bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2023–05–21
24 papers selected by
Oltea Sampetrean, Keio University
  1. GBP3-STING interaction in glioblastoma coordinates autophagy, anti-oxidative, and DNA repair programs in response to temozolomide.
  2. A Molecular Blueprint to Targeting ALK Gene Fusions in Glioblastoma.
  3. Neuronal-glioma cross-talk.
  4. Advancing combination therapy for recurrent glioblastoma.
  5. Pericyte-Glioblastoma Cell Interaction: A Key Target to Prevent Glioblastoma Progression.
  6. Concurrent Activation of Both Survival-Promoting and Death-Inducing Signaling by Chloroquine in Glioblastoma Stem Cells: Implications for Potential Risks and Benefits of Using Chloroquine as Radiosensitizer.
  7. Retraction of: PTEN loss drives resistance to the neddylation inhibitor MLN4924 in glioblastoma and can be overcome with TOP2A inhibitors.
  8. An immunosuppressed microenvironment distinguishes lateral ventricle-contacting glioblastomas.
  9. Ribonucleotide reductase regulatory subunit M2 drives glioblastoma TMZ resistance through modulation of dNTP production.
  10. Mitogen-Induced Defective Mitosis Transforms Neural Progenitor Cells.
  11. Tailoring vascular phenotype through AAV therapy promotes anti-tumor immunity in glioma.
  12. Cell-based therapies for glioblastoma: Promising tools against tumor heterogeneity.
  13. "Sabotaging the Protein Factory to Overcome Glioma Stem Cell Resistance".
  14. Oncolytic DNX-2401 virotherapy plus pembrolizumab in recurrent glioblastoma: a phase 1/2 trial.
  15. ONC201 in Combination with Paxalisib for the Treatment of H3K27-Altered Diffuse Midline Glioma.
  16. External Control Arms and Data Analysis Methods in Nonrandomized Trial of Patients With Glioblastoma-Reply.
  17. Correction: Distinct Cell Adhesion Signature Defines Glioblastoma Myeloid-Derived Suppressor Cell Subsets.
  18. Enhanced Sestrin expression through Tanshinone 2A treatment improves PI3K-dependent inhibition of glioma growth.
  19. Genomic profiles of IDH-mutant gliomas: MYCN-amplified IDH-mutant astrocytoma had the worst prognosis.
  20. Association of MGMT Promotor Methylation With Survival in Low-grade and Anaplastic Gliomas After Alkylating Chemotherapy.
  21. A local water molecular-heating strategy for near-infrared long-lifetime imaging-guided photothermal therapy of glioblastoma.
  22. MGMT Methylation Status in Grades 2 and 3 Gliomas Is Important, but Is It Prognostic?
  23. External Control Arms and Data Analysis Methods in Nonrandomized Trial of Patients With Glioblastoma.
  24. External Control Arms and Data Analysis Methods in Nonrandomized Trial of Patients With Glioblastoma.
  1. Oncotarget. 2023 May 19. 14 483-484
    GBP3-STING interaction in glioblastoma coordinates autophagy, anti-oxidative, and DNA repair programs in response to temozolomide.
    Jun Ma, Ziyu Wang, Clark C Chen, Ming Li.
      
    Keywords:  GBP3; MGMT; STING; glioblastoma; temozolomide resistance
    DOI:  https://doi.org/10.18632/oncotarget.28370
  2. Clin Cancer Res. 2023 May 15. pii: CCR-23-0472. [Epub ahead of print]
    A Molecular Blueprint to Targeting ALK Gene Fusions in Glioblastoma.
    Stephen C Mack, Kelsey C Bertrand.
      Glioblastoma (GBM) is a heterogeneous brain tumor entity from infancy through adulthood. ALK gene fusions enriched in congenital and infant GBM have emerged as druggable driver alterations. Understanding the molecular basis and prevalence of ALK gene rearrangements will help define GBM patients that may benefit from ALK targeted therapy.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-23-0472
  3. Sci Signal. 2023 May 16. 16(785): eadi6672
    Neuronal-glioma cross-talk.
    Amy E Baek.
      Remodeling of neural circuits by glioma cells decreases patient survival.
    DOI:  https://doi.org/10.1126/scisignal.adi6672
  4. Nat Med. 2023 May 15.
    Advancing combination therapy for recurrent glioblastoma.
    Adela Wu, Michael Lim.
      
    DOI:  https://doi.org/10.1038/s41591-023-02350-3
  5. Cells. 2023 05 05. pii: 1324. [Epub ahead of print]12(9):
    Pericyte-Glioblastoma Cell Interaction: A Key Target to Prevent Glioblastoma Progression.
