bims-malgli 2022-11-13 papers

bims-malgli

Biomed News

on Biology of malignant gliomas

Issue of 2022–11–13
twelve papers selected by
Oