bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2022‒02‒06
27 papers selected by
Oltea Sampetrean
Keio University
  1. Convection-enhanced delivery for high-grade glioma.
  2. Repurposing the drug verteporfin as anti-neoplastic therapy for glioblastoma.
  3. Prognostic significance of TERT promoter mutations in adult-type diffuse gliomas.
  4. A multiparametric pharmacogenomic strategy for drug repositioning predicts therapeutic efficacy for glioblastoma cell lines.
  5. Arginine deprivation alters microglia polarity and synergises with radiation to eradicate non arginine auxotrophic glioblastoma tumors.
  6. Pharmacological inhibition of BACE1 suppresses glioblastoma growth by stimulating macrophage phagocytosis of tumor cells.
  7. Identification of vascular cues contributing to cancer cell stemness and function.
  8. Mitochondrial DNA copy number as a prognostic marker is age-dependent in adult glioblastoma.
  9. Polycystin-1 and hydrostatic pressure are implicated in glioblastoma pathogenesis in vitro.
  10. Immune Checkpoint Inhibition in GBM Primed with Radiation by Engineered Extracellular Vesicles.
  11. Splicing is an alternate oncogenic pathway activation mechanism in glioma.
  12. ERK1/2 phosphorylation predicts survival following anti-PD-1 immunotherapy in recurrent glioblastoma.
  13. A vaccine for glioma.
  14. Targeting PAK4 to reprogram the vascular microenvironment and improve CAR-T immunotherapy for glioblastoma.
  15. Radiation-induced neuroinflammation: a potential protective role for poly(ADP-ribose) polymerase inhibitors?
  16. Seeing the GBM diversity spectrum.
  17. Off-the-shelf, Steroid Resistant, IL13Rα2-Specific CAR T Cells for Treatment of Glioblastoma.
  18. Immune Activity and Response Differences of Oncolytic Viral Therapy in Recurrent Glioblastoma: Gene Expression Analyses of a Phase IB Study.
  19. Targeting PUS7 suppresses tRNA pseudouridylation and glioblastoma tumorigenesis.
  20. Tryptophan metabolism drives dynamic immunosuppressive myeloid states in IDH-mutant gliomas.
  21. MGMT promoter methylation determined by the MGMT-STP27 algorithm is not predictive for outcome to temozolomide in IDH-mutant anaplastic astrocytomas.
  22. PPM1D mutations are oncogenic drivers of de novo diffuse midline glioma formation.
  23. 2-HG modulates glioma macrophages via Trp metabolism.
  24. Gradient of Developmental and Injury Response transcriptional states defines functional vulnerabilities underpinning glioblastoma heterogeneity.
  25. Isolation and characterization of the immune cell fraction from murine brain tumor microenvironment.
  26. Neurotrophic tyrosine receptor kinase fusion in pediatric central nervous system tumors.
  27. The current landscape of immunotherapy for pediatric brain tumors.
  1. Neurooncol Pract. 2022 Feb;9(1): 24-34
    Convection-enhanced delivery for high-grade glioma.
    Jennifer H Kang, Annick Desjardins.
      Glioblastoma (GBM) is the most common adult primary malignant brain tumor and is associated with a dire prognosis. Despite multi-modality therapies of surgery, radiation, and chemotherapy, its 5-year survival rate is 6.8%. The presence of the blood-brain barrier (BBB) is one factor that has made GBM difficult to treat. Convection-enhanced delivery (CED) is a modality that bypasses the BBB, which allows the intracranial delivery of therapies that would not otherwise cross the BBB and avoids systemic toxicities. This review will summarize prior and ongoing studies and highlights practical considerations related to clinical care to aid providers caring for a high-grade glioma patient being treated with CED. Although not the main scope of this paper, this review also touches upon relevant technical considerations of using CED, an area still under much development.
    Keywords:  BBB; CED; glioblastoma; immune therapy; treatment
    DOI:  https://doi.org/10.1093/nop/npab065
  2. Neuro Oncol. 2022 Jan 31. pii: noac019. [Epub ahead of print]
    Repurposing the drug verteporfin as anti-neoplastic therapy for glioblastoma.
    Renee D Read.
      
    DOI:  https://doi.org/10.1093/neuonc/noac019
  3. Brain Tumor Pathol. 2022 Jan 31.
    Prognostic significance of TERT promoter mutations in adult-type diffuse gliomas.
    Hideyuki Arita, Koichi Ichimura.
      TERT promoter mutations are one of the most common genetic alterations in adult-type diffuse gliomas and show specific patterns compared with other genetic alterations according to glioma subtypes. This mutation has variable impacts on patient outcomes in association with other genetic alterations, including IDH1/2 mutations or histological types. The purpose of this paper is to review the current knowledge on the values of TERT promoter mutations in the diagnosis and prognostication of adult-type diffuse gliomas. We also aimed to discuss the interaction between the prognostic impacts of TERT promoter mutations and other molecular alterations. Although its impact on prognosis is somewhat complicated and enigmatic, the mutational status of the TERT promoter provides highly useful information for predicting patients' outcomes in the conventional classification of gliomas defined by IDH1/2 and 1p/19q status.
    Keywords:  Glioblastoma; Glioma; IDH; TERT
    DOI:  https://doi.org/10.1007/s10014-021-00424-z
  4. Neurooncol Adv. 2022 Jan-Dec;4(1):4(1): vdab192
    A multiparametric pharmacogenomic strategy for drug repositioning predicts therapeutic efficacy for glioblastoma cell lines.