    Ana Pombero, Raquel Garcia-Lopez, Salvador Martínez.
      Multiple biological processes rely on direct intercellular interactions to regulate cell proliferation and migration in embryonic development and cancer processes. Tumor development and growth depends on close interactions between cancer cells and cells in the tumor microenvironment. During embryonic development, morphogenetic signals and direct cell contacts control cell proliferation, polarity, and morphogenesis. Cancer cells communicate with cells in the tumor niche through molecular signals and intercellular contacts, thereby modifying the vascular architecture and antitumor surveillance processes and consequently enabling tumor growth and survival. While looking for cell-to-cell signaling mechanisms that are common to both brain development and cancer progression, we have studied the infiltration process in glioblastoma multiforme (GBM), which is the most malignant primary brain tumor and with the worst prognosis. Cell-to-cell contacts, by means of filopodia-like structures, between GBM cells and brain pericytes (PCs) are necessary for adequate cell signaling during cancer infiltration; similarly, contacts between embryonic regions, via cytonemes, are required for embryo regionalization and development. This GBM-PC interaction provokes two important changes in the physiological function of these perivascular cells, namely, (i) vascular co-option with changes in cell contractility and vascular malformation, and (ii) changes in the PC transcriptome, modifying the microvesicles and protein secretome, which leads to the development of an immunosuppressive phenotype that promotes tumor immune tolerance. Moreover, the GTPase Cdc42 regulates cell polarity across organisms, from yeast to humans, playing a central role in GBM cell-PC interaction and maintaining vascular co-option. As such, a review of the molecular and cellular mechanisms underlying the development and maintenance of the physical interactions between cancer cells and PCs is of particular interest.
    Keywords:  cell–cell contact; filopodia; glioblastoma; high-grade glial neoplasm; pericytes
    DOI:  https://doi.org/10.3390/cells12091324
  6. Cells. 2023 04 30. pii: 1290. [Epub ahead of print]12(9):
    Concurrent Activation of Both Survival-Promoting and Death-Inducing Signaling by Chloroquine in Glioblastoma Stem Cells: Implications for Potential Risks and Benefits of Using Chloroquine as Radiosensitizer.
    Andreas Müller, Patrick Weyerhäuser, Nancy Berte, Fitriasari Jonin, Bogdan Lyubarskyy, Bettina Sprang, Sven Rainer Kantelhardt, Gabriela Salinas, Lennart Opitz, Walter Schulz-Schaeffer, Alf Giese, Ella L Kim.
      Lysosomotropic agent chloroquine was shown to sensitize non-stem glioblastoma cells to radiation in vitro with p53-dependent apoptosis implicated as one of the underlying mechanisms. The in vivo outcomes of chloroquine or its effects on glioblastoma stem cells have not been previously addressed. This study undertakes a combinatorial approach encompassing in vitro, in vivo and in silico investigations to address the relationship between chloroquine-mediated radiosensitization and p53 status in glioblastoma stem cells. Our findings reveal that chloroquine elicits antagonistic impacts on signaling pathways involved in the regulation of cell fate via both transcription-dependent and transcription-independent mechanisms. Evidence is provided that transcriptional impacts of chloroquine are primarily determined by p53 with chloroquine-mediated activation of pro-survival mevalonate and p21-DREAM pathways being the dominant response in the background of wild type p53. Non-transcriptional effects of chloroquine are conserved and converge on key cell fate regulators ATM, HIPK2 and AKT in glioblastoma stem cells irrespective of their p53 status. Our findings indicate that pro-survival responses elicited by chloroquine predominate in the context of wild type p53 and are diminished in cells with transcriptionally impaired p53. We conclude that p53 is an important determinant of the balance between pro-survival and pro-death impacts of chloroquine and propose that p53 functional status should be taken into consideration when evaluating the efficacy of glioblastoma radiosensitization by chloroquine.
    Keywords:  AKT; ATM; HIPK2; chloroquine; glioblastoma radiosensitization; glioblastoma stem cells; p21-DREAM; p53
    DOI:  https://doi.org/10.3390/cells12091290
  7. Neuro Oncol. 2023 May 13. pii: noad081. [Epub ahead of print]
    Retraction of: PTEN loss drives resistance to the neddylation inhibitor MLN4924 in glioblastoma and can be overcome with TOP2A inhibitors.
