2025-06-1310:00
Bieke Van den EndeMatteo RivaFrederik De SmetSandra JacobsEsther HullemanAn Coosemans
Diffuse intrinsic pontine glioma (DIPG) is a rare and highly aggressive pediatric brain tumor with a median survival of less than 12 months. The tumor arises in the pons, making surgical resection unfeasible and limiting treatment options to palliative radiation, which offers minimal survival benefit. One of the major challenges in treating DIPG is the poorly understood tumor immune microenvironment, which has hindered the development of effective immunotherapies. DIPG tumors are considered to...
Diffuse intrinsic pontine glioma (DIPG) is a rare and highly aggressive pediatric brain tumor with a median survival of less than 12 months. The tumor arises in the pons, making surgical resection unfeasible and limiting treatment options to palliative radiation, which offers minimal survival benefit. One of the major challenges in treating DIPG is the poorly understood tumor immune microenvironment, which has hindered the development of effective immunotherapies. DIPG tumors are considered to...
J Immunother Cancer. 2025 Jun 12;13(6):e012009. doi: 10.1136/jitc-2025-012009.
ABSTRACT
Diffuse intrinsic pontine glioma (DIPG) is a rare and highly aggressive pediatric brain tumor with a median survival of less than 12 months. The tumor arises in the pons, making surgical resection unfeasible and limiting treatment options to palliative radiation, which offers minimal survival benefit. One of the major challenges in treating DIPG is the poorly understood tumor immune microenvironment, which has hindered the development of effective immunotherapies. DIPG tumors are considered to be immunologically cold with limited immune cell infiltration. Recent studies have begun to reveal the complex and heterogeneous immune landscape of DIPG, highlighting distinct immunological subgroups. This review aims to provide a comprehensive overview of the immune landscape of DIPG based on the latest insights, identify research gaps, and suggest potential areas for future investigation to improve treatment outcomes for patients with DIPG.
PMID:40514066 | PMC:PMC12164617 | DOI:10.1136/jitc-2025-012009
2025-06-1110:00
Alaa Daoud SarsourSara KinstlingerRephael NizarNaama AmosNarkis ArbeliGila KazimirskyIrena Bronshtein-BergerIris FriedRon UngerChaya BrodieMoran Dvela-Levitt
Glioblastoma is one of the most aggressive and lethal forms of brain cancer, with limited therapeutic options and poor patient prognosis. Recent research has identified the TMED family of proteins as key regulators of tumor progression and aggressiveness across multiple cancer types. TMED members are cargo receptors expressed within the early secretory pathway and involved in bidirectional traffic of various proteins including EGFR, TGF-ɑ and WNT. In this study, we explored the therapeutic...
Glioblastoma is one of the most aggressive and lethal forms of brain cancer, with limited therapeutic options and poor patient prognosis. Recent research has identified the TMED family of proteins as key regulators of tumor progression and aggressiveness across multiple cancer types. TMED members are cargo receptors expressed within the early secretory pathway and involved in bidirectional traffic of various proteins including EGFR, TGF-ɑ and WNT. In this study, we explored the therapeutic...
Cells. 2025 May 23;14(11):772. doi: 10.3390/cells14110772.
ABSTRACT
Glioblastoma is one of the most aggressive and lethal forms of brain cancer, with limited therapeutic options and poor patient prognosis. Recent research has identified the TMED family of proteins as key regulators of tumor progression and aggressiveness across multiple cancer types. TMED members are cargo receptors expressed within the early secretory pathway and involved in bidirectional traffic of various proteins including EGFR, TGF-ɑ and WNT. In this study, we explored the therapeutic potential of genetic and pharmacologic inhibition of the cargo receptor TMED9 in glial tumor models. Our findings demonstrate that TMED9 expression is upregulated in glioma and that this upregulation is associated with poor patient survival. Using patient-derived glioma tumor cells, we demonstrate that TMED9 is highly expressed in the cancer stem cell population and that this upregulation promotes the cells' self-renewal and migration. This is the first time, to the best of our knowledge, that TMED9 has been shown to play a major role in the function and tumorigenesis of brain tumor cancer stem cells. BRD4780, a small molecule that targets TMED9, effectively reduced TMED9 abundance, resulting in decreased viability, migration and stemness of patient-derived glioma stem cells. Moreover, BRD4780 mitigated the proliferation and migration of differentiated glioma tumor cells. When applied together with temozolomide, an established glioblastoma treatment, BRD4780 elicited an enhanced anti-tumor response. Lastly, to demonstrate the broad applicability of our findings, we targeted TMED9 in pediatric glioma cells and showed efficient inhibition of various oncogenic functions. Collectively, our study identifies TMED9 inhibition as a promising therapeutic approach that impairs the tumorigenesis and aggressiveness of brain tumors, with high efficacy against the tumor stem cell population. The effectiveness of TMED9 targeting in different tumor cell populations, the potential of combining this strategy with established therapies and the broad applicability of this approach to multiple cancer types highlight the significance of these findings.