    Ashish H Shah, Robert Suter, Pavan Gudoor, Tara T Doucet-O'Hare, Vasileios Stathias, Iahn Cajigas, Macarena de la Fuente, Vaidya Govindarajan, Alexis A Morell, Daniel G Eichberg, Evan Luther, Victor M Lu, John Heiss, Ricardo J Komotar, Michael E Ivan, Stephan Schurer, Mark R Gilbert, Nagi G Ayad.
      Background: Poor prognosis of glioblastoma patients and the extensive heterogeneity of glioblastoma at both the molecular and cellular level necessitates developing novel individualized treatment modalities via genomics-driven approaches.Methods: This study leverages numerous pharmacogenomic and tissue databases to examine drug repositioning for glioblastoma. RNA-seq of glioblastoma tumor samples from The Cancer Genome Atlas (TCGA, n = 117) were compared to "normal" frontal lobe samples from Genotype-Tissue Expression Portal (GTEX, n = 120) to find differentially expressed genes (DEGs). Using compound gene expression data and drug activity data from the Library of Integrated Network-Based Cellular Signatures (LINCS, n = 66,512 compounds) CCLE (71 glioma cell lines), and Chemical European Molecular Biology Laboratory (ChEMBL) platforms, we employed a summarized reversal gene expression metric (sRGES) to "reverse" the resultant disease signature for GBM and its subtypes. A multiparametric strategy was employed to stratify compounds capable of blood-brain barrier penetrance with a favorable pharmacokinetic profile (CNS-MPO).
    Results: Significant correlations were identified between sRGES and drug efficacy in GBM cell lines in both ChEMBL(r = 0.37, P < .001) and Cancer Therapeutic Response Portal (CTRP) databases (r = 0.35, P < 0.001). Our multiparametric algorithm identified two classes of drugs with highest sRGES and CNS-MPO: HDAC inhibitors (vorinostat and entinostat) and topoisomerase inhibitors suitable for drug repurposing.
    Conclusions: Our studies suggest that reversal of glioblastoma disease signature correlates with drug potency for various GBM subtypes. This multiparametric approach may set the foundation for an early-phase personalized -omics clinical trial for glioblastoma by effectively identifying drugs that are capable of reversing the disease signature and have favorable pharmacokinetic and safety profiles.
    Keywords:  LINCS; bioinformatics; drug repositioning; glioblastoma
    DOI:  https://doi.org/10.1093/noajnl/vdab192
  5. J Clin Invest. 2022 Feb 03. pii: e142137. [Epub ahead of print]
    Arginine deprivation alters microglia polarity and synergises with radiation to eradicate non arginine auxotrophic glioblastoma tumors.
    Nabil Hajji, Juan Garcia-Revilla, Manuel Sarmiento Soto, Richard Perryman, Jake J Symington, Chad C Quarles, Deborah R Healey, Yijie Guo, Manuel Luis Orta-Vázquez, Santiago Mateos-Cordero, Khalid Shah, John Bomalaski, Giulio Anichini, Andreas G Tzakos, Timothy Crook, Kevin O'Neill, Adrienne C Scheck, Jose Luis Venero, Nelofer Syed.
      New approaches for the management of glioblastoma (GBM) are an urgent and unmet clinical need. Here, we illustrate that the efficacy of radiotherapy for GBM is strikingly potentiated by concomitant therapy with the arginine depleting agent ADI-PEG20 in a non-arginine auxotrophic cellular background (Arginine Succinate Synthetase 1 positive). Moreover, this combination led to durable and complete radiological and pathological response with extended disease-free survival in an orthotopic immune competent model of GBM with no significant toxicity. ADI-PEG20 not only enhances the cellular sensitivity of Arginine succinate synthetase 1 positive GBM to ionising radiation by elevated production of nitric oxide (NO) and hence generation of cytotoxic peroxynitrites, but also promotes glioma-associated macrophages/microglia infiltration into tumors and turns their classical anti-inflammatory (pro-tumor) phenotype into a pro-inflammatory (anti-tumor) phenotype. Our results provide an effective, well-tolerated and simple strategy to improve GBM treatment which merits consideration for early evaluation in clinical trials.
    Keywords:  Amino acid metabolism; Brain cancer; Nitric oxide; Oncology; Therapeutics
    DOI:  https://doi.org/10.1172/JCI142137
  6. Nat Cancer. 2021 Nov;2(11): 1136-1151
    Pharmacological inhibition of BACE1 suppresses glioblastoma growth by stimulating macrophage phagocytosis of tumor cells.
    Kui Zhai, Zhi Huang, Qian Huang, Weiwei Tao, Xiaoguang Fang, Aili Zhang, Xiaoxia Li, George R Stark, Thomas A Hamilton, Shideng Bao.
      Glioblastoma (GBM) contains abundant tumor-associated macrophages (TAMs). The majority of TAMs are tumor-promoting macrophages (pTAMs), while tumor-suppressive macrophages (sTAMs) are the minority. Thus, reprogramming pTAMs into sTAMs represents an attractive therapeutic strategy. By screening a collection of small-molecule compounds, we find that inhibiting β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) with MK-8931 potently reprograms pTAMs into sTAMs and promotes macrophage phagocytosis of glioma cells; moreover, low-dose radiation markedly enhances TAM infiltration and synergizes with MK-8931 treatment to suppress malignant growth. BACE1 is preferentially expressed by pTAMs in human GBMs and is required to maintain pTAM polarization through trans-interleukin 6 (IL-6)-soluble IL-6 receptor (sIL-6R)-signal transducer and activator of transcription 3 (STAT3) signaling. Because MK-8931 and other BACE1 inhibitors have been developed for Alzheimer's disease and have been shown to be safe for humans in clinical trials, these inhibitors could potentially be streamlined for cancer therapy. Collectively, this study offers a promising therapeutic approach to enhance macrophage-based therapy for malignant tumors.