      
    DOI:  https://doi.org/10.1093/neuonc/noad081
  8. JCI Insight. 2023 May 16. pii: e160652. [Epub ahead of print]
    An immunosuppressed microenvironment distinguishes lateral ventricle-contacting glioblastomas.
    Todd Bartkowiak, Sierra M Lima, Madeline J Hayes, Akshitkumar M Mistry, Asa A Brockman, Justine Sinnaeve, Nalin Leelatian, Caroline E Roe, Bret C Mobley, Silky Chotai, Kyle D Weaver, Reid C Thompson, Lola B Chambless, Rebecca A Ihrie, Jonathan M Irish.
      Radiographic contact of glioblastoma (GBM) tumors with the lateral ventricle and adjacent stem cell niche correlates with poor patient prognosis, but the cellular basis of this difference is unclear. Here, we reveal and functionally characterize distinct immune microenvironments that predominate in subtypes of GBM distinguished by proximity to the lateral ventricle. Mass cytometry analysis of IDH-wildtype human tumors identified elevated T cell checkpoint receptor expression and greater abundance of a specific CD32+CD44+HLA-DRhigh macrophage population in ventricle-contacting GBM. Multiple computational analysis approaches, phospho-specific cytometry, and focal resection of GBMs confirmed and extended these findings. Phospho-flow quantified cytokine-induced immune cell signaling in ventricle-contacting GBM revealing differential signaling between GBM subtypes. Subregion analysis within a given tumor supported initial findings and revealed intratumoral compartmentalization of T cell memory and exhaustion phenotypes within GBM subtypes. Collectively, these results characterize immunotherapeutically targetable features of macrophages and suppressed lymphocytes in glioblastomas defined by MRI-detectable lateral ventricle contact.
    Keywords:  Bioinformatics; Brain cancer; Immunology; Oncology; T cells
    DOI:  https://doi.org/10.1172/jci.insight.160652
  9. Sci Adv. 2023 May 19. 9(20): eade7236
    Ribonucleotide reductase regulatory subunit M2 drives glioblastoma TMZ resistance through modulation of dNTP production.
    Ella N Perrault, Jack M Shireman, Eunus S Ali, Peiyu Lin, Isabelle Preddy, Cheol Park, Shreya Budhiraja, Shivani Baisiwala, Karan Dixit, C David James, Dieter H Heiland, Issam Ben-Sahra, Sebastian Pott, Anindita Basu, Jason Miska, Atique U Ahmed.
      During therapy, adaptations driven by cellular plasticity are partly responsible for driving the inevitable recurrence of glioblastoma (GBM). To investigate plasticity-induced adaptation during standard-of-care chemotherapy temozolomide (TMZ), we performed in vivo single-cell RNA sequencing in patient-derived xenograft (PDX) tumors of GBM before, during, and after therapy. Comparing single-cell transcriptomic patterns identified distinct cellular populations present during TMZ therapy. Of interest was the increased expression of ribonucleotide reductase regulatory subunit M2 (RRM2), which we found to regulate dGTP and dCTP production vital for DNA damage response during TMZ therapy. Furthermore, multidimensional modeling of spatially resolved transcriptomic and metabolomic analysis in patients' tissues revealed strong correlations between RRM2 and dGTP. This supports our data that RRM2 regulates the demand for specific dNTPs during therapy. In addition, treatment with the RRM2 inhibitor 3-AP (Triapine) enhances the efficacy of TMZ therapy in PDX models. We present a previously unidentified understanding of chemoresistance through critical RRM2-mediated nucleotide production.
    DOI:  https://doi.org/10.1126/sciadv.ade7236
  10. Neuro Oncol. 2023 Apr 26. pii: noad082. [Epub ahead of print]
    Mitogen-Induced Defective Mitosis Transforms Neural Progenitor Cells.
    Hiba K Omairi, Cameron J Grisdale, Mathieu Meode, Alexandra K Bohm, Sophie Black, Nancy J Adam, Cassidy P Chapman, Tatiana Maroilley, John J Kelly, Maja Tarailo-Graovac, Steven J M Jones, Michael D Blough, J Gregory Cairncross.
       BACKGROUND: Chromosome instability (CIN) with recurrent copy number alterations is a feature of many solid tumors, including glioblastoma (GBM), yet the genes that regulate cell division are rarely mutated in cancers. Here, we show that the brain-abundant mitogen, platelet-derived growth factor-A (PDGFA) fails to induce the expression of kinetochore and spindle assembly checkpoint genes leading to defective mitosis in neural progenitor cells (NPCs).
