Developing H3K27M mutant selective radiosensitization strategies in diffuse intrinsic pontine glioma

Parsels, Leslie A.; Wahl, Daniel R.; Koschmann, Carl; Morgan, Meredith A.; Zhang, Qiang

doi:10.1016/j.neo.2023.100881

Cited by 4 publications

(4 citation statements)

References 109 publications

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“…The standard of care for DMG/DIPG includes radiation therapy, which is typically used to manage symptoms such as pain and difficulty with motor function. Radiation therapy can reduce the size of the tumor and alleviate some of the symptoms, but it is not a cure [ 5 42 ]. Ongoing clinical trials are exploring new treatments for DMG/DIPG, including targeted therapies, immunotherapy, and gene therapy [ 5 42 43 44 45 ].…”

Section: Treatment By Epigenetic or Metabolomic Regulationmentioning

confidence: 99%

“…Radiation therapy can reduce the size of the tumor and alleviate some of the symptoms, but it is not a cure [ 5 42 ]. Ongoing clinical trials are exploring new treatments for DMG/DIPG, including targeted therapies, immunotherapy, and gene therapy [ 5 42 43 44 45 ]. Some of these treatments target specific molecular pathways involved in the growth and survival of DMG/DIPG cells.…”

Section: Treatment By Epigenetic or Metabolomic Regulationmentioning

confidence: 99%

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Epigenetic and Metabolic Changes in Diffuse Intrinsic Pontine Glioma

Park

Chung

2023

Brain Tumor Res Treat

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Diffuse midline glioma (DMG), hitherto known as diffuse intrinsic pontine glioma (DIPG), is a rare and aggressive form of brain cancer that primarily affects children. Although the exact cause of DMG/DIPG is not known, a large proportion of DMG/DIPG tumors harbor mutations in the gene encoding the histone H3 protein, specifically the H3K27M mutation. This mutation decreases the level of H3K27me3, a histone modification that plays a vital role in regulating gene expression through epigenetic regulation. The mutation also alters the function of polycomb repressive complex 2 (PRC2), thereby preventing the repression of genes associated with cancer development. The decrease in H3K27me3 caused by the histone H3 mutation is accompanied by an increase in the level of H3K27ac, a post-translational modification related to active transcription. Dysregulation of histone modification markedly affects gene expression, contributing to cancer development and progression by promoting uncontrolled cell proliferation, tumor growth, and metabolism. DMG/DIPG alters the metabolism of methionine and the tricarboxylic acid cycle, as well as glucose and glutamine uptake. The role of epigenetic and metabolic changes in the development of DMG/DIPG has been studied extensively, and understanding these changes is critical to developing therapies targeting these pathways. Studies are currently underway to identify new therapeutic targets for DMG/DIPG, which may lead to the development of effective treatments for this devastating disease.

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Section: Treatment By Epigenetic or Metabolomic Regulationmentioning

confidence: 99%

Section: Treatment By Epigenetic or Metabolomic Regulationmentioning

confidence: 99%

Epigenetic and Metabolic Changes in Diffuse Intrinsic Pontine Glioma

Park

Chung

2023

Brain Tumor Res Treat

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“…A recurrent monoallelic, nonsynonymous mutation at amino acid position 27 in the histone-3.3 or 3.1 genes (H3K27M) defines a distinct subtype of highly aggressive diffuse midline glioma (DMG) characterized by high mortality and morbidity rates [1][2][3] . Due to infiltrative growth in midline brain structures and resistance to chemotherapy 4 , radiotherapy remains the main effective treatment option for DMG [5][6][7] . Due to a low mutational burden and a lack of immune cell infiltration, DMG is generally nonresponsive to immune checkpoint inhibition treatment but may benefit from personalized treatment or targeted immunotherapies [5][6][7] .…”

Section: Mainmentioning

confidence: 99%

Neoepitope-specific vaccination of a patient with diffuse midline glioma targeting H3K27M induces polyclonal B and T cell responses across diverse HLA alleles

Boschert

Kromer

Lerner

et al. 2023

Preprint

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H3K27M, a driver mutation with T- and B-cell neoepitope characteristics, defines an aggressive subtype of diffuse glioma with poor survival. We functionally dissect the immune response of one patient who was treated with an H3K27M peptide vaccine and subsequently entered complete remission. The vaccine robustly expanded class II HLA-restricted peripheral H3K27M-specific T cells. Using functional assays, we characterized 34 clonally unique H3K27M-reactive T cell receptors and identified critical, conserved motifs in their CDR3 regions. Using detailed HLA mapping, we further demonstrate that diverse HLA-DQ, and -DR alleles present immunogenic H3K27M epitopes. Furthermore, we identified and profiled H3K27M-reactive B cell receptors from activated B cells in the cerebrospinal fluid. Our results uncover the breadth of the adaptive immune response against a shared clonal neoantigen across multiple HLA allelotypes and support the use of class II-restricted peptide vaccines to stimulate tumor-specific T and B cells harboring receptors with therapeutic potential.

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“…A recurrent monoallelic, nonsynonymous mutation at amino acid position 27 in the genes encoding histone-3.3 or 3.1 (H3K27M) defines a distinct subtype of highly aggressive diffuse midline glioma (DMG) characterized by high morbidity and universal lethality, with a median overall survival of 11 months after diagnosis (1)(2)(3). Because of infiltrative growth in midline brain structures and resistance to chemotherapy (4), radiotherapy remains the main effective treatment option for DMG (5)(6)(7). Because of a low mutational burden and a lack of immune cell infiltration, DMG is generally nonresponsive to immune checkpoint inhibition treatment but may benefit from personalized treatment or targeted immunotherapies (5)(6)(7).…”

Section: Introductionmentioning

confidence: 99%

H3K27M neoepitope vaccination in diffuse midline glioma induces B and T cell responses across diverse HLA loci of a recovered patient

Boschert,

Kromer,

Lerner

et al. 2024

Sci. Adv.

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H3K27M, a driver mutation with T and B cell neoepitope characteristics, defines an aggressive subtype of diffuse glioma with poor survival. We functionally dissect the immune response of one patient treated with an H3K27M peptide vaccine who subsequently entered complete remission. The vaccine robustly expanded class II human leukocyte antigen (HLA)–restricted peripheral H3K27M-specific T cells. Using functional assays, we characterized 34 clonally unique H3K27M-reactive T cell receptors and identified critical, conserved motifs in their complementarity-determining region 3 regions. Using detailed HLA mapping, we further demonstrate that diverse HLA-DQ and HLA-DR alleles present immunogenic H3K27M epitopes. Furthermore, we identified and profiled H3K27M-reactive B cell receptors from activated B cells in the cerebrospinal fluid. Our results uncover the breadth of the adaptive immune response against a shared clonal neoantigen across multiple HLA allelotypes and support the use of class II–restricted peptide vaccines to stimulate tumor-specific T and B cells harboring receptors with therapeutic potential.

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Developing H3K27M mutant selective radiosensitization strategies in diffuse intrinsic pontine glioma

Cited by 4 publications

References 109 publications

Epigenetic and Metabolic Changes in Diffuse Intrinsic Pontine Glioma

Epigenetic and Metabolic Changes in Diffuse Intrinsic Pontine Glioma

Neoepitope-specific vaccination of a patient with diffuse midline glioma targeting H3K27M induces polyclonal B and T cell responses across diverse HLA alleles

H3K27M neoepitope vaccination in diffuse midline glioma induces B and T cell responses across diverse HLA loci of a recovered patient

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