    DOI:  https://doi.org/10.1038/s43018-021-00267-9
  7. Angiogenesis. 2022 Feb 03.
    Identification of vascular cues contributing to cancer cell stemness and function.
    Saran Kumar, Libat Bar-Lev, Husni Sharife, Myriam Grunewald, Maxim Mogilevsky, Tamar Licht, Jermaine Goveia, Federico Taverna, Iddo Paldor, Peter Carmeliet, Eli Keshet.
      Glioblastoma stem cells (GSCs) reside close to blood vessels (BVs) but vascular cues contributing to GSC stemness and the nature of GSC-BVs cross talk are not fully understood. Here, we dissected vascular cues influencing GSC gene expression and function to perfusion-based vascular cues, as well as to those requiring direct GSC-endothelial cell (EC) contacts. In light of our previous finding that perivascular tumor cells are metabolically different from tumor cells residing further downstream, cancer cells residing within a narrow, < 60 µm wide perivascular niche were isolated and confirmed to possess a superior tumor-initiation potential compared with those residing further downstream. To circumvent reliance on marker expression, perivascular GSCs were isolated from the respective locales based on their relative state of quiescence. Combined use of these procedures uncovered a large number of previously unrecognized differentially expressed GSC genes. We show that the unique metabolic milieu of the perivascular niche dominated by the highly restricted zone of mTOR activity is conducive for acquisition of GSC properties, primarily in the regulation of genes implicated in cell cycle control. A complementary role of vascular cues including those requiring direct glioma/EC contacts was revealed using glioma/EC co-cultures. Outstanding in the group of glioma cells impacted by nearby ECs were multiple genes responsible for maintaining GSCs in an undifferentiated state, a large fraction of which also relied on Notch-mediated signaling. Glioma-EC communication was found to be bidirectional, evidenced by extensive Notch-mediated EC reprogramming by contacting tumor cells, primarily metabolic EC reprogramming.
    Keywords:  Cancer stem cells; Endothelial cells; Glioblastoma; Notch signaling; Perivascular niche; Tumor vasculature
    DOI:  https://doi.org/10.1007/s10456-022-09830-z
  8. Neurooncol Adv. 2022 Jan-Dec;4(1):4(1): vdab191
    Mitochondrial DNA copy number as a prognostic marker is age-dependent in adult glioblastoma.
    Baptiste Sourty, Laure-Marie Dardaud, Céline Bris, Valérie Desquiret-Dumas, Blandine Boisselier, Laëtitia Basset, Dominique Figarella-Branger, Alain Morel, Marc Sanson, Vincent Procaccio, Audrey Rousseau.
      Background: Glioblastoma (GBM) is the most common and aggressive form of glioma. GBM frequently displays chromosome (chr) 7 gain, chr 10 loss and/or EGFR amplification (chr7+/chr10-/EGFRamp). Overall survival (OS) is 15 months after treatment. In young adults, IDH1/2 mutations are associated with longer survival. In children, histone H3 mutations portend a dismal prognosis. Novel reliable prognostic markers are needed in GBM. We assessed the prognostic value of mitochondrial DNA (mtDNA) copy number in adult GBM.Methods: mtDNA copy number was assessed using real-time quantitative PCR in 232 primary GBM. Methylation of POLG and TFAM genes, involved in mtDNA replication, was assessed by bisulfite-pyrosequencing in 44 and 51 cases, respectively.
    Results: Median age at diagnosis was 56.6 years-old and median OS, 13.3 months. 153/232 GBM (66 %) displayed chr7+/chr10-/EGFRamp, 23 (9.9 %) IDH1/2 mutation, 3 (1.3 %) H3 mutation and 53 (22.8 %) no key genetic alterations. GBM were divided into two groups, "Low" (n = 116) and "High" (n = 116), according to the median mtDNA/nuclear DNA ratio (237.7). There was no significant difference in OS between the two groups. By dividing the whole cohort according to the median age at diagnosis, OS was longer in the "High" vs "Low" subgroup (27.3 vs 15 months, P = .0203) in young adult GBM (n = 117) and longer in the "Low" vs "High" subgroup (14.5 vs 10.2 months, P = .0116) in older adult GBM (n = 115). POLG was highly methylated, whereas TFAM remained unmethylated.
    Conclusion: mtDNA copy number may be a novel prognostic biomarker in GBM, its impact depending on age.
    Keywords:  glioblastoma; metabolism; methylation; mitochondrial DNA; prognosis
    DOI:  https://doi.org/10.1093/noajnl/vdab191
  9. J Cell Mol Med. 2022 Feb 01.
    Polycystin-1 and hydrostatic pressure are implicated in glioblastoma pathogenesis in vitro.
    Ilianna Zoi, Antonios N Gargalionis, Kostas A Papavassiliou, Narjes Nasiri-Ansari, Christina Piperi, Efthimia K Basdra, Athanasios G Papavassiliou.