    METHODS: Using a recently reported in vitro model of the initiation of high-grade gliomas from murine NPCs, we investigated the immediate effects of PDGFA exposure on the nuclear and mitotic phenotypes and patterns of gene and protein expression in NPCs, a putative GBM cell of origin.
    RESULTS: NPCs divided abnormally in defined media containing PDGFA with P53-dependent effects. In wild type cells, defective mitosis was associated with P53 activation and cell death, but in some null cells defective mitosis was tolerated. Surviving cells had unstable genomes and proliferated in the presence of PDGFA accumulating random and clonal chromosomal rearrangements. The outcome of this process was a population of tumorigenic NPCs with recurrent gains and losses of chromosomal regions that were syntenic to those recurrently gained and lost in human GBM. By stimulating proliferation without setting the stage for successful mitosis, PDGFA transformed NPCs lacking P53 function.
    CONCLUSION: Our work describes a mechanism of transformation of NPCs by a brain-associated mitogen, raising the possibility that the unique genomic architecture of GBM is an adaptation to defective mitosis that ensures the survival of affected cells.
    Keywords:  GBM; P53; PDGFA; kinetochore; mitosis
    DOI:  https://doi.org/10.1093/neuonc/noad082
  11. Cancer Cell. 2023 May 06. pii: S1535-6108(23)00136-8. [Epub ahead of print]
    Tailoring vascular phenotype through AAV therapy promotes anti-tumor immunity in glioma.
    Mohanraj Ramachandran, Alessandra Vaccaro, Tiarne van de Walle, Maria Georganaki, Roberta Lugano, Kalyani Vemuri, Despoina Kourougkiaouri, Konstantinos Vazaios, Marie Hedlund, Georgia Tsaridou, Lene Uhrbom, Ilkka Pietilä, Miika Martikainen, Luuk van Hooren, Thomas Olsson Bontell, Asgeir S Jakola, Di Yu, Bengt Westermark, Magnus Essand, Anna Dimberg.
      Glioblastomas are aggressive brain tumors that are largely immunotherapy resistant. This is associated with immunosuppression and a dysfunctional tumor vasculature, which hinder T cell infiltration. LIGHT/TNFSF14 can induce high endothelial venules (HEVs) and tertiary lymphoid structures (TLS), suggesting that its therapeutic expression could promote T cell recruitment. Here, we use a brain endothelial cell-targeted adeno-associated viral (AAV) vector to express LIGHT in the glioma vasculature (AAV-LIGHT). We found that systemic AAV-LIGHT treatment induces tumor-associated HEVs and T cell-rich TLS, prolonging survival in αPD-1-resistant murine glioma. AAV-LIGHT treatment reduces T cell exhaustion and promotes TCF1+CD8+ stem-like T cells, which reside in TLS and intratumoral antigen-presenting niches. Tumor regression upon AAV-LIGHT therapy correlates with tumor-specific cytotoxic/memory T cell responses. Our work reveals that altering vascular phenotype through vessel-targeted expression of LIGHT promotes efficient anti-tumor T cell responses and prolongs survival in glioma. These findings have broader implications for treatment of other immunotherapy-resistant cancers.
    Keywords:  LIGHT; TNFSF14; antigen-presenting niches; glioblastoma; high endothelial venules; lymphotoxin αβ; stem-like T cells; tertiary lymphoid structures
    DOI:  https://doi.org/10.1016/j.ccell.2023.04.010
  12. Neuro Oncol. 2023 May 14. pii: noad092. [Epub ahead of print]
    Cell-based therapies for glioblastoma: Promising tools against tumor heterogeneity.
    Dean Nehama, Alex S Woodell, Spencer M Maingi, Shawn D Hingtgen, Gianpietro Dotti.
      Glioblastoma (GBM) is a highly aggressive tumor with a devastating impact on quality-of-life and abysmal survivorship. Patients have very limited effective treatment options. The successes of targeted small molecule drugs and immune checkpoint inhibitors seen in various solid tumors have not translated to GBM, despite significant advances in our understanding of its molecular, immune, and microenvironment landscapes. These discoveries, however, have unveiled GBM's incredible heterogeneity and its role in treatment failure and survival. Novel cellular therapy technologies are finding successes in oncology and harbor characteristics that make them uniquely suited to overcome challenges posed by GBM, such as increased resistance to tumor heterogeneity, modularity, localized delivery, and safety. Considering these advantages, we compiled this review article on cellular therapies for GBM, focusing on cellular immunotherapies and stem cell-based therapies, to evaluate their utility. We categorize them based on their specificity, review their preclinical and clinical data, and extract valuable insights to help guide future cellular therapy development.
