safety of the adult RP2D scaled by body weight to pediatric patients. Twenty-two patients with a median age of 9 (range 3-18) years old who received at least prior radiation have been treated with ONC201: 15 with diffuse intrinsic pontine glioma (DIPG) (4 recurrent; 11 not recurrent) and 7 with non-DIPG H3 K27M-mutant glioma (all not recurrent). As of February 5, 2019, patients have received a median of 18 ONC201 doses (range 3-41) without instance of dose-limiting toxicity. Pharmacokinetic profiles were comparable to those observed in adults (Cmax ~2.1ug/mL; AUC ~2.3hr*ug/mL) and exposure was similar across body weights. Nine of 22 patients remain on therapy, 13 have discontinued due to progression, and 4 off-study patients are alive with a median follow up of 5.8 months. Five of the 11 (45%) DIPG patients who initiated ONC201 following radiation, but prior to recurrence, remain on therapy (median 7.4 months; range 4.4-9.6): median PFS is 4.4 months from initiation of ONC201 and 9.7 months from diagnosis; 7 of 11 (64%) patients are alive with median follow up of 11.8 months from diagnosis. Conclusions: ONC201 was well tolerated and achieved therapeutic exposure in pediatric H3 K27M-mutant glioma patients at the adult RP2D scaled by body weight. Further investigation of first-line ONC201 to treat H3 K27M-mutant glioma and/or DIPG is ongoing. Clinical trial information: NCT03416530.
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Odia, Yazmin, Carl Johannes Koschmann, Rohinton Tarapore, Jeffrey Allen, Wafik Tharwat Zaky, Matthew David Hall, Doured Daghistani, et al. "Window-of-opportunity study of ONC201 in pediatric patients with diffuse intrinsic pontine glioma (DIPG) and thalamic glioma." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): TPS2082. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.tps2082.
Анотація:
TPS2082 Background: H3 K27M-mutant diffuse midline glioma is a universally fatal malignancy primarily affecting children and young adults; while radiotherapy (RT) provides transient benefit, no effective systemic therapy is currently available. ONC201, a first-in-class imipridone, is an oral, blood-brain barrier penetrating, selective small molecule antagonist of dopamine receptor D2/3 and agonist of the mitochondrial protease ClpP. Previously, ONC201 monotherapy demonstrated durable objective responses in adults with recurrent H3 K27M-mutant glioma. This phase 1 trial was designed to evaluate ONC201±RT in pediatric patients with H3 K27M-mutant midline glioma DIPG. Methods: This multicenter, open-label, dose escalation and expansion phase 1 study of ONC201 is comprised of eight arms that will evaluate the recommended phase 2 dose (RP2D) of ONC201, biomarkers, and pharmacokinetics (PK) of ONC201±RT in various treatment settings. Arm G previously defined the RP2D for ONC201 administered twice weekly on consecutive days in patients with H3 K27M-mutant glioma who had completed radiotherapy. Arm H, for which enrollment is ongoing, will estimate the influence of tumor location and blood-brain barrier integrity on PK and intratumoral ONC201 exposure in biopsy-eligible pediatric tumors (DIPG or contrast-enhancing thalamic glioma). Patients eligible for Arm H will be aged 2-≤19 years, ≥2 weeks from last RT administration, and have a Karnofsky/Lansky performance score ≥50; prior confirmation of H3 K27M mutation is not required. In Arm H, single-agent ONC201 administration will occur on two consecutive days each week during each 21-day cycle at the RP2D defined in Arm G. Evidence of disease progression is not required; as such, ONC201 may be administered in the maintenance setting or for recurrent disease. Arm H has a planned enrollment of 27 patients. Each patient will undergo biopsy at a single prespecified biopsy window, which will be assigned at enrollment (Table); plasma for PK analysis will be collected from all patients at all time points shown in the Table, with additional collection pre-dose and 0.5 h post first dose. Clinical trial information: NCT03416530. [Table: see text]
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Liu, Ilon, Jiang Li, Erik Samuelsson, Sergio Marco Salas, Alexander Beck, Olivia Hack, Daeun Jeong, et al. "EPCO-21. THE SPATIAL ORGANIZATION OF H3-K27M MUTANT DIFFUSE MIDLINE GLIOMA." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii120. http://dx.doi.org/10.1093/neuonc/noac209.456.
Анотація:
Abstract Histone 3 lysine27-to-methionine mutant diffuse midline gliomas (H3-K27M DMGs) are among the most lethal brain tumors. Their putative cellular hierarchy has been shown to be driven by self-renewing stem-like cells arrested in an oligodendrocyte precursor-like (OPC-like) state, of which few cells are able to differentiate towards more mature astrocyte (AC)-like and oligodendrocyte (OC)-like cells. However, the spatial organization underlying this tumor cell architecture and its microenvironmental interactions in intact H3-K27M DMG tissues remain unknown. Here, we profiled the single cell transcriptomes of 45 patient H3-K27M DMGs and derived cell population-specific marker gene combinations to characterize the single cell spatial organization of 16 tumors using targeted in situ sequencing. We thereby resolved different malignant and non-malignant cell populations including cycling, OPC-like, AC-like, OC-like, mesenchymal tumor cells, and non-malignant oligodendrocytes, astrocytes, neurons, myeloid cells, T cells, and vascular cells directly in situ. Global neighborhood analyses indicate a higher tendency of cycling OPC-like cells, vascular cells, and neurons to localize within a more restricted homogeneous compartment, whereas AC-like cells, non-malignant astrocytes and myeloid cells tend to intermingle with different cell populations in a more diffuse manner. Among malignant cells, we observed cycling OPC-like and OC-like cells to co-localize within a niche-like structure that is surrounded by more differentiated AC-like cells. We further validated this stem-like niche at the protein level using multiplexed immunofluorescence via the CODEX system. Finally, we characterized relationships between malignant and non-malignant cells, consistently identifying preferred neighborhoods of mesenchymal tumor cells with vascular and myeloid cells. Together, this study resolves the spatial architecture of H3-K27M DMG malignant and non-malignant cells at single cell resolution and identifies a local niche of the oligodendroglial lineage containing the OPC-like cancer stem-like cells, thus providing novel insights into the cancer stem-like compartment in H3-K27M DMGs and suggesting potential avenues for its perturbation.