      The mechanobiological aspects of glioblastoma (GBM) pathogenesis are largely unknown. Polycystin-1 (PC1) is a key mechanosensitive protein which perceives extracellular mechanical cues and transforms them into intracellular biochemical signals that elicit a change in cell behaviour. The aim of the present study was to investigate if and how PC1 participates in GBM pathogenesis under a mechanically induced microenvironment. Therefore, we subjected T98G GBM cells to continuous hydrostatic pressure (HP) and/or PC1 blockade and evaluated their effect on cell behaviour, the activity of signalling pathways and the expression of mechano-induced transcriptional regulators and markers associated with properties of cancer cells. According to our data, PC1 and HP affect GBM cell proliferation, clonogenicity and migration; the diameter of GBM spheroids; the phosphorylation of mechanistic target of rapamycin (mTOR), extracellular signal-regulated kinase (ERK) and focal adhesion kinase (FAK); the protein expression of transcription cofactors YES-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ); and the mRNA expression of markers related to anti-apoptosis, apoptosis, angiogenesis, epithelial to mesenchymal transition (EMT) and proliferation. Together, our in vitro results suggest that PC1 plays an important role in GBM mechanobiology.
    Keywords:  glioblastoma; hydrostatic pressure; mechanobiology; polycystin-1
    DOI:  https://doi.org/10.1111/jcmm.17212
  10. ACS Nano. 2022 Jan 31.
    Immune Checkpoint Inhibition in GBM Primed with Radiation by Engineered Extracellular Vesicles.
    Tian Tian, Ruyu Liang, Gulsah Erel-Akbaba, Lorenzo Saad, Pierre J Obeid, Jun Gao, E Antonio Chiocca, Ralph Weissleder, Bakhos A Tannous.
      The lack of safe and effective delivery across the blood-brain barrier and the profound immune suppressive microenvironment are two main hurdles to glioblastoma (GBM) therapies. Extracellular vesicles (EVs) have been used as therapeutic delivery vehicles to GBM but with limited efficacy. We hypothesized that EV delivery to GBM can be enhanced by (i) modifying the EV surface with a brain-tumor-targeting cyclic RGDyK peptide (RGD-EV) and (ii) using bursts of radiation for enhanced accumulation. In addition, EVs were loaded with small interfering RNA (siRNA) against programmed cell death ligand-1 (PD-L1) for immune checkpoint blockade. We show that this EV-based strategy dramatically enhanced the targeting efficiency of RGD-EV to murine GBM, while the loaded siRNA reversed radiation-stimulated PD-L1 expression on tumor cells and recruited tumor-associated myeloid cells, offering a synergistic effect. The combined therapy significantly increased CD8+ cytotoxic T cells activity, halting tumor growth and prolonging animal survival. The selected cell source for EVs isolation and the presented functionalization strategy are suitable for large-scale production. These results provide an EV-based therapeutic strategy for GBM immune checkpoint therapy which can be translated to clinical applications.
    Keywords:  extracellular vesicles; glioblastoma; immunotherapy; radiation therapy; targeted delivery
    DOI:  https://doi.org/10.1021/acsnano.1c05505
  11. Nat Commun. 2022 Jan 31. 13(1): 588
    Splicing is an alternate oncogenic pathway activation mechanism in glioma.
    Robert Siddaway, Scott Milos, Arun Kumaran Anguraj Vadivel, Tara H W Dobson, Jyothishmathi Swaminathan, Scott Ryall, Sanja Pajovic, Palak G Patel, Javad Nazarian, Oren Becher, Michael Brudno, Arun Ramani, Vidya Gopalakrishnan, Cynthia Hawkins.
      High-grade diffuse glioma (HGG) is the leading cause of brain tumour death. While the genetic drivers of HGG have been well described, targeting these has thus far had little impact on survival suggesting other mechanisms are at play. Here we interrogate the alternative splicing landscape of pediatric and adult HGG through multi-omic analyses, uncovering an increased splicing burden compared with normal brain. The rate of recurrent alternative splicing in cancer drivers exceeds their mutation rate, a pattern that is recapitulated in pan-cancer analyses, and is associated with worse prognosis in HGG. We investigate potential oncogenicity by interrogating cancer pathways affected by alternative splicing in HGG; spliced cancer drivers include members of the RAS/MAPK pathway. RAS suppressor neurofibromin 1 is differentially spliced to a less active isoform in >80% of HGG downstream from REST upregulation, activating the RAS/MAPK pathway and reducing glioblastoma patient survival. Overall, our results identify non-mutagenic mechanisms by which cancers activate oncogenic pathways which need to accounted for in personalized medicine approaches.
    DOI:  https://doi.org/10.1038/s41467-022-28253-4
  12. Nat Cancer. 2021 Dec;2(12): 1372-1386
    ERK1/2 phosphorylation predicts survival following anti-PD-1 immunotherapy in recurrent glioblastoma.
    Víctor A Arrieta, Andrew X Chen, J Robert Kane, Seong Jae Kang, Cynthia Kassab, Crismita Dmello, Junfei Zhao, Kirsten B Burdett, Pavan S Upadhyayula, Catalina Lee-Chang, Joseph Shilati, Dinesh Jaishankar, Li Chen, Andrew Gould, Daniel Zhang, Jinzhou Yuan, Wenting Zhao, Xiaoyang Ling, Jared K Burks, Brice Laffleur, Christina Amidei, Jeffrey N Bruce, Rimas V Lukas, Jonathan T Yamaguchi, David Cieremans, Gerson Rothschild, Uttiya Basu, Matthew McCord, Daniel J Brat, Hui Zhang, Lee A D Cooper, Bin Zhang, Peter Sims, Tim F Cloughesy, Robert Prins, Peter Canoll, Roger Stupp, Amy B Heimberger, Craig Horbinski, Fabio M Iwamoto, Raul Rabadan, Adam M Sonabend.