    Keywords:  Glioblastoma; cell therapy; immunotherapy; stem cell therapy; tumor heterogeneity
    DOI:  https://doi.org/10.1093/neuonc/noad092
  13. Neuro Oncol. 2023 May 13. pii: noad090. [Epub ahead of print]
    "Sabotaging the Protein Factory to Overcome Glioma Stem Cell Resistance".
    Santiago Haase, Pedro R Lowenstein, Maria G Castro.
      
    DOI:  https://doi.org/10.1093/neuonc/noad090
  14. Nat Med. 2023 May 15.
    Oncolytic DNX-2401 virotherapy plus pembrolizumab in recurrent glioblastoma: a phase 1/2 trial.
    Farshad Nassiri, Vikas Patil, Leeor S Yefet, Olivia Singh, Jeff Liu, Rachel M A Dang, Takafumi N Yamaguchi, Mariza Daras, Timothy F Cloughesy, Howard Colman, Priya U Kumthekar, Clark C Chen, Robert Aiken, Morris D Groves, Shirley S Ong, Rohan Ramakrishna, Michael A Vogelbaum, Simon Khagi, Thomas Kaley, Jason M Melear, David M Peereboom, Analiz Rodriguez, Maxim Yankelevich, Suresh G Nair, Vinay K Puduvalli, Kenneth Aldape, Andrew Gao, Álvaro López-Janeiro, Carlos E de Andrea, Marta M Alonso, Paul Boutros, Joan Robbins, Warren P Mason, Adam M Sonabend, Roger Stupp, Juan Fueyo, Candelaria Gomez-Manzano, Frederick F Lang, Gelareh Zadeh.
      Immune-mediated anti-tumoral responses, elicited by oncolytic viruses and augmented with checkpoint inhibition, may be an effective treatment approach for glioblastoma. Here in this multicenter phase 1/2 study we evaluated the combination of intratumoral delivery of oncolytic virus DNX-2401 followed by intravenous anti-PD-1 antibody pembrolizumab in recurrent glioblastoma, first in a dose-escalation and then in a dose-expansion phase, in 49 patients. The primary endpoints were overall safety and objective response rate. The primary safety endpoint was met, whereas the primary efficacy endpoint was not met. There were no dose-limiting toxicities, and full dose combined treatment was well tolerated. The objective response rate was 10.4% (90% confidence interval (CI) 4.2-20.7%), which was not statistically greater than the prespecified control rate of 5%. The secondary endpoint of overall survival at 12 months was 52.7% (95% CI 40.1-69.2%), which was statistically greater than the prespecified control rate of 20%. Median overall survival was 12.5 months (10.7-13.5 months). Objective responses led to longer survival (hazard ratio 0.20, 95% CI 0.05-0.87). A total of 56.2% (95% CI 41.1-70.5%) of patients had a clinical benefit defined as stable disease or better. Three patients completed treatment with durable responses and remain alive at 45, 48 and 60 months. Exploratory mutational, gene-expression and immunophenotypic analyses revealed that the balance between immune cell infiltration and expression of checkpoint inhibitors may potentially inform on response to treatment and mechanisms of resistance. Overall, the combination of intratumoral DNX-2401 followed by pembrolizumab was safe with notable survival benefit in select patients (ClinicalTrials.gov registration: NCT02798406).
    DOI:  https://doi.org/10.1038/s41591-023-02347-y
  15. Cancer Res. 2023 May 17. OF1-OF17
    ONC201 in Combination with Paxalisib for the Treatment of H3K27-Altered Diffuse Midline Glioma.
    Evangeline R Jackson, Ryan J Duchatel, Dilana E Staudt, Mika L Persson, Abdul Mannan, Sridevi Yadavilli, Sarah Parackal, Shaye Game, Wai Chin Chong, W Samantha N Jayasekara, Marion Le Grand, Padraic S Kearney, Alicia M Douglas, Izac J Findlay, Zacary P Germon, Holly P McEwen, Tyrone S Beitaki, Adjanie Patabendige, David A Skerrett-Byrne, Brett Nixon, Nathan D Smith, Bryan Day, Neevika Manoharan, Sumanth Nagabushan, Jordan R Hansford, Dinisha Govender, Geoff B McCowage, Ron Firestein, Meegan Howlett, Raelene Endersby, Nicholas G Gottardo, Frank Alvaro, Sebastian M Waszak, Martin R Larsen, Yolanda Colino-Sanguino, Fatima Valdes-Mora, Andria Rakotomalala, Samuel Meignan, Eddy Pasquier, Nicolas André, Esther Hulleman, David D Eisenstat, Nicholas A Vitanza, Javad Nazarian, Carl Koschmann, Sabine Mueller, Jason E Cain, Matthew D Dun.
      Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPG), are the most lethal of childhood cancers. Palliative radiotherapy is the only established treatment, with median patient survival of 9 to 11 months. ONC201 is a DRD2 antagonist and ClpP agonist that has shown preclinical and emerging clinical efficacy in DMG. However, further work is needed to identify the mechanisms of response of DIPGs to ONC201 treatment and to determine whether recurring genomic features influence response. Using a systems-biological approach, we showed that ONC201 elicits potent agonism of the mitochondrial protease ClpP to drive proteolysis of electron transport chain and tricarboxylic acid cycle proteins. DIPGs harboring PIK3CA mutations showed increased sensitivity to ONC201, whereas those harboring TP53 mutations were more resistant. Metabolic adaptation and reduced sensitivity to ONC201 was promoted by redox-activated PI3K/Akt signaling, which could be counteracted using the brain penetrant PI3K/Akt inhibitor, paxalisib. Together, these discoveries coupled with the powerful anti-DIPG/DMG pharmacokinetic and pharmacodynamic properties of ONC201 and paxalisib have provided the rationale for the ongoing DIPG/DMG phase II combination clinical trial NCT05009992.
    SIGNIFICANCE: PI3K/Akt signaling promotes metabolic adaptation to ONC201-mediated disruption of mitochondrial energy homeostasis in diffuse intrinsic pontine glioma, highlighting the utility of a combination treatment strategy using ONC201 and the PI3K/Akt inhibitor paxalisib.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-0186
  16. JAMA Oncol. 2023 May 18.
    External Control Arms and Data Analysis Methods in Nonrandomized Trial of Patients With Glioblastoma-Reply.
    Linda M Liau, Keyoumars Ashkan, Marnix L Bosch.
      
    DOI:  https://doi.org/10.1001/jamaoncol.2023.1072
  17. Cancer Res. 2023 May 15. 83(10): 1757
    Correction: Distinct Cell Adhesion Signature Defines Glioblastoma Myeloid-Derived Suppressor Cell Subsets.
    Defne Bayik, Cynthia F Bartels, Katreya Lovrenert, Dionysios C Watson, Duo Zhang, Kristen Kay, Juyeun Lee, Adam Lauko, Sadie Johnson, Alice Lo, Daniel J Silver, Mary McGraw, Matthew Grabowski, Alireza M Mohammadi, Filippo Veglia, Yi Fan, Michael A Vogelbaum, Peter Scacheri, Justin D Lathia.
      
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-0773
  18. Cell Death Discov. 2023 May 19. 9(1): 172
    Enhanced Sestrin expression through Tanshinone 2A treatment improves PI3K-dependent inhibition of glioma growth.
    Judith Schaf, Sonia Shinhmar, Qingyu Zeng, Olivier E Pardo, Philip Beesley, Nelofer Syed, Robin S B Williams.
      Glioblastomas are a highly aggressive cancer type which respond poorly to current pharmaceutical treatments, thus novel therapeutic approaches need to be investigated. One such approach involves the use of the bioactive natural product Tanshinone IIA (T2A) derived from the Chinese herb Danshen, where mechanistic insight for this anti-cancer agent is needed to validate its use. Here, we employ a tractable model system, Dictyostelium discoideum, to provide this insight. T2A potently inhibits cellular proliferation of Dictyostelium, suggesting molecular targets in this model. We show that T2A rapidly reduces phosphoinositide 3 kinase (PI3K) and protein kinase B (PKB) activity, but surprisingly, the downstream complex mechanistic target of rapamycin complex 1 (mTORC1) is only inhibited following chronic treatment. Investigating regulators of mTORC1, including PKB, tuberous sclerosis complex (TSC), and AMP-activated protein kinase (AMPK), suggests these enzymes were not responsible for this effect, implicating an additional molecular mechanism of T2A. We identify this mechanism as the increased expression of sestrin, a negative regulator of mTORC1. We further show that combinatory treatment using a PI3K inhibitor and T2A gives rise to a synergistic inhibition of cell proliferation. We then translate our findings to human and mouse-derived glioblastoma cell lines, where both a PI3K inhibitor (Paxalisib) and T2A reduces glioblastoma proliferation in monolayer cultures and in spheroid expansion, with combinatory treatment significantly enhancing this effect. Thus, we propose a new approach for cancer treatment, including glioblastomas, through combinatory treatment with PI3K inhibitors and T2A.