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Jia, Deze, Yi Lu, Xiaomin Li, Tiantian Han, Wanglong Deng, Fanfeng Bu, and Guanghua Lu. "Comparison of next-generation sequencing and FISH/IHC for molecular classification in glioma." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e14021-e14021. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e14021.
Анотація:
e14021 Background: The updated 2016 edition of the WHO Classification of CNS tumors indicates that IDH1 R132H, H3 K27M mutations, and co-deletion of 1p19q are strong stratification and prognostic markers glioma. FISH/IHC, as the commonly detected methods, present specific false-negative rates in the actual condition. Methods: In our study, IDH1 R132H status of 158 cases was assessed by IHC and NGS, and H3 K27M statuses of 83 patients were evaluated by IHC and NGS. 22 positive cases of 1p/19q co-deletion, all confirmed by FISH, were assessed by NGS. Results: For IDH1 R132H, 2 cases were IHC negative and were positive as confirmed by NGS. Another 10 patients with weakly IHC positive results were negative in NGS. Combined with histologic hallmarks, 6 cases of these samples could be diagnosed as glioblastoma, IDH wildtype; 1 case with POLE could be diagnosed as giant cell glioblastoma; 3 cases with BRAF V600E mutation, BRAF fusion, and ATRX mutation, respectively, could be diagnosed as pilocytic astrocytoma. Towards H3 K27M, 3 cases with IHC weakly positive were negative in NGS. Among these samples, 2 cases were diagnosed as glioblastoma, IDH wildtype by molecular and histologic hallmarks, and 1 case was medulloblastoma, SHH. Using NGS, IDH1 R132H /H3 K27M statues can be distinctly distinguished in which that is unknown by IHC. The results of NGS and FISH showed a 90.9%(20/22) consistent rate for the 1p19q co-deletion. 1 case was 1p deletion and intact 19q by FISH while 1p19q co-deletion by NGS because of the 19p deletion. 1 case was 1p19q co-deletion by FISH but 1p19q wildtype by NGS, diagnosed as glioblastoma, IDH wildtype with chr7+/10-. Conclusions: In our study, the agreement between NGS results and clinical pathology diagnosis was approximately 100%. NGS may act as the primary technology of molecular classification in glioma in the future.
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Odia, Yazmin, Carl Koschmann, Rohinton Tarapore, Jeffrey Allen, Matthew Hall, Doured Daghistani, Ziad Khatib, et al. "SYST-07 WINDOW-OF-OPPORTUNITY STUDY OF ONC201 IN PEDIATRIC PATIENTS WITH DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) AND THALAMIC GLIOMA." Neuro-Oncology Advances 4, Supplement_1 (August 1, 2022): i22. http://dx.doi.org/10.1093/noajnl/vdac078.086.
Анотація:
Abstract BACKGROUND H3 K27M-mutant diffuse midline glioma is a universally fatal malignancy primarily affecting children and young adults; no effective systemic therapy is available. ONC201, a first-in-class imipridone, is an oral, blood-brain barrier penetrating, selective small molecule antagonist of dopamine receptor D2/3 and agonist of the mitochondrial protease ClpP. ONC201 monotherapy demonstrated durable objective responses in adults with recurrent H3 K27M-mutant glioma. This phase 1 trial will evaluate ONC201±radiotherapy (RT) in pediatric patients with H3 K27M-mutant midline glioma DIPG. METHODS This multicenter, open-label, dose escalation and expansion phase 1 study of ONC201 is comprised of eight arms that will evaluate the recommended phase 2 dose (RP2D) of ONC201, biomarkers, and pharmacokinetics (PK) of ONC201±RT in various treatment settings (NCT03416530). Arm G previously defined the RP2D for twice-weekly ONC201 on consecutive days. Arm H, for which enrollment is ongoing, will estimate the influence of tumor location and blood-brain barrier integrity on PK and intratumoral ONC201 exposure in biopsy-eligible pediatric tumors (DIPG or contrast-enhancing thalamic glioma). Patients eligible for Arm H will be aged 2-≤19 years, ≥2 weeks from last RT administration, and have a KPS/LPS ≥50; prior confirmation of H3 K27M mutation is not required. In Arm H, single-agent ONC201 administration will occur twice-weekly on consecutive days during each 21-day cycle at the RP2D defined in Arm G. Arm H has a planned enrollment of 27 patients (DIPG, n=15; thalamic glioma, n=12), with three patients undergoing a single biopsy at each of the following time points: 1-3 h post-first dose, 22-26 h post-second dose, 1-3 h post-first dose, 6-10 h post-second dose, and 22-26 h post-second dose. The 22-26 h post-first dose biopsy in thalamic glioma was previously collected and will not be assessed in this treatment arm. Plasma for PK analysis will be collected from all patients.
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Arrillaga-Romany, Isabel, Sylvia Kurz, Ashley Sumrall, Nicholas Butowski, Rebecca Harrison, John DeGroot, Andrew Chi, et al. "ACTR-34. SINGLE AGENT ONC201 IN PREVIOUSLY-TREATED, PROGRESSIVE ADULT H3 K27M-MUTANT GLIOMA." Neuro-Oncology 21, Supplement_6 (November 2019): vi20—vi21. http://dx.doi.org/10.1093/neuonc/noz175.077.
Анотація:
Abstract H3 K27M-mutant gliomas often manifest as midline gliomas, have a dismal prognosis, and have no established or effective treatments at recurrence. ONC201 is the first clinical bitopic DRD2 antagonist/ClpP agonist and is under evaluation in Phase II trials for gliomas and other cancers. We previously reported in vitro studies suggesting dysregulated dopamine receptor expression and enhanced ONC201 sensitivity among H3 K27M-mutant gliomas. Following these observations, adults with midline H3 K27M-mutant glioma patients were enrolled to a dedicated Phase II clinical trial (NCT03295396), a multi-arm Phase II trial (NCT0252569), and expanded access protocols under the Sponsor’s IND. An integrated radiographic analysis with an objective response rate primary endpoint in patients who received ONC201 monotherapy with confirmed H3 K27M-mutant glioma (not primarily in the pons or spinal cord and without leptomeningeal spread) that was progressive and measurable disease by RANO criteria, >90 days from completion of prior radiation, and had KPS >60. As of December 15, 2018, 15 patients have received single agent ONC201 who meet these criteria (n=9 NCT03295396; n=5 NCT0252569; n=1 expanded access). ONC201 was orally administered at 625 mg weekly, except for one patient dosed once every 3 weeks. As midline gliomas can exhibit a mixture of contrast-enhancing and non-contrast-enhancing disease, objective response was assessed by blinded independent central review using RANO-HGG and RANO-LGG criteria for each patient. Best response to date by RANO-HGG criteria is at least 27%: 1 CR, 3 PR, 7 SD, and 4 PD; by RANO-LGG is at least 36%: 1 CR, 1 PR, 3 minor response (MR), 4 SD, 5 PD, 1 unevaluable. By RANO-HGG, median onset of response is 2.6 months (range 1.3–3.4); median duration of response has not been reached with a median follow-up of 7.7 months (range 1.8–29.8). Updated radiographic response, pharmacodynamics, safety, and other clinical outcomes will be reported.
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Kurz, Sylvia Christine, Rohinton Tarapore, Yazmin Odia, Nicholas A. Butowski, Carl Johannes Koschmann, Dolly Aguilera, Tobey J. MacDonald, et al. "Clinical experience of ONC201 in patients with recurrent H3 K27M-mutant spinal cord glioma." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 2563. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.2563.
Анотація:
2563 Background: High-grade gliomas of the spinal cord are a rare and understudied entity, representing < 5% of all spinal cord tumors. Reported median survival times range from 10-16 months. Up to 53% of tumors harbor the H3 K27M mutation, which is associated with an unfavorable prognosis. Postsurgical treatment often includes radiation ± temozolomide, although the role of chemotherapy has not been conclusively established. At recurrence, there are no effective therapies and most clinical studies exclude patients with spinal cord tumors. We report our clinical experience with ONC201, a small molecule DRD2 antagonist and caseinolytic protease P agonist, in patients with recurrent H3 K27M-mutant diffuse gliomas of the spinal cord (scDG). Methods: Adults and children with recurrent H3 K27M-mutant scDG received ONC201 in two Phase II clinical trials enrolling adult recurrent H3 K27M-mutant glioma patients (NCT02525692; NCT03295396) and in one Phase I clinical trial enrolling pediatric patients (NCT03416530). Adult patients received ONC201 at the RP2D dose of 625 mg weekly and pediatric patients received the RP2D of 625 mg weekly, scaled by body weight. All patients began ONC201 as a single agent until disease progression. Five patients continued ONC201 combined with bevacizumab beyond progression. Results: As of January 15, 2020, 12 evaluable patients (adult n = 8, pediatric n = 4) received ONC201. The median age was 20.9 (range: 7-72) years. The median follow-up time for the single agent ONC201 group was 5.4 (range 1.3-9.7) months while that of the combination group is 7.4 (range 6.2-25.1) months. The median number of ONC201 doses was 10 (range: 5-39) for the ONC201 single agent group and 34 (range: 21-100) for the combination group. Five of 7 patients remain alive in the ONC201 single agent group while 3 of 5 patients remain alive in the combination group. Three patients in the ONC201 single agent group and 2 patients in the combination group continue on treatment. There were no drug-related toxicities requiring dose reduction or discontinuation. Conclusions: Treatment with ONC201 alone or combined with bevacizumab is well tolerated in patients with recurrent H3 K27M-mutant scDG and a subset of patients experiences prolonged survival that exceeds historical outcomes. Clinical trial information: NCT02525692; NCT03295396; NCT03416530 .
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Arrillaga-Romany, Isabel, Sylvia Christine Kurz, Rohinton Tarapore, Ashley Sumrall, Nicholas A. Butowski, Rebecca A. Harrison, John Frederick De Groot, et al. "Single-agent ONC201 in recurrent H3 K27M-mutant diffuse midline glioma." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 3615. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.3615.