PMID:40497947 | PMC:PMC12153874 | DOI:10.3390/cells14110772
2025-06-1010:00
Yamini DharmashaktuMadhavi TripathiSanjana BallalK P HareshSubhash GuptaNishikant A DamleC S Bal
Of the pediatric brainstem gliomas, around 80% develop in the pons, with the vast majority of pontine tumors being diffuse intrinsic brainstem gliomas (DIPG), which tend to be high grade, locally infiltrative, and have a poor prognosis. We present a 12-year-old girl diagnosed with DIPG in July 2022, who received 60 Gy, 30 fractions of radical radiotherapy over 6 weeks, followed by temozolomide. With residual disease, the patient was referred to our department for the possibility of...
Of the pediatric brainstem gliomas, around 80% develop in the pons, with the vast majority of pontine tumors being diffuse intrinsic brainstem gliomas (DIPG), which tend to be high grade, locally infiltrative, and have a poor prognosis. We present a 12-year-old girl diagnosed with DIPG in July 2022, who received 60 Gy, 30 fractions of radical radiotherapy over 6 weeks, followed by temozolomide. With residual disease, the patient was referred to our department for the possibility of...
Clin Nucl Med. 2025 Jun 9. doi: 10.1097/RLU.0000000000005980. Online ahead of print.
ABSTRACT
Of the pediatric brainstem gliomas, around 80% develop in the pons, with the vast majority of pontine tumors being diffuse intrinsic brainstem gliomas (DIPG), which tend to be high grade, locally infiltrative, and have a poor prognosis. We present a 12-year-old girl diagnosed with DIPG in July 2022, who received 60 Gy, 30 fractions of radical radiotherapy over 6 weeks, followed by temozolomide. With residual disease, the patient was referred to our department for the possibility of radiotheranostics. She underwent 68Ga PSMA PET/CT, which revealed tracer accumulation in the pontine mass and was subsequently given 2 cycles of Lu-177 PSMA 617 and 1 cycle of Ac-225 PSMA 617 therapy.
PMID:40494369 | DOI:10.1097/RLU.0000000000005980
2025-06-0610:00
Ian MersichSunny CongroveMatthew HorcharRoman CaceresRanjithmenon MuraleedharanJanki DesaiPankaj DesaiLarry SallansJulie A ReiszAbby GrierMatthew R HassOmer DonmezCailing YinMatthew T WeirauchLeah KottyanCharles B StevensonClaire SunPeter de BlankNatasha Pillay-SmileyTrent R HummelNagarajan ElumalaiAli TavassoliRon FiresteinTimothy N PhoenixAngelo D'AlessandroBiplab Dasgupta
Diffuse intrinsic pontine glioma (DIPG) is a devastating brainstem cancer in children, with a median survival of under one year and limited treatment options. Over 80% of DIPGs possess a H3K27M mutation. To identify metabolic vulnerabilities linked to this mutation, we utilized a multi-omics approach in H3K27M-expressing cells, patient-derived cell lines, and mouse models. We show that by reprogramming chromatin landscape the mutation aberrantly induces NFI transcriptional activity, leading to...
Diffuse intrinsic pontine glioma (DIPG) is a devastating brainstem cancer in children, with a median survival of under one year and limited treatment options. Over 80% of DIPGs possess a H3K27M mutation. To identify metabolic vulnerabilities linked to this mutation, we utilized a multi-omics approach in H3K27M-expressing cells, patient-derived cell lines, and mouse models. We show that by reprogramming chromatin landscape the mutation aberrantly induces NFI transcriptional activity, leading to...
bioRxiv [Preprint]. 2025 May 24:2025.05.21.655327. doi: 10.1101/2025.05.21.655327.
ABSTRACT
Diffuse intrinsic pontine glioma (DIPG) is a devastating brainstem cancer in children, with a median survival of under one year and limited treatment options. Over 80% of DIPGs possess a H3K27M mutation. To identify metabolic vulnerabilities linked to this mutation, we utilized a multi-omics approach in H3K27M-expressing cells, patient-derived cell lines, and mouse models. We show that by reprogramming chromatin landscape the mutation aberrantly induces NFI transcriptional activity, leading to misregulated purine metabolism. The mutation amplifies purine biosynthesis and degradation via the enzymes ATIC and PNP, respectively. Unregulated purine degradation relieves the negative feedback of purines on their own synthesis allowing continuous synthesis, use and degradation making DIPGs reliant on purine biosynthesis. Targeting ATIC reduced tumor progression and improved survival in mice. We propose ATIC as a potential novel target in DIPG.
