bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2024–12–29
nine papers selected by
Oltea Sampetrean, Keio University
  1. The role of vorasidenib in the treatment of isocitrate dehydrogenase-mutant glioma.
  2. Phase II trial of blood-brain barrier permeable peptide-paclitaxel conjugate ANG1005 in patients with recurrent high-grade glioma.
  3. A Role for the Hippo/YAP1 Pathway in the Regulation of In Vitro Vasculogenic Mimicry in Glioblastoma Cells.
  4. IL13RA2-integrated genetically engineered mouse model allows for CAR T cells targeting pediatric high-grade gliomas.
  5. Autophagy Modulates Glioblastoma Cell Sensitivity to Selinexor-mediated XPO1 inhibition.
  6. Inhibiting glioblastoma stem cells by targeting pyruvate carboxylase: A novel therapeutic strategy with both opportunities and challenges.
  7. Longitudinal glioma monitoring via cerebrospinal fluid cell-free DNA.
  8. Inhibition of thioredoxin reductase 1 sensitizes glucose-starved glioblastoma cells to disulfidptosis.
  9. Inhibiting glioblastoma stem cells by targeting pyruvate carboxylase: a novel therapeutic strategy with both opportunities and challenges.
  1. Neuro Oncol. 2024 Dec 25. pii: noae259. [Epub ahead of print]
    The role of vorasidenib in the treatment of isocitrate dehydrogenase-mutant glioma.
    Macarena I de la Fuente, Mehdi Touat, Martin J van den Bent, Matthias Preusser, Katherine B Peters, Robert J Young, Raymond Y Huang, Benjamin M Ellingson, David Capper, Joanna J Phillips, Lia M Halasz, Helen A Shih, Roberta Rudà, Mary Jane Lim-Fat, Deborah T Blumenthal, Michael Weller, Yoshiki Arakawa, James R Whittle, François Ducray, David A Reardon, Wenya Linda Bi, Giuseppe Minniti, Rifaquat Rahman, Shawn Hervey-Jumper, Susan M Chang, Patrick Y Wen.
      Isocitrate dehydrogenase (IDH)-mutant gliomas are the most common malignant primary brain tumors in young adults. This condition imposes a substantial burden on patients and their caregivers, marked by neurocognitive deficits and high mortality rates due to tumor progression, coupled with significant morbidity from current treatment modalities. Although surgery, radiation therapy, and chemotherapy improve survival, these treatments can adversely affect cognitive function, quality of life, finances, employment status, and overall independence. Consequently, there is an urgent need for innovative strategies that delay progression and the use of radiation therapy and chemotherapy. The recent Federal Drug Administration (FDA) approval of vorasidenib, a brain-penetrant small molecule targeting mutant IDH1/2 proteins, heralds a shift in the therapeutic landscape for IDH-mutant gliomas. In this review, we address the role of vorasidenib in the treatment of IDH-mutant gliomas, providing a roadmap for its incorporation into daily practice. We discuss ongoing clinical trials with vorasidenib and other IDH inhibitors, as single-agent or in combination with other therapies, as well as current challenges and future directions.
    Keywords:  1p-19q co-deleted oligodendroglioma | glioma | IDH-mutant astrocytoma | IDH-mutant | isocitrate dehydrogenase (IDH) | vorasidenib
    DOI:  https://doi.org/10.1093/neuonc/noae259
  2. Neurooncol Adv. 2024 Jan-Dec;6(1):6(1): vdae186
    Phase II trial of blood-brain barrier permeable peptide-paclitaxel conjugate ANG1005 in patients with recurrent high-grade glioma.
    Crismita Dmello, Andrew Brenner, David Piccioni, Patrick Y Wen, Jan Drappatz, Maciej Mrugala, Lionel D Lewis, David Schiff, Camilo E Fadul, Marc Chamberlain, Santosh Kesari, Manmeet Ahluwalia, Debora Ghosh, Adam M Sonabend, Priya Kumthekar.
       Background: This study is a phase II clinical trial to evaluate the efficacy, safety, and tolerability of the blood-brain barrier (BBB) permeable peptide-paclitaxel conjugate ANG1005 in patients with recurrent high-grade glioma (HGG) (NCT01967810).
    Methods: Seventy-three patients were enrolled in 3 separate arms-recurrent glioblastoma (GBM) (Arm 1), bevacizumab refractory GBM (Arm 2), and grade 3 anaplastic gliomas (AGs) (Arm 3). The study was started in October 2013, and the data were locked on September 29, 2017. Safety was evaluated for all three arms (n = 73), and the primary endpoint for Arms 1 and 3 was objective response rate (ORR), and Arm 2 primary endpoint was progression-free survival rate at 3 months (PFS3).