Анотація:
3615 Background: Recurrent H3 K27M-mutant diffuse midline glioma is a lethal brain tumor that predominantly affects children and young adults and has no effective therapy. ONC201 is a first-in-class orally administered, anti-cancer small molecule that selectively antagonizes the dopamine receptors DRD2/DRD3 and agonizes ClpP, a mitochondrial protease. Prior studies have indicated dysregulated dopamine receptor expression and enhanced ONC201 sensitivity among H3 K27M-mutant gliomas. Methods: Adults with midline H3 K27M-mutant glioma patients were enrolled to a dedicated Phase II clinical trial (NCT03295396), a multi-arm Phase II clinical trial (NCT02525692), and expanded access protocols under the Sponsor’s IND. Results were pooled among patients treated with ONC201 monotherapy through any of these trial with H3 K27M confirmed glioma, progressive and measurable disease by RANO, > 90 days from completion of prior radiation, no evidence of leptomeningeal dissemination, midline location other than primarily pons or spinal cord, and baseline KPS > 60. Using an enrollment cutoff of February 15, 2019 and data cutoff of July 31, 2019, there were 20 patients (NCT03295396, 12; NCT02525692, 7; expanded access, 1). Dosage was 625 mg weekly in 19 and once every 3 weeks in 1. Results: No DLTs or treatment discontinuations due to toxicity occurred. Midline gliomas can exhibit minimal contrast enhancement or exhibit a mixture of contrast-enhancing and non-contrast enhancing regions in the tumor. As a result, blinded independent central review (BICR) of tumor response by MRI was assessed by RANO-HGG and RANO-LGG for each patient to capture contrast-enhancing lesions by T1 post-contrast and non-contrast-enhancing assessments by T2/FLAIR, respectively, in the object response rate. The best response by RANO-HGG or RANO-LGG is 30% (95% CI, 11.9-54.3%). Duration of response by RANO-HGG is median 52.7 weeks (range 15.9-138.3). One patient with stable disease as of this data cutoff has continued on treatment beyond 12 months and recently underwent an investigator-reported PR by RANO-HGG that is pending confirmation. Conclusions: Single agent ONC201 is well tolerated and clinically active in recurrent H3 K27M-mutant diffuse midline glioma patients. Clinical trial information: NCT03295396, NCT02525692 .
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Gessi, Marco, David Capper, Felix Sahm, Kristin Huang, Andreas von Deimling, Stephan Tippelt, Gudrun Fleischhack, et al. "Evidence of H3 K27M mutations in posterior fossa ependymomas." Acta Neuropathologica 132, no. 4 (August 18, 2016): 635–37. http://dx.doi.org/10.1007/s00401-016-1608-3.
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Schniederjan, Matthew J., Cahil Potnis, Varshini Vasudevaraja, Catherine D. Moser, Bethany Watson, Matija Snuderl, Tobey MacDonald, and Beverly B. Rogers. "DNA Methylation Profiles Are Stable in H3 K27M-Mutant Diffuse Midline Glioma Neurosphere Cell Lines." Children 11, no. 4 (April 20, 2024): 492. http://dx.doi.org/10.3390/children11040492.
Анотація:
Diffuse midline gliomas are among the deadliest human cancers and have had little progress in treatment in the last 50 years. Cell cultures of these tumors have been developed recently, but the degree to which such cultures retain the characteristics of the source tumors is unknown. DNA methylation profiling offers a powerful tool to look at genome-wide epigenetic changes that are biologically meaningful and can help assess the similarity of cultured tumor cells to their in vivo progenitors. Paraffinized diagnostic tissue from three diffuse intrinsic pontine gliomas with H3 K27M mutations was compared with subsequent passages of neurosphere cell cultures from those tumors. Each cell line was passaged 3–4 times and analyzed with DNA methylation arrays and standard algorithms that provided a comparison of diagnostic classification and cluster analysis. All samples tested maintained high classifier scores and clustered within the reference group of H3 K27M-mutant diffuse midline gliomas. There was a gain of 1q in all cell lines, with two cell lines initially manifesting the gain of 1q only during culture. In vitro cell cultures of H3 K27M-mutant gliomas maintain high degrees of similarity in DNA methylation profiles to their source tumor, confirming their fidelity even with some chromosomal changes.
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Diaz, Maria, Carlos Eduardo Silva Correia, Andrew Lin, Alexandra Miller, and Elena Pentsova. "PATH-04. LEPTOMENINGEAL DISEASE IN PATIENTS WITH HISTONE-MUTANT GLIOMAS." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi115. http://dx.doi.org/10.1093/neuonc/noab196.457.