      Only a subset of recurrent glioblastoma (rGBM) responds to anti-PD-1 immunotherapy. Previously, we reported enrichment of BRAF/PTPN11 mutations in 30% of rGBM that responded to PD-1 blockade. Given that BRAF and PTPN11 promote MAPK/ERK signaling, we investigated whether activation of this pathway is associated with response to PD-1 inhibitors in rGBM, including patients that do not harbor BRAF/PTPN11 mutations. Here we show that immunohistochemistry for ERK1/2 phosphorylation (p-ERK), a marker of MAPK/ERK pathway activation, is predictive of overall survival following adjuvant PD-1 blockade in two independent rGBM patient cohorts. Single-cell RNA-sequencing and multiplex immunofluorescence analyses revealed that p-ERK was mainly localized in tumor cells and that high-p-ERK GBMs contained tumor-infiltrating myeloid cells and microglia with elevated expression of MHC class II and associated genes. These findings indicate that ERK1/2 activation in rGBM is predictive of response to PD-1 blockade and is associated with a distinct myeloid cell phenotype.
    DOI:  https://doi.org/10.1038/s43018-021-00260-2
  13. Nat Cancer. 2021 Jun;2(6): 584-586
    A vaccine for glioma.
    Sameer Agnihotri, Kailin Yang, Duane A Mitchell, Jeremy N Rich.
      
    DOI:  https://doi.org/10.1038/s43018-021-00228-2
  14. Nat Cancer. 2021 Jan;2(1): 83-97
    Targeting PAK4 to reprogram the vascular microenvironment and improve CAR-T immunotherapy for glioblastoma.
    Wenjuan Ma, Yanling Wang, Rongxin Zhang, Fan Yang, Duo Zhang, Menggui Huang, Lin Zhang, Jay F Dorsey, Zev A Binder, Donald M O'Rourke, Joseph A Fraietta, Yanqing Gong, Yi Fan.
      Malignant solid tumors are characterized by aberrant vascularity that fuels the formation of an immune-hostile microenvironment and induces resistance to immunotherapy. Vascular abnormalities may be driven by pro-angiogenic pathway activation and genetic reprogramming in tumor endothelial cells (ECs). Here, our kinome-wide screening of mesenchymal-like transcriptional activation in human glioblastoma (GBM)-derived ECs identifies p21-activated kinase 4 (PAK4) as a selective regulator of genetic reprogramming and aberrant vascularization. PAK4 knockout induces adhesion protein re-expression in ECs, reduces vascular abnormalities, improves T cell infiltration and inhibits GBM growth in mice. Moreover, PAK4 inhibition normalizes the tumor vascular microenvironment and sensitizes GBM to chimeric antigen receptor-T cell immunotherapy. Finally, we reveal a MEF2D/ZEB1- and SLUG-mediated mechanism by which PAK4 reprograms the EC transcriptome and downregulates claudin-14 and VCAM-1 expression, enhancing vessel permeability and reducing T cell adhesion to the endothelium. Thus, targeting PAK4-mediated EC plasticity may offer a unique opportunity to recondition the vascular microenvironment and strengthen cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s43018-020-00147-8
  15. Neurooncol Adv. 2022 Jan-Dec;4(1):4(1): vdab190
    Radiation-induced neuroinflammation: a potential protective role for poly(ADP-ribose) polymerase inhibitors?
    Rodrigo Gutierrez-Quintana, David J Walker, Kaye J Williams, Duncan M Forster, Anthony J Chalmers.
      Radiotherapy (RT) plays a fundamental role in the treatment of glioblastoma (GBM). GBM are notoriously invasive and harbor a subpopulation of cells with stem-like features which exhibit upregulation of the DNA damage response (DDR) and are radioresistant. High radiation doses are therefore delivered to large brain volumes and are known to extend survival but also cause delayed toxicity with 50%-90% of patients developing neurocognitive dysfunction. Emerging evidence identifies neuroinflammation as a critical mediator of the adverse effects of RT on cognitive function. In addition to its well-established role in promoting repair of radiation-induced DNA damage, activation of poly(ADP-ribose) polymerase (PARP) can exacerbate neuroinflammation by promoting secretion of inflammatory mediators. Therefore, PARP represents an intriguing mechanistic link between radiation-induced activation of the DDR and subsequent neuroinflammation. PARP inhibitors (PARPi) have emerged as promising new agents for GBM when given in combination with RT, with multiple preclinical studies demonstrating radiosensitizing effects and at least 3 compounds being evaluated in clinical trials. We propose that concomitant use of PARPi could reduce radiation-induced neuroinflammation and reduce the severity of radiation-induced cognitive dysfunction while at the same time improving tumor control by enhancing radiosensitivity.
    Keywords:  DNA damage; glioblastoma; microglia; neuroinflammation; neuroprotection; radiation therapy
    DOI:  https://doi.org/10.1093/noajnl/vdab190
  16. Nat Cancer. 2021 Feb;2(2): 135-137
    Seeing the GBM diversity spectrum.
    Christopher G Hubert, Justin D Lathia.
      
    DOI:  https://doi.org/10.1038/s43018-021-00176-x
  17. Neuro Oncol. 2022 Jan 31. pii: noac024. [Epub ahead of print]
    Off-the-shelf, Steroid Resistant, IL13Rα2-Specific CAR T Cells for Treatment of Glioblastoma.
    Christine E Brown, Analiz Rodriguez, Joycelynne Palmer, Julie R Ostberg, Araceli Naranjo, Jamie Wagner, Brenda Aguilar, Renate Starr, Lihong Weng, Timothy W Synold, Vivi Tran, Shelley Wang, Andreas Reik, Massimo D'Apuzzo, Julie A Ressler, Yuanyue Zhou, Matthew Mendel, Philip D Gregory, Michael C Holmes, Winson W Tang, Stephen J Forman, Michael C Jensen, Behnam Badie.