    Results: Overall, the safety of ANG1005 was found to be consistent with a taxane toxicity profile. Otherwise, the primary efficacy endpoints of ORR and PFS were not met. The most common adverse events (AEs) were hematologic (32.9%), alopecia (31.5%), and fatigue (30.1%). The median PFS was 1.4 months (95% CI: 1.4, 2.1) and similar across all the treatment arms. The median overall survival was 13.4 months (95% CI: 3.4, 14.6) in Arm 1, 5.8 months (95% CI: 1.9, 9.7) in Arm 2, and 18.2 months (95% CI: 10.7, 35.3) in Arm 3.
    Conclusion: A dose of 600 mg/m2 was determined to be safe in this study. However, the primary efficacy endpoint was not met in the NCT01967810-ANG1005 trial, and no further studies are planned in the glioma setting with this compound.
    Keywords:  ANG1005; high-grade glioma; paclitaxel; phase II clinical trial
    DOI:  https://doi.org/10.1093/noajnl/vdae186
  3. J Cell Mol Med. 2024 Dec;28(24): e70304
    A Role for the Hippo/YAP1 Pathway in the Regulation of In Vitro Vasculogenic Mimicry in Glioblastoma Cells.
    Marie-Eve Roy, Rahil Elimam, Alain Zgheib, Borhane Annabi.
      The Hippo pathway plays a tumorigenic role in highly angiogenic glioblastoma (GBM), whereas little is known about clinically relevant Hippo pathway inhibitors' ability to target adaptive mechanisms involved in GBM chemoresistance. Their molecular impact was investigated here in vitro against an alternative process to tumour angiogenesis termed vasculogenic mimicry (VM) in GBM-derived cell models. In silico analysis of the downstream Hippo signalling members YAP1, TAZ and TEAD1 transcript levels in low-grade glioblastoma (LGG) and GBM tumour tissues was performed using GEPIA. TAZ transcript levels did not differ between the healthy and tumour tissues data analysed. In contrast, YAP1 transcript levels were elevated in GBM tissues, whereas TEAD1 levels were high in both LGG and GBM. All three Hippo pathway inhibitors tested, GNE7883, VT107 and IAG933 effectively inhibited U87 and U251 cell migration and in vitro VM as assessed on Cultrex matrix. YAP1 gene and protein expression were induced upon VM, and its translocation to the nucleus was inhibited by the Hippo pathway inhibitors tested. SiRNA-mediated transient silencing of YAP1 repressed cell migration, VM formation and CTGF and Cyr61 transcription. In conclusion, targeting of VM using Hippo pathway inhibitors could help circumvent GBM chemoresistance and effectively complement other brain cancer treatments.
    Keywords:  YAP/TEAD; chemoresistance; glioblastoma; hippo pathway; vasculogenic mimicry
    DOI:  https://doi.org/10.1111/jcmm.70304
  4. Res Sq. 2024 Dec 11. pii: rs.3.rs-5398280. [Epub ahead of print]
    IL13RA2-integrated genetically engineered mouse model allows for CAR T cells targeting pediatric high-grade gliomas.
    Maggie Seblani, Markella Zannikou, Joseph Duffy, Rebecca Levine, Aditi Thakur, Montserrat Puigdelloses- Vallcorba, Crag Horbinski, Jason Miska, Dolores Hambardzumyan, Oren Becher, Irina Balyasnikova.
      Pediatric high-grade gliomas (pHGG) and pediatric diffuse midline gliomas (pDMG) are devastating diseases without durable and curative options. Although targeted immunotherapy has shown promise, the field lacks immunocompetent animal models to study these processes in detail. To achieve this, we developed a fully immunocompetent, genetically engineered mouse model (GEMM) for pDMG and pHGG that incorporates the glioma-associated antigen, interleukin 13 receptor alpha 2 (IL13RA2). Utilizing the RCAS-Tva delivery system in Nestin-Tva mice, we induced gliomagenesis by overexpressing PDGFB and deleting p53 (p53 fl/fl ) or both p53 and PTEN (p53 fl/fl PTEN fl/fl ), with or without IL13RA2 in neonatal mice. De novo tumors developed in models with and without IL13RA2, showing no statistical difference in onset (n = 33, 38 days, p = 0.62). The p53 fl/fl PTEN fl/fl tumors displayed more aggressive characteristics (n = 12, 31 days). Tumors exhibited features typical of high-grade glioma, including infiltration, pseudopalisading necrosis, and microvascular proliferation. They also showed a high Ki-67 index, variable IL13RA2 expression, a high frequency of CD11b + macrophages, and a low proportion of CD3 + T cells. The model proved effective for evaluating IL13RA2-targeted immunotherapies, with a significant response to CAR T-cell treatment that extended survival (46 days vs. 28 days control; p < 0.0001) and achieved 25% long-term survival in mice. This model facilitates the preclinical assessment of IL13RA2-directed therapies and holds potential for clinical application.