Анотація:
Abstract INTRODUCTION The 2016 WHO classification describes a subtype of midline gliomas harboring histone 3 (H3) K27M mutations, and the upcoming 2021 edition may include a new subtype of hemispheric diffuse gliomas with H3 G34R/V mutations. Since we began to perform molecular profiling at Memorial Sloan Kettering Cancer Center (MSKCC) we have observed an increased prevalence of leptomeningeal disease (LMD) in this population. However, the incidence and clinical behavior of LMD has not been well defined. METHODS This is a retrospective study of patients with H3-mutant gliomas at MSKCC diagnosed from 01/2012 to 02/2021, either by tumor biopsy or by cerebrospinal fluid (CSF). Histone mutations were identified through next-generation sequencing (NGS). RESULTS We found 40 patients (pts) harboring H3 mutations (K27M mutations in 31 pts, G34R/V in 8, and both in one), with 2/40 (5%) mutations identified through CSF NGS only and rest in tumor tissue. Median age was 20.5 years (4-70); 25 were male. Tumor location was midline for K27M-mutant tumors (thalamus [N=15], brainstem [N=10], spine [N=5], pineal gland [N=1]) and hemispheric for G34R/V-mutant tumors; tumor with both mutations was thalamic. LMD was diagnosed in 22/40 (55%) pts radiographically, including 19/31 (61%) of K27M-mutant pts and 3/8 (38%) of G34R/V-mutant pts (patient with both mutations did not develop LMD). At analysis, 10 patients remain alive. Median time from diagnosis to LMD was 8.8 months (0-44.4), with median OS of 6.5 months (0.3-34) after LMD diagnosis. CONCLUSION More than half of patients with histone-mutant gliomas develop LMD, including over a third of patients with G34R/V mutations. Neuroaxis imaging should be performed in conjunction with CSF studies in histone-mutant gliomas. Besides, CSF NGS represents an important tool to identify molecular profile of tumors when biopsy is not feasible or there is limited tissue for analysis.
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Porter, William, Joshua Sulman, Katie Foot, Ruman Rahman, Richard Grundy, Robert Layfield, and Farhana Haque. "HGG-47. Comparative analysis of the Histone H3 mutant protein interactome landscape in paediatric high-grade gliomas." Neuro-Oncology 24, Supplement_1 (June 1, 2022): i71—i72. http://dx.doi.org/10.1093/neuonc/noac079.262.
Анотація:
Abstract There have been no significant improvements in the treatments for childhood and adolescent High-Grade Glioma (pHGG) and Diffuse Intrinsic Pontine Glioblastoma (DIPG), which have a very poor prognosis. These cancers harbour mutations affecting histone 3 (H3) proteins, 80% of DIPGs harbour histone H3.1 and H3.3 K27M somatic mutations whilst 30% of pHGGs exhibit H3.3 G34R or G34V mutations. Several studies have highlighted the epigenetic changes associated with these mutations, however their precise role in tumourigenesis is still unknown. We hypothesize that H3 mutations promote an aberrant interaction landscape and analysis of these interactome will highlight important pathophysiological consequences in these tumours. Two different affinity chromatographic proteomic analyses were performed using different recombinant H3 wild type (WT) and H3 mutant histone proteins (K27M, G34R and G34V) to purify their binding partners, from cell extracts of control and pHGG/DIPG patients cell lines. The purified samples were then subjected to Liquid Chromatography-Mass Spectrometry (LC-MS) to identify their co-bound partners. The results have isolated unique and common differential interaction partners of the H3 mutants and with cellular proteins in comparison to H3 WT protein, in the pHGG tumour cells. The role these altered protein interactions are being investigating in tumour initiation, progression and/or maintenance of H3 mutated pHGG/DIPG, with the aim to manipulate their function as alternate therapeutic intervention. Results of these analyses/experiments will be presented.
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Arrillaga-Romany, Isabel, Sylvia Kurz, Rohinton S. Tarapore, Ashley Sumrall, Nicholas Butowski, Rebecca Harrison, John de Groot, et al. "CTNI-37. EFFICACY OF ONC201 IN PATIENTS WITH ONC201 FOR RECURRENT H3 K27M-MUTANT DIFFUSE MIDLINE GLIOMA." Neuro-Oncology 22, Supplement_2 (November 2020): ii50—ii51. http://dx.doi.org/10.1093/neuonc/noaa215.204.
Анотація:
Abstract H3 K27M-mutant diffuse midline gliomas (DMG) have a dismal prognosis. We report an integrated analysis for ONC201, a DRD2 antagonist and ClpP agonist, in patients with recurrent H3 K27M DMG administered as monotherapy in 3 clinical studies (NCT03295396, n=20; NCT02525692, n=6; or expanded access, n=4) by independent, central radiology review among 30 patients. At baseline, patients had measurable contrast-enhancing disease by RANO criteria, KPS>60, and were >90 days from prior radiation. Patients with primary lesions that involved the pons or spinal cord or had evidence of leptomeningeal or cerebrospinal fluid dissemination were excluded. ONC201 was orally administered at 625 mg (scaled by body weight for patients < 18 years old) weekly in 29 patients and every 3 weeks in 1 patient. Median age was 31 years (range 8–70; two patients < 18). There were 16 women and 14 men. Tumors were predominantly thalamic (73%), with other locations including the cerebellum (5%), brainstem (non-pontine) (3%), basal ganglia (3%), and midbrain (3%). Median time from prior radiation was 7.5 months. The most frequent drug-related adverse events were low grade nausea (10%) and fatigue (10%). Nine patients (30%) had >50% regression of T1 contrast enhancement and 11 (36.7%) patients had regression of T2/FLAIR. Objective response rate and progression-free survival by RANO criteria, as well overall survival will be reported. Among 8 patients with sustained radiographic regressions, 6 were tapered off dexamethasone and 4 had improvement in KPS. Five patients (16.7%) remain on treatment with a median of 9.5 months (range 7.3–12). In conclusion, single agent ONC201 is well tolerated and clinically active in recurrent H3 K27M DMG patients.
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Haque, Farhana. "Comparative Analysis of the Histone H3 Mutant Protein Interactome Landscape in Paediatric High-Grade Gliomas." Neuro-Oncology 24, Supplement_4 (October 1, 2022): iv4. http://dx.doi.org/10.1093/neuonc/noac200.016.