      BACKGROUND: Wide-spread application of chimeric antigen receptor (CAR) T cell therapy for cancer is limited by the current use of autologous CAR T cells necessitating the manufacture of individualized therapeutic products for each patient. To address this challenge, we have generated an off-the-shelf, allogeneic CAR T cell product for the treatment of glioblastoma (GBM), and present here the feasibility, safety and therapeutic potential of this approach.METHODS: We generated for clinical use a healthy-donor derived IL13Rα2-targeted CAR+ (IL13-zetakine+) cytolytic T-lymphocyte (CTL) product genetically engineered using zinc finger nucleases (ZFNs) to permanently disrupt the glucocorticoid receptor (GR) (GRm13Z40-2) and endow resistance to glucocorticoid treatment. In a phase I safety and feasibility trial we evaluated these allogeneic GRm13Z40-2 T cells in combination with intracranial administration of recombinant human IL-2 (rhIL-2; aldesleukin) in six patients with unresectable recurrent GBM that were maintained on systemic dexamethasone (4-12 mg/day).
    RESULTS: The GRm13Z40-2 product displayed dexamethasone-resistant effector activity without evidence for in vitro alloreactivity. Intracranial administration of GRm13Z40-2 in four doses of 10 8 cells over a two-week period with aldesleukin (9 infusions ranging from 2500 - 5000 IU) was well tolerated, with indications of transient tumor reduction and/or tumor necrosis at the site of T cell infusion in four of the six treated research subjects. Antibody reactivity against GRm13Z40-2 cells was detected in the serum of only one of the four tested subjects.
    CONCLUSIONS: This first-in-human experience establishes a foundation for future adoptive therapy studies using off-the-shelf, zinc-finger modified and/or glucocorticoid resistant CAR T cells.
    Keywords:  IL13Rα2-CAR T cells; allogeneic; glioblastoma; glucocorticoid receptor; off-the-shelf
    DOI:  https://doi.org/10.1093/neuonc/noac024
  18. Clin Cancer Res. 2022 Feb 01. 28(3): 498-506
    Immune Activity and Response Differences of Oncolytic Viral Therapy in Recurrent Glioblastoma: Gene Expression Analyses of a Phase IB Study.
    Katherine E Miller, Kevin A Cassady, Justin C Roth, Jennifer Clements, Kathleen M Schieffer, Kristen Leraas, Anthony R Miller, Nripesh Prasad, Jianmei W Leavenworth, Inmaculada B Aban, Richard J Whitley, G Yancey Gillespie, Elaine R Mardis, James M Markert.
      PURPOSE: Previously, clinical trials of experimental virotherapy for recurrent glioblastoma multiforme (GBM) demonstrated that inoculation with a conditionally replication-competent Δγ134.5 oncolytic herpes simplex virus (oHSV), G207, was safe. Following the initial safety study, a phase Ib trial enrolled 6 adult patients diagnosed with GBM recurrence from which tumor tissue was banked for future studies.PATIENTS AND METHODS: Here, we analyzed tumor RNA sequencing (RNA-seq) data obtained from pre- and posttreatment (collected 2 or 5 days after G207 injection) biopsies from the phase Ib study patients.
    RESULTS: Using a Spearman rank-order correlation analysis, we identified approximately 500 genes whose expression pattern correlated with survival duration. Many of these genes were enriched for the intrinsic IFN-mediated antiviral and adaptive immune functional responses, including immune cell chemotaxis and antigen presentation to T-cells. Furthermore, we show that the expression of several T-cell-related genes was highest in the patient with the longest survival after G207 inoculation.
    CONCLUSIONS: Our data support that the oHSV-induced type I IFN production and the subsequent recruitment of an adaptive immune response differed between enrolled patients and showed association with survival duration in patients with recurrent malignant glioma after treatment with an early generation oHSV.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-21-2636
  19. Nat Cancer. 2021 Sep;2(9): 932-949
    Targeting PUS7 suppresses tRNA pseudouridylation and glioblastoma tumorigenesis.
    Qi Cui, Kailin Yin, Xiaoting Zhang, Peng Ye, Xianwei Chen, Jianfei Chao, Haowei Meng, Jiangbo Wei, Daniel Roeth, Li Li, Yue Qin, Guihua Sun, Mingzi Zhang, Jeremy Klein, Marvin Huynhle, Cheng Wang, Leying Zhang, Behnam Badie, Markus Kalkum, Chuan He, Chengqi Yi, Yanhong Shi.
      Pseudouridine is the most frequent epitranscriptomic modification. However, its cellular functions remain largely unknown. Here, we show that pseudouridine synthase 7 (PUS7) is highly expressed in glioblastoma versus normal brain tissues, and high PUS7 expression levels are associated with worse survival in patients with glioblastoma. PUS7 expression and catalytic activity are required for glioblastoma stem cell (GSC) tumorigenesis. Mechanistically, we identify PUS7 targets in GSCs through small RNA pseudouridine sequencing and show that pseudouridylation of PUS7-regulated transfer RNA is critical for codon-specific translational control of key regulators of GSCs. Moreover, we identify chemical inhibitors for PUS7 and show that these compounds prevent PUS7-mediated pseudouridine modification, suppress tumorigenesis and extend the life span of tumor-bearing mice. Overall, we identify an epitranscriptomic regulatory mechanism in glioblastoma and provide preclinical evidence of a potential therapeutic strategy for glioblastoma.