    DOI:  https://doi.org/10.21203/rs.3.rs-5398280/v1
  5. Neuro Oncol. 2024 Dec 28. pii: noae280. [Epub ahead of print]
    Autophagy Modulates Glioblastoma Cell Sensitivity to Selinexor-mediated XPO1 inhibition.
    Yongjian Tang, Lisa Sprinzen, Yukinori Terada, Karrie M Kiang, Chuntao Li, Yu Zeng, Fangkun Liu, Hongshu Zhou, Xisong Liang, Jianzhong Zhang, Russell O Pieper, Bo Chen, Liyang Zhang.
       BACKGROUND: Selinexor is a selective inhibitor of exportin-1 (XPO1), a key mediator of the nucleocytoplasmic transport for molecules critical to tumor cell survival. Selinexor's lethality is generally associated with the induction of apoptosis, and in some cases, with autophagy-induced apoptosis. We performed this study to determine Selinexor's action in glioblastoma (GBM) cells, which are notoriously resistant to apoptosis.
    METHODS: Patient-derived GBM cells were treated with Selinexor, and drug response and autophagy levels were monitored. Homozygous C528S XPO1 mutant GBM43 cells were generated by CRISPR/Cas9 editing. Single Selinexor or combination treatment with autophagy inhibitors was evaluated. In addition, bulk-tissue, single-cell, and spatial transcriptome were analyzed, and molecular docking was performed.
    RESULTS: Although all cell lines exhibited a dose- and time-dependent reduction of cell viability, the most profound molecular response to Selinexor was induction of autophagy instead of apoptosis. Selinexor-induced autophagy was an on-target consequence of XPO1 inhibition, and could be mitigated by expression of a mutant, Selinexor-resistant form of XPO1, and Selinexor-induced autophagy was related at least in part to nuclear trapping of the transcription factor TFEB. Furthermore, genetic or pharmacologic suppression of autophagy sensitized the cells to Selinexor-induced toxicity in association with the induction of apoptosis. Finally, in intracranial PDX studies, the combination of Selinexor with the autophagy inhibitor chloroquine significantly impeded tumor growth and extended mouse survival relative to single-agent treatment.
    CONCLUSION: These results suggest that activation of autophagy confers a protective mechanism against Selinexor in GBM cells, and that the combination of Selinexor with autophagy inhibitors may serve as a viable means to enhance Selinexor-induced cell death.
    Keywords:  Selinexor; XPO1; autophagy; glioma; nuclear export
    DOI:  https://doi.org/10.1093/neuonc/noae280
  6. Neuro Oncol. 2024 Dec 26. pii: noae250. [Epub ahead of print]
    Inhibiting glioblastoma stem cells by targeting pyruvate carboxylase: A novel therapeutic strategy with both opportunities and challenges.
    Ophélie Renoult, Mélanie Laurent-Blond, Claire Pecqueur.
      
    DOI:  https://doi.org/10.1093/neuonc/noae250
  7. Clin Cancer Res. 2024 Dec 23.
    Longitudinal glioma monitoring via cerebrospinal fluid cell-free DNA.
    Cecile Riviere-Cazaux, Xiaoxi Dong, Wei Mo, Rahul Kumar, Chao Dai, Lucas P Carlstrom, Amanda Munoz-Casabella, Keyvan Ghadimi, Cody L Nesvick, Katherine M Andersen, Matthew D Hoplin, Nicholas Canaday, Ignacio Jusue-Torres, Noor Malik, Jian L Campian, Michael W Ruff, Joon H Uhm, Jeanette E Eckel-Passow, Timothy J Kaufmann, David M Routman, Sani H Kizilbash, Ugur Sener, Arthur E Warrington, Robert B Jenkins, Pan Du, Shidong Jia, Terry C Burns.