Анотація:
Abstract AIMS There have been no significant improvements in the treatments for childhood and adolescent High-Grade Glioma (pHGG) and Diffuse Intrinsic Pontine Glioblastoma (DIPG), which have a very poor prognosis. These cancers harbour mutations affecting histone 3 (H3) proteins, 80% of DIPGs harbour histone H3.1 and H3.3 K27M somatic mutations whilst 30% of pHGGs exhibit H3.3 G34R or G34V mutations. Several studies have highlighted the epigenetic changes associated with these mutations, however their precise role in tumourigenesis is still unknown. We hypothesize that H3 mutations promote an aberrant interaction landscape and analysis of these interactome will highlight important pathophysiological consequences in these tumours. METHOD Two different affinity chromatographic proteomic analyses were performed using different recombinant H3 wild type (WT) and H3 mutant histone proteins (K27M, G34R and G34V) to purify their binding partners, from cell extracts of control and pHGG/DIPG patients cell lines. The purified samples were then subjected to Liquid Chromatography-Mass Spectrometry (LC-MS) to identify their co-bound partners. RESULTS The results have isolated unique and common differential interaction partners of the H3 mutants and with cellular proteins in comparison to H3 WT protein, in the pHGG tumour cells. CONCLUSION The role these altered protein interactions are being investigating in tumour initiation, progression and/or maintenance of H3 mutated pHGG/DIPG, with the aim to manipulate their function as alternate therapeutic intervention. Results of these analyses/experiments will be presented.
44
Balakrishnan, Samantha, Ivan Carabenciov, Michael Ruff, Joon Uhm, and Sani Kizilbash. "RARE-37. TREATMENT OF H3K27M MUTANT GLIOMAS WITH PANOBINOSTAT." Neuro-Oncology 21, Supplement_6 (November 2019): vi229. http://dx.doi.org/10.1093/neuonc/noz175.960.
Анотація:
Abstract Panobinostat (PBST) is a histone deacetylase inhibitor with biologic rationale in the treatment of gliomas harboring H3 K27M mutation. METHODS We performed a retrospective medical record review of adult patients with H3 K27M mutant diffuse midline glioma treated with PBST at Mayo Clinic (Rochester, MN). RESULTS Four patients were identified with a mean age 40 years (range 22–62 years). Tumor location was: spinal cord (thoracic n=1, cervical n=1), brainstem (n=1), and thalamus (n=1).Two patients underwent biopsy alone while two underwent a partial resection. Three patients were treated with radiation (36–54 Gy) immediately prior to PBST monotherapy, and one patient was treated with PBST monotherapy without preceding radiation. All patients were otherwise chemotherapy naïve and did not receive any concurrent chemotherapy with PBST. PBST was dosed at either 10 mg (n=1) or 20mg (n=3) administered on days 1, 3, 5, 8, 10 and 12 of 21 day cycles. The mean duration of PBST therapy was 5 months (range 2–11 months). PBST was well tolerated overall. One patient experienced an objective response per RANO criteria. Two patients continue on therapy (5 cycles, 12 cycles) with stable disease. One patient rapidly progressed after 2 cycles of PBST therapy. In contrast with the patients who derived benefit from PBST, this patient was younger (22) and had multifocal disease with leptomeningeal involvement at treatment onset. The average progression free survival post PBST initiation was 8 months. CONCLUSION This single institution case series shows promise that PBST may have therapeutic benefit in adult patients with H3 K27M mutant diffuse midline glioma.
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Sumrall, Ashley Love, Joanne Xiu, Jennifer M. Eschbacher, Sandeep Mittal, Zoran Gatalica, Manjari K. Pandey, Surasak Phuphanich, Wolfgang Michael Korn, Gregory N. Fuller, and Amy B. Heimberger. "Mutations of H3.3 and H3.1 in a large cohort of glioma tumors." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e13540-e13540. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e13540.
Анотація:
e13540 Background: Mutations in the histone genes H3.3 and H3.1 are driver events in pediatric and adult gliomas and carry diagnostic and prognostic importance for tumors originating from midline structures. Patients with tumors affected by these mutations are notoriously difficult to treat, and the prevalence and molecular correlates of H3 mutations in a large glioma population have not been systematically reported. We aim to survey a large cohort of gliomas for H3-mutations. Methods: Consecutive gliomas submitted for tumor profiling at Caris Life Sciences from 2015- 2018 were analyzed. NextGen sequencing was done on 592 genes (NextSEQ Illumina); MGMT promoter methylation was tested by pyrosequencing; and EGFRvIII and gene fusions were tested by RNA-sequencing (ArcherDx FusionPlex). Results: Of the 1763 tumors analyzed, 41 harbored H3F3A alterations, including 33 with the K27M mutation (4 arose from the spinal cord, 1 from cerebellum, 1 from brain stem, 4 from thalamus, and 23 from brain, NOS). Eight G34R mutations were identified. A HIST1H3B-K27M was detected in a tumor from the brain stem. Overall, H3 mutations were more prevalent in pediatric tumors (8 of 26, 31%) than adult tumors (34 of 1737, 2%). All H3 mutations seen in pediatric tumors were from grade IV tumors. Among the 34 H3-mutated adult tumors, histology differed. There were 2 grade II tumors (diffuse astrocytoma), 1 low grade glioma from the spinal cord, 1 anaplastic ganglioglioma and 2 anaplastic astrocytomas. In the investigated cohort, H3-mutations were mutually exclusive of IDH1/2 mutations and EGFR alterations. Significantly higher mutation rates were seen in H3-mutated tumors for TP53 (69%. Vs. 37%), ATRX (46% vs. 24%), NF1 (23% vs. 12%) , PDGFRA (17% vs. 1%), FGFR1 (12% vs. 1%), FBXW7 (5% vs. 0), BLM (3% vs. 0) and TSC2 (2% vs.0) compared with H3-WT (p < 0.05). The H3-WT tumors were more enriched for MGMT-methylation (53% vs. 26%) and PTEN mutation (22% vs. 7%) (p < 0.05). In H3-mutated tumors that were MGMT-methylated (n = 10), most H3-mutations seen were G34R (n = 8) while K27M (n = 2) was largely exclusive. Conclusions: This survey of a large cohort of gliomas revealed a heterogeneous distribution of H3 mutations. The co-occurring molecular alterations seen in H3-mutated tumors further support the hypothesis that these tumors are a distinct molecular entity. By better characterizing these associations, we are closer to developing more insight into novel treatment strategies for a class of tumors with historically dismal prognosis.