    DOI:  https://doi.org/10.1038/s41420-023-01462-6
  19. Sci Rep. 2023 Apr 25. 13(1): 6761
    Genomic profiles of IDH-mutant gliomas: MYCN-amplified IDH-mutant astrocytoma had the worst prognosis.
    Kwanghoon Lee, Seong-Ik Kim, Eric Eunshik Kim, Yu-Mi Shim, Jae-Kyung Won, Chul-Kee Park, Seung Hong Choi, Hongseok Yun, Hyunju Lee, Sung-Hye Park.
      This study aimed to find any ambiguous genetic outlier for "oligodendroglioma, IDH-mutant and 1p/19q-codeleted (O_IDH_mut)" and "astrocytoma, IDH-mutant (A_IDH_mut)" and to redefine the genetic landscape and prognostic factors of IDH-mutant gliomas. Next-generation sequencing (NGS) using a brain tumor-targeted gene panel, methylation profiles, and clinicopathological features were analyzed for O_IDH_mut (n = 74) in 70 patients and for A_IDH_mut (n = 95) in 90 patients. 97.3% of O_IDH_mut and 98.9% of A_IDH_mut displayed a classic genomic landscape. Combined CIC (75.7%) and/or FUBP1 (45.9%) mutations were detected in 93.2% and MGMTp methylation in 95.9% of O_IDH_mut patients. In A_IDH_mut, TP53 mutations were found in 86.3% and combined ATRX (82.1%) and TERTp (6.3%) mutations in 88.4%. Although there were 3 confusing cases, NOS (not otherwise specified) category, based on genetic profiles, but they were clearly classified by combining histopathology and DKFZ methylation classifier algorithms. The patients with MYCN amplification and/or CDKN2A/2B homozygous deletion in the A_IDH_mut category had a worse prognosis than those without these gene alterations and MYCN-amplified A_IDH_mut showed the worst prognosis. However, there was no prognostic genetic marker in O_IDH_mut. In histopathologically or genetically ambiguous cases, methylation profiles can be used as an objective tool to avoid a diagnosis of NOS or NEC (not elsewhere classified), as well as for tumor classification. The authors have not encountered a case of true mixed oligoastrocytoma using an integrated diagnosis of histopathological, genetic and methylation profiles. MYCN amplification, in addition to CDKN2A/2B homozygous deletion, should be included in the genetic criteria for CNS WHO grade 4 A_IDH_mut.
    DOI:  https://doi.org/10.1038/s41598-023-32153-y
  20. JAMA Oncol. 2023 May 18.
    Association of MGMT Promotor Methylation With Survival in Low-grade and Anaplastic Gliomas After Alkylating Chemotherapy.
    Connor J Kinslow, Ann Mercurio, Prashanth Kumar, Ali I Rae, Markus D Siegelin, Jack Grinband, Kekoa Taparra, Pavan S Upadhyayula, Guy M McKhann, Michael B Sisti, Jeffrey N Bruce, Peter D Canoll, Fabio M Iwamoto, Lisa A Kachnic, James B Yu, Simon K Cheng, Tony J C Wang.
       Importance: O6-methylguanine-DNA methyltransferase (MGMT [OMIM 156569]) promoter methylation (mMGMT) is predictive of response to alkylating chemotherapy for glioblastomas and is routinely used to guide treatment decisions. However, the utility of MGMT promoter status for low-grade and anaplastic gliomas remains unclear due to molecular heterogeneity and the lack of sufficiently large data sets.
    Objective: To evaluate the association of mMGMT for low-grade and anaplastic gliomas with chemotherapy response.
    Design, Setting, and Participants: This cohort study aggregated grade II and III primary glioma data from 3 prospective cohort studies with patient data collected from August 13, 1995, to August 3, 2022, comprising 411 patients: MSK-IMPACT, EORTC (European Organization of Research and Treatment of Cancer) 26951, and Columbia University. Statistical analysis was performed from April 2022 to January 2023.
    Exposure: MGMT promoter methylation status.
    Main Outcomes and Measures: Multivariable Cox proportional hazards regression modeling was used to assess the association of mMGMT status with progression-free survival (PFS) and overall survival (OS) after adjusting for age, sex, molecular class, grade, chemotherapy, and radiotherapy. Subgroups were stratified by treatment status and World Health Organization 2016 molecular classification.