    DOI:  https://doi.org/10.1038/s43018-021-00238-0
  20. Nat Cancer. 2021 Jul;2(7): 723-740
    Tryptophan metabolism drives dynamic immunosuppressive myeloid states in IDH-mutant gliomas.
    Mirco Friedrich, Roman Sankowski, Lukas Bunse, Michael Kilian, Edward Green, Carina Ramallo Guevara, Stefan Pusch, Gernot Poschet, Khwab Sanghvi, Markus Hahn, Theresa Bunse, Philipp Münch, Hagen M Gegner, Jana K Sonner, Anna von Landenberg, Frederik Cichon, Katrin Aslan, Tim Trobisch, Lucas Schirmer, Denis Abu-Sammour, Tobias Kessler, Miriam Ratliff, Daniel Schrimpf, Felix Sahm, Carsten Hopf, Dieter H Heiland, Oliver Schnell, Jürgen Beck, Chotima Böttcher, Camila Fernandez-Zapata, Josef Priller, Sabine Heiland, Ilona Gutcher, Francisco J Quintana, Andreas von Deimling, Wolfgang Wick, Marco Prinz, Michael Platten.
      The dynamics and phenotypes of intratumoral myeloid cells during tumor progression are poorly understood. Here we define myeloid cellular states in gliomas by longitudinal single-cell profiling and demonstrate their strict control by the tumor genotype: in isocitrate dehydrogenase (IDH)-mutant tumors, differentiation of infiltrating myeloid cells is blocked, resulting in an immature phenotype. In late-stage gliomas, monocyte-derived macrophages drive tolerogenic alignment of the microenvironment, thus preventing T cell response. We define the IDH-dependent tumor education of infiltrating macrophages to be causally related to a complex re-orchestration of tryptophan metabolism, resulting in activation of the aryl hydrocarbon receptor. We further show that the altered metabolism of IDH-mutant gliomas maintains this axis in bystander cells and that pharmacological inhibition of tryptophan metabolism can reverse immunosuppression. In conclusion, we provide evidence of a glioma genotype-dependent intratumoral network of resident and recruited myeloid cells and identify tryptophan metabolism as a target for immunotherapy of IDH-mutant tumors.
    DOI:  https://doi.org/10.1038/s43018-021-00201-z
  21. Neuro Oncol. 2022 Jan 31. pii: noac014. [Epub ahead of print]
    MGMT promoter methylation determined by the MGMT-STP27 algorithm is not predictive for outcome to temozolomide in IDH-mutant anaplastic astrocytomas.
    C Mircea S Tesileanu, Thierry Gorlia, Vassilis Golfinopoulos, Pim J French, Martin J van den Bent.
      
    DOI:  https://doi.org/10.1093/neuonc/noac014
  22. Nat Commun. 2022 Feb 01. 13(1): 604
    PPM1D mutations are oncogenic drivers of de novo diffuse midline glioma formation.
    Prasidda Khadka, Zachary J Reitman, Sophie Lu, Graham Buchan, Gabrielle Gionet, Frank Dubois, Diana M Carvalho, Juliann Shih, Shu Zhang, Noah F Greenwald, Travis Zack, Ofer Shapira, Kristine Pelton, Rachel Hartley, Heather Bear, Yohanna Georgis, Spandana Jarmale, Randy Melanson, Kevin Bonanno, Kathleen Schoolcraft, Peter G Miller, Alexandra L Condurat, Elizabeth M Gonzalez, Kenin Qian, Eric Morin, Jaldeep Langhnoja, Leslie E Lupien, Veronica Rendo, Jeromy Digiacomo, Dayle Wang, Kevin Zhou, Rushil Kumbhani, Maria E Guerra Garcia, Claire E Sinai, Sarah Becker, Rachel Schneider, Jayne Vogelzang, Karsten Krug, Amy Goodale, Tanaz Abid, Zohra Kalani, Federica Piccioni, Rameen Beroukhim, Nicole S Persky, David E Root, Angel M Carcaboso, Benjamin L Ebert, Christine Fuller, Ozgun Babur, Mark W Kieran, Chris Jones, Hasmik Keshishian, Keith L Ligon, Steven A Carr, Timothy N Phoenix, Pratiti Bandopadhayay.
      The role of PPM1D mutations in de novo gliomagenesis has not been systematically explored. Here we analyze whole genome sequences of 170 pediatric high-grade gliomas and find that truncating mutations in PPM1D that increase the stability of its phosphatase are clonal driver events in 11% of Diffuse Midline Gliomas (DMGs) and are enriched in primary pontine tumors. Through the development of DMG mouse models, we show that PPM1D mutations potentiate gliomagenesis and that PPM1D phosphatase activity is required for in vivo oncogenesis. Finally, we apply integrative phosphoproteomic and functional genomics assays and find that oncogenic effects of PPM1D truncation converge on regulators of cell cycle, DNA damage response, and p53 pathways, revealing therapeutic vulnerabilities including MDM2 inhibition.
    DOI:  https://doi.org/10.1038/s41467-022-28198-8
  23. Nat Cancer. 2021 Jul;2(7): 677-679
    2-HG modulates glioma macrophages via Trp metabolism.
    Marie Jo Halaby, Tracy L McGaha.
      
    DOI:  https://doi.org/10.1038/s43018-021-00231-7
  24. Nat Cancer. 2021 Feb;2(2): 157-173
    Gradient of Developmental and Injury Response transcriptional states defines functional vulnerabilities underpinning glioblastoma heterogeneity.