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Arrillaga, Isabel, Sylvia Kurz, Ashley Sumrall, Nicholas A. Butowski, Rebecca A. Harrison, John Frederick De Groot, Nicole A. Shonka, et al. "Single agent ONC201 in adult recurrent H3 K27M-mutant glioma." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 3005. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.3005.
Анотація:
3005 Background: H3 K27M-mutant glioma is associated with a poor prognosis and there is no effective therapy following radiation. We report the clinical experience with single agent ONC201, the first small molecule DRD2 antagonist in oncology, in adults with recurrent H3 K27M-mutant glioma. Methods: Twenty-nine adult patients with recurrent H3 K27M-mutant glioma have been treated with single agent ONC201 as of January 20, 2019: 19 patients on NCT03295396; 8 patients on NCT02525692; 2 patients on compassionate use protocols under the Sponsor’s IND. Median age was 57 years old (range: 17-74), median prior lines of therapy was 2 (range: 1-4) and all patients received prior radiation (median 8.5 months from radiation completion to ONC201 initiation). ONC201 was orally administered at 625 mg weekly, except for one patient dosed once every 3 weeks. Results: As of February 5, 2019, 13 of 29 patients remain on-trial within median follow up of 6.5 months (range: 0.6-33.6), 8 patients are alive but off-trial with median follow up of 2.4 months (range: 0.2-9), and 8 patients have expired. Nine of 29 patients (31%) remain progression-free on ONC201 with a median follow up of 6.5 months (range 0.6-33.6). No dose-limiting toxicities or treatment discontinuations due to toxicity occurred. Three patients have experienced durable partial responses by RANO (4.3-28.5 months). In addition, one patient experienced complete regression that continues for > 14 months of all < 1 cm tumor lesions that are not measurable by RANO. Furthermore, 10 patients had a best response of stable disease by RANO, 12 patients experienced progressive disease, and 3 patients are not yet evaluable. Among the patients with a best response of stable disease by RANO, one patient had > 50% tumor regression in the basal ganglia that did not qualify as a partial response by RANO due to a new lesion on a confirmatory scan. Another patient with stable disease by RANO has had 37% tumor regression so far in the brainstem and remains on-treatment for 6 months. All tumor regressions remain durable to date and some were associated with improvements in disease-associated neurological symptoms. Conclusions: Single agent ONC201 is well tolerated and clinically active in adult recurrent H3 K27M-mutant glioma patients. Clinical trial information: NCT03295396; NCT02525692.
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Azadi, Amir, Ekokobe Fonkem, and Tejas Ranade. "EPID-12. TREATMENT OUTCOMES OF MIDLINE GLIOMAS WITH H3K27 M: OUR BARROW NEUROLOGICAL INSTITUTE EXPERIENCE." Neuro-Oncology 22, Supplement_2 (November 2020): ii81. http://dx.doi.org/10.1093/neuonc/noaa215.330.
Анотація:
Abstract BACKGROUND H3 K27M glioblastoma is an aggressive grade IV tumor located in midline structures, added in 2016 by the WHO. Current outcomes are poor. The rarity of these tumors presents a challenge for definitive research on developing optimal treatments. METHODS We conducted a case series of 12 patients at the Barrow Neurological Institute who were diagnosed with biopsy-proven H3 K27M glioblastoma. The clinical status of these patients was followed from dates of first and last contact. Factors included first line treatment, best response to first line treatment, recurrences, second line treatments, response assessment criteria for all treatment rounds, any discovered metastases, and vital status by date of last contact. RESULTS Of the initial 12 patients, 5 were lost to follow-up before meaningful clinical outcomes could be recorded. Of the remaining 7, all underwent temozolomide and radiation as components of first-line treatment. After first-line treatment, 1/7 (14.2%) had partial response, 3/7 (42.8%) had stable disease, and 3/7 (42.8%) had progressive disease. 4 patients elected to undergo second line treatment: 2 underwent bevacizumab with lomustine, 1 underwent bevacizumab and irinotecan, and 1 underwent surgery with carmustine. Of the 2 who underwent bevacizumab and lomustine, 1 (50%) improved from progressive to stable disease and 1 (50%) stayed at stable disease. Of the 1 patient who underwent bevacizumab and lomustine, outcome worsened from stable to progressive disease. Of the 1 patient who underwent surgery and carmustine, outcome improved from progressive to stable disease. CONCLUSIONS H3 K27M is a highly aggressive tumor with poor outcomes. This case series demonstrates that multiple treatment rounds with chemotherapy and radiation therapy may benefit patients, with bevacizumab/lomustine and surgery/carmustine appearing to lead to promising outcomes. Further research is needed to establish evidence-based protocols so quality of life and survival time in these patients may improve.