       PURPOSE: Current methods for glioma response assessment are limited. This study aimed to assess the technical and clinical feasibility of molecular profiling using longitudinal intracranial CSF from patients with gliomas.
    EXPERIMENTAL DESIGN: Adults with gliomas underwent longitudinal intracranial CSF collection via Ommaya reservoirs or ventriculoperitoneal shunts. cfDNA was extracted and analyzed using PredicineCARE for cancer variant profiling and/or PredicineSCORE for low-pass whole genome sequencing (LP-WGS).
    RESULTS: Five patients (2 females, 3 males; median age: 40 years, range 32-64 years) underwent longitudinal intracranial CSF collection via Ommaya reservoirs (n=4) or ventriculoperitoneal shunts (n=1). In total, forty-seven CSF samples were obtained (median volume: 4.00 mL; 0.5-5 mL). Forty-one samples (87.2%) yielded sufficient cfDNA for testing. Patient-specific tumor-associated variant allelic frequencies (VAFs), and thus tumor fraction, decreased in pre-versus-post chemoradiation samples, including through pseudoprogression. These also increased with radiographic progression in three patients, although identifying the time of definitive disease progression from MRIs was a significant limitation. In two patients with isocitrate dehydrogenase (IDH) mutant gliomas, decreasing IDH1 VAF after resection and chemoradiation correlated with decreased CSF D-2-hydroxyglutarate (D-2-HG) levels (0.64x and 0.62x, respectively, for the first patient, and 0.01x and 0.07x for the other patient), although D-2-HG and IDH1 VAF were not concordant in one patient thereafter. Moreover, CNB decreased below the limit of quantification during treatment and increased above the limit at progression.
    CONCLUSION: Longitudinal intracranial CSF cfDNA can feasibly be obtained in patients with gliomas during their disease course. Numerous questions and challenges should be answered before deploying this technique.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-24-1814
  8. Cell Death Differ. 2024 Dec 23.
    Inhibition of thioredoxin reductase 1 sensitizes glucose-starved glioblastoma cells to disulfidptosis.
    Miaolu Tang, Kaitlyn Dirks, Soo Yeon Kim, Zhiqiang Qiu, Yan Gao, Dongxiao Sun, Gabrielle Peruggia, Jessica Sallavanti, Wei Li.
      Disulfidptosis is a recently identified form of cell death characterized by the aberrant accumulation of cellular disulfides. This process primarily occurs in glucose-starved cells expressing higher levels of SLC7A11 and has been proposed as a therapeutic strategy for cancers with hyperactive SCL7A11. However, the potential for inducing disulfidptosis through other mechanisms in cancers remains unclear. Here, we found that inhibiting thioredoxin reductase 1 (TrxR1), a key enzyme in the thioredoxin system, induces disulfidptosis in glioblastoma (GBM) cells. TrxR1 expression is elevated in GBM with activated transcriptional coactivator with PDZ-binding motif (TAZ) and correlates with poor prognosis. TrxR1 inhibitors induced GBM cell death that can be rescued by disulfide reducers but not by ROS scavengers or inhibitors of apoptosis, ferroptosis, or necroptosis. Glucose-starved cells, but not those deprived of oxygen or glutamine, increased TrxR1 expression in an NRF2-dependent manner and were more sensitive to TrxR1 inhibition-induced cell death. The dying cells initially exhibited highly dynamic lamellipodia, followed by actin cytoskeleton collapse. This process involved the accumulation of cytosolic peroxisomes and micropinocytic caveolae, as well as small gaps in the plasma membrane. Depletion of the WAVE complex component NCKAP1 partially rescued the cells, whereas Rac inhibition enhanced cell death. In an orthotopic xenograft GBM mouse model, TrxR1 depletion inhibited tumor growth and improved survival. Furthermore, cells undergoing TrxR1 inhibition exhibited features of immunogenic cell death. Therefore, this study suggests the potential of targeting TrxR1 as a therapeutic strategy in GBM.
    DOI:  https://doi.org/10.1038/s41418-024-01440-0
  9. Neuro Oncol. 2024 Dec 26. pii: noae249. [Epub ahead of print]
    Inhibiting glioblastoma stem cells by targeting pyruvate carboxylase: a novel therapeutic strategy with both opportunities and challenges.
    Menghua Chen, Guangjing Mu, Yibo Wu, Rolf Bjerkvig, Hongwei Wang, Donghai Wang, Mingzhi Han.
      
    DOI:  https://doi.org/10.1093/neuonc/noae249
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