    Laura M Richards, Owen K N Whitley, Graham MacLeod, Florence M G Cavalli, Fiona J Coutinho, Julia E Jaramillo, Nataliia Svergun, Mazdak Riverin, Danielle C Croucher, Michelle Kushida, Kenny Yu, Paul Guilhamon, Naghmeh Rastegar, Moloud Ahmadi, Jasmine K Bhatti, Danielle A Bozek, Naijin Li, Lilian Lee, Clare Che, Erika Luis, Nicole I Park, Zhiyu Xu, Troy Ketela, Richard A Moore, Marco A Marra, Julian Spears, Michael D Cusimano, Sunit Das, Mark Bernstein, Benjamin Haibe-Kains, Mathieu Lupien, H Artee Luchman, Samuel Weiss, Stephane Angers, Peter B Dirks, Gary D Bader, Trevor J Pugh.
      Glioblastomas harbor diverse cell populations, including rare glioblastoma stem cells (GSCs) that drive tumorigenesis. To characterize functional diversity within this population, we performed single-cell RNA sequencing on >69,000 GSCs cultured from the tumors of 26 patients. We observed a high degree of inter- and intra-GSC transcriptional heterogeneity that could not be fully explained by DNA somatic alterations. Instead, we found that GSCs mapped along a transcriptional gradient spanning two cellular states reminiscent of normal neural development and inflammatory wound response. Genome-wide CRISPR-Cas9 dropout screens independently recapitulated this observation, with each state characterized by unique essential genes. Further single-cell RNA sequencing of >56,000 malignant cells from primary tumors found that the majority organize along an orthogonal astrocyte maturation gradient yet retain expression of founder GSC transcriptional programs. We propose that glioblastomas grow out of a fundamental GSC-based neural wound response transcriptional program, which is a promising target for new therapy development.
    DOI:  https://doi.org/10.1038/s43018-020-00154-9
  25. STAR Protoc. 2022 Mar 18. 3(1): 101106
    Isolation and characterization of the immune cell fraction from murine brain tumor microenvironment.
    Ignacio Mastandrea, Divsha Sher, Prerna Magod, Dinorah Friedmann-Morvinski.
      The immune fraction of the tumor microenvironment has been proven to play a fundamental role in glioblastoma progression and therapeutic response. Here, we present a detailed magnetic-bead-enrichment-based protocol to isolate and analyze the composition of this fraction from mouse brain tumors. The protocol is optimized to achieve high yields of viable immune cells. We also detail characterization of the immune subtypes by FACS analysis. Our procedure is applicable for either lentiviral-induced tumors or transplant models in syngeneic immunocompetent mice. For complete details on the use and execution of this protocol, please refer to Magod et al. (2021).
    Keywords:  Cancer; Cell Biology; Cell isolation; Flow Cytometry/Mass Cytometry; Immunology; Model Organisms; Neuroscience
    DOI:  https://doi.org/10.1016/j.xpro.2021.101106
  26. Cancer Genet. 2022 Jan 19. pii: S2210-7762(22)00002-3. [Epub ahead of print]262-263 64-70
    Neurotrophic tyrosine receptor kinase fusion in pediatric central nervous system tumors.
    Shih-Shan Lang, Nankee K Kumar, Peter Madsen, Avi A Gajjar, Esha Gajjar, Adam C Resnick, Phillip B Storm.
      Neurotrophins and their related tyrosine kinase receptors (TRKs), encoded by the neurotrophic tyrosine receptor kinase genes NTRKs, play a crucial role in central nervous system development. Oncogenic NTRK gene fusion events have been identified in several cancer subtypes and cause constitutive activation of the TRK receptor, promoting tumorigenesis. While NTRK fusions are rare in cancers overall, they have been identified in appreciable frequency in certain CNS tumors subtypes recently. In other non-CNS neoplasms, the development of NTRK fusion directed therapies has been developed with TRK inhibitors showing promise in clinical trials. Given the difficulty in treating certain pediatric CNS tumors such as high grade gliomas, understanding NTRK fusions in pediatric CNS tumors may lead to more directed treatment and subsequent therapeutic benefit. This review examines the biology of NTRK fusions, the frequency and clinical significance in pediatric CNS tumors, and methods for detection of NTRK fusion in CNS tumors.
    Keywords:  Genetics; Glioma; NTRK; Pediatric; Tumor
    DOI:  https://doi.org/10.1016/j.cancergen.2022.01.003
  27. Nat Cancer. 2022 Jan;3(1): 11-24
    The current landscape of immunotherapy for pediatric brain tumors.
    Eugene I Hwang, Elias J Sayour, Catherine T Flores, Gerald Grant, Robert Wechsler-Reya, Lan B Hoang-Minh, Mark W Kieran, Joanne Salcido, Robert M Prins, John W Figg, Michael Platten, Kate M Candelario, Paul G Hale, Jason E Blatt, Lance S Governale, Hideho Okada, Duane A Mitchell, Ian F Pollack.
      Pediatric central nervous system tumors are the most common solid malignancies in childhood, and aggressive therapy often leads to long-term sequelae in survivors, making these tumors challenging to treat. Immunotherapy has revolutionized prospects for many cancer types in adults, but the intrinsic complexity of treating pediatric patients and the scarcity of clinical studies of children to inform effective approaches have hampered the development of effective immunotherapies in pediatric settings. Here, we review recent advances and ongoing challenges in pediatric brain cancer immunotherapy, as well as considerations for efficient clinical translation of efficacious immunotherapies into pediatric settings.
    DOI:  https://doi.org/10.1038/s43018-021-00319-0
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