PMID:40475444 | PMC:PMC12139796 | DOI:10.1101/2025.05.21.655327
2025-06-0610:00
Banlanjo UmaruDeepak Kumar MishraShiva Senthil KumarHao-Han PangBrendan DevineKomal KhanRachid Drissi
BMI-1 (B cell-specific Moloney murine leukemia virus integration site 1) has been implicated in both normal and cancer cell biology. While the canonical function of BMI-1 involves epigenetic repression, novel extra-nuclear functions have been recently reported. In the present study, we demonstrate that the phosphorylation of BMI-1 in diffuse intrinsic pontine glioma (DIPG) cells occurs in M phase and that triggers simultaneous translocation of the phosphorylated BMI-1 to the cytoplasm. This...
BMI-1 (B cell-specific Moloney murine leukemia virus integration site 1) has been implicated in both normal and cancer cell biology. While the canonical function of BMI-1 involves epigenetic repression, novel extra-nuclear functions have been recently reported. In the present study, we demonstrate that the phosphorylation of BMI-1 in diffuse intrinsic pontine glioma (DIPG) cells occurs in M phase and that triggers simultaneous translocation of the phosphorylated BMI-1 to the cytoplasm. This...
bioRxiv [Preprint]. 2025 May 22:2025.05.16.654605. doi: 10.1101/2025.05.16.654605.
ABSTRACT
BMI-1 (B cell-specific Moloney murine leukemia virus integration site 1) has been implicated in both normal and cancer cell biology. While the canonical function of BMI-1 involves epigenetic repression, novel extra-nuclear functions have been recently reported. In the present study, we demonstrate that the phosphorylation of BMI-1 in diffuse intrinsic pontine glioma (DIPG) cells occurs in M phase and that triggers simultaneous translocation of the phosphorylated BMI-1 to the cytoplasm. This translocation is mediated by the RanGTP-dependent transporter CRM1, also known as exportin. Furthermore, we uncovered a previously unidentified nuclear export signal (NES) in BMI-1 protein, suggesting an active transport type of modified BMI-1 mediated by CRM1. These findings associate BMI-1 phosphorylation with its trafficking in M phase. Collectively, this study sheds light on the molecular mechanisms underlying BMI-1 functions in DIPG, thereby potentially paving the way for the development of targeted therapeutic strategies related to M phase progression.
PMID:40475549 | PMC:PMC12139911 | DOI:10.1101/2025.05.16.654605
2025-06-0310:00
Kawaljit KaurAnahid Jewett
High-grade glioma tumors are the common cause of death in pediatric patients. K27M cell line is regularly used as tumor model to study diffuse intrinsic pontine glioma (DIPG) since they harbor genetic mutation in which the lysine of the histone H3 protein is replaced with a methionine. The objective of this study is to demonstrate the significance of supercharged NK (sNK) cells alone or in combination with ONC201 or ONC206 to target such aggressive pediatric brain tumor K27M. We have observed...
High-grade glioma tumors are the common cause of death in pediatric patients. K27M cell line is regularly used as tumor model to study diffuse intrinsic pontine glioma (DIPG) since they harbor genetic mutation in which the lysine of the histone H3 protein is replaced with a methionine. The objective of this study is to demonstrate the significance of supercharged NK (sNK) cells alone or in combination with ONC201 or ONC206 to target such aggressive pediatric brain tumor K27M. We have observed...
Crit Rev Immunol. 2025;45(3):0. doi: 10.1615/CritRevImmunol.2025058345.
ABSTRACT
High-grade glioma tumors are the common cause of death in pediatric patients. K27M cell line is regularly used as tumor model to study diffuse intrinsic pontine glioma (DIPG) since they harbor genetic mutation in which the lysine of the histone H3 protein is replaced with a methionine. The objective of this study is to demonstrate the significance of supercharged NK (sNK) cells alone or in combination with ONC201 or ONC206 to target such aggressive pediatric brain tumor K27M. We have observed increased secretion of IFN-γ by sNK cells compared to primary IL-2-activated NK cells. Combining sNK cells with ONC201 or ONC206 further increased IFN-γ in sNK cells. When primary NK cells and sNK cells were used as effectors against the glioma tumor cell line K27M, tumor cells were found to be highly susceptible to sNK cell-mediated cytotoxicity compared to primary NK cell-mediated cytotoxicity. sNK cell-mediated cytotoxicity against K27M was significantly increased when sNK cells were combined with ONC201 and ONC206. This study suggests the potential use of sNK cells alone or in combination with ONC201 or ONC206 as therapeutic strategies in treating and preventing the recurrence of aggressive pediatric brain tumors.
PMID:40460384 | DOI:10.1615/CritRevImmunol.2025058345