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Gardner, Sharon, Carl Koschmann, Rohinton Tarapore, Jeffrey Allen, Wafik Zaky, Yazmin Odia, Matthew Hall, et al. "CTNI-36. SAFETY OF ONC201 ADMINISTERED TWO CONSECUTIVE DAYS PER WEEK IN PEDIATRIC H3 K27M-MUTANT GLIOMA PATIENTS." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi67. http://dx.doi.org/10.1093/neuonc/noab196.261.
Анотація:
Abstract ONC201, an anti-cancer DRD2 antagonist and ClpP agonist, is in Phase II trials for adult H3 K27M-mutant diffuse midline gliomas. The recommended phase 2 dose (RP2D) of 625mg ONC201 once a week has been established as a biologically active dose that is well tolerated in adult and pediatric populations. Radiographic regressions with single agent ONC201 have been reported in recurrent H3 K27M-mutant glioma patients. In another study, twice/week dosing was explored in adult patients and deemed to be safe (no DLTs observed). This warranted exploration of twice/week dosing in pediatric patients and will be discussed in this presentation. This multi-arm, dose-escalation and dose-expansion trial (ONC014; NCT03416530) determined the pediatric RP2D of ONC201 administered once per week and twice per week on two consecutive days. ONC201 was orally administered and scaled by body weight. Dose escalation was performed by a 3 + 3 design beginning with two 125mg capsules less than the adult RP2D equivalent. Twelve children (8 females; 4 males) with H3 K27M-mutant gliomas (pons: 8; thalamus: 2; spinal cord: 2) aged 4-19 years have been treated post-radiation: 3 at dose level -1; 3 at dose level 1; 6 as part of the dose expansion cohort on dose level 2. Median KPS was 90 (range 70-100). One treatment cycle was 21 days (6 doses), which also defined the DLT window. Patients were on-treatment for a median length of 4 cycles (range: 2-11). Twice weekly dosing of ONC201 was tolerated well, as observed with weekly dosing, with no instance of DLT. A total of 4 SAEs were reported, none of which were related to the study drug. The most common AEs (regardless of relatedness) included headache, facial nerve disorder, abducens nerve disorder, nausea, fatigue and ataxia. Additional safety data, PK, and clinical outcomes from this arm will be reported.
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Damodharan, Sudarshawn, Montserrat Lara-Velazquez, Brooke Carmen Williamsen, Jeffrey Helgager, and Mahua Dey. "Diffuse Intrinsic Pontine Glioma: Molecular Landscape, Evolving Treatment Strategies and Emerging Clinical Trials." Journal of Personalized Medicine 12, no. 5 (May 20, 2022): 840. http://dx.doi.org/10.3390/jpm12050840.
Анотація:
Diffuse intrinsic pontine glioma (DIPG) is a type of intrinsic brainstem glial tumor that occurs primarily in the pediatric population. DIPG is initially diagnosed based on clinical symptoms and the characteristic location on imaging. Histologically, these tumors are characterized by a heterogenous population of cells with multiple genetic mutations and high infiltrative capacity. The most common mutation seen in this group is a lysine to methionine point mutation seen at position 27 (K27M) within histone 3 (H3). Tumors with the H3 K27M mutation, are considered grade 4 and are now categorized within the H3 K27-altered diffuse midline glioma category by World Health Organization classification. Due to its critical location and aggressive nature, DIPG is resistant to the most eradicative treatment and is universally fatal; however, modern advances in the surgical techniques resulting in safe biopsy of the lesion have significantly improved our understanding of this disease at the molecular level. Genomic analysis has shown several mutations that play a role in the pathophysiology of the disease and can be targeted therapeutically. In this review, we will elaborate on DIPG from general aspects and the evolving molecular landscape. We will also review innovative therapeutic options that have been trialed along with new promising treatments on the horizon.
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Grebstad Tune, Benedicte, Heena Sareen, Branka Powter, Smadar Kahana-Edwin, Adam Cooper, Eng-Siew Koh, Cheok S. Lee, et al. "From Pediatric to Adult Brain Cancer: Exploring Histone H3 Mutations in Australian Brain Cancer Patients." Biomedicines 11, no. 11 (October 27, 2023): 2907. http://dx.doi.org/10.3390/biomedicines11112907.
Анотація:
Genetic histone variants have been implicated in cancer development and progression. Mutations affecting the histone 3 (H3) family, H3.1 (encoded by HIST1H3B and HIST1H3C) and H3.3 (encoded by H3F3A), are mainly associated with pediatric brain cancers. While considered poor prognostic brain cancer biomarkers in children, more recent studies have reported H3 alterations in adult brain cancer as well. Here, we established reliable droplet digital PCR based assays to detect three histone mutations (H3.3-K27M, H3.3-G34R, and H3.1-K27M) primarily linked to childhood brain cancer. We demonstrate the utility of our assays for sensitively detecting these mutations in cell-free DNA released from cultured diffuse intrinsic pontine glioma (DIPG) cells and in the cerebral spinal fluid of a pediatric patient with DIPG. We further screened tumor tissue DNA from 89 adult patients with glioma and 1 with diffuse hemispheric glioma from Southwestern Sydney, Australia, an ethnically diverse region, for these three mutations. No histone mutations were detected in adult glioma tissue, while H3.3-G34R presence was confirmed in the diffuse hemispheric glioma patient.