    Results: A total of 411 patients (mean [SD] age, 44.1 [14.5] years; 283 men [58%]) met the inclusion criteria, 288 of whom received alkylating chemotherapy. MGMT promoter methylation was observed in 42% of isocitrate dehydrogenase (IDH)-wild-type gliomas (56 of 135), 53% of IDH-mutant and non-codeleted gliomas (79 of 149), and 74% of IDH-mutant and 1p/19q-codeleted gliomas (94 of 127). Among patients who received chemotherapy, mMGMT was associated with improved PFS (median, 68 months [95% CI, 54-132 months] vs 30 months [95% CI, 15-54 months]; log-rank P < .001; adjusted hazard ratio [aHR] for unmethylated MGMT, 1.95 [95% CI, 1.39-2.75]; P < .001) and OS (median, 137 months [95% CI, 104 months to not reached] vs 61 months [95% CI, 47-97 months]; log-rank P < .001; aHR, 1.65 [95% CI, 1.11-2.46]; P = .01). After adjusting for clinical factors, MGMT promoter status was associated with chemotherapy response in IDH-wild-type gliomas (aHR for PFS, 2.15 [95% CI, 1.26-3.66]; P = .005; aHR for OS, 1.69 [95% CI, 0.98-2.91]; P = .06) and IDH-mutant and codeleted gliomas (aHR for PFS, 2.99 [95% CI, 1.44-6.21]; P = .003; aHR for OS, 4.21 [95% CI, 1.25-14.2]; P = .02), but not IDH-mutant and non-codeleted gliomas (aHR for PFS, 1.19 [95% CI, 0.67-2.12]; P = .56; aHR for OS, 1.07 [95% CI, 0.54-2.12]; P = .85). Among patients who did not receive chemotherapy, mMGMT status was not associated with PFS or OS.
    Conclusions and Relevance: This study suggests that mMGMT is associated with response to alkylating chemotherapy for low-grade and anaplastic gliomas and may be considered as a stratification factor in future clinical trials of patients with IDH-wild-type and IDH-mutant and codeleted tumors.
    DOI:  https://doi.org/10.1001/jamaoncol.2023.0990
  21. Nat Commun. 2023 May 13. 14(1): 2755
    A local water molecular-heating strategy for near-infrared long-lifetime imaging-guided photothermal therapy of glioblastoma.
    Dongkyu Kang, Hyung Shik Kim, Soohyun Han, Yeonju Lee, Young-Pil Kim, Dong Yun Lee, Joonseok Lee.
      Owing to the strong absorption of water in the near-infrared (NIR) region near 1.0 μm, this wavelength is considered unsuitable as an imaging and analytical signal in biological environments. However, 1.0 μm NIR can be converted into heat and used as a local water-molecular heating strategy for the photothermal therapy of biological tissues. Herein, we describe a Nd-Yb co-doped nanomaterial (water-heating nanoparticles (NPs)) as strong 1.0 μm emissive NPs to target the absorption band of water. Furthermore, introducing Tm ions into the water-heating NPs improve the NIR lifetime, enabling the development of a NIR imaging-guided water-heating probe (water-heating NIR NPs). In the glioblastoma multiforme male mouse model, tumor-targeted water-heating NIR NPs reduce the tumor volume by 78.9% in the presence of high-resolution intracranial NIR long-lifetime imaging. Hence, water-heating NIR NPs can be used as a promising nanomaterial for imaging and photothermal ablation in deep-tissue-bearing tumor therapy.
    DOI:  https://doi.org/10.1038/s41467-023-38451-3
  22. JAMA Oncol. 2023 May 18.
    MGMT Methylation Status in Grades 2 and 3 Gliomas Is Important, but Is It Prognostic?
    Kelli B Pointer, Na Tosha N Gatson.
      
    DOI:  https://doi.org/10.1001/jamaoncol.2023.0759
  23. JAMA Oncol. 2023 May 18.
    External Control Arms and Data Analysis Methods in Nonrandomized Trial of Patients With Glioblastoma.
    Jacob J Mandel, John F de Groot.
      
    DOI:  https://doi.org/10.1001/jamaoncol.2023.1066
  24. JAMA Oncol. 2023 May 18.
    External Control Arms and Data Analysis Methods in Nonrandomized Trial of Patients With Glioblastoma.
    Rifaquat Rahman, Steffen Ventz, Lorenzo Trippa.
      
    DOI:  https://doi.org/10.1001/jamaoncol.2023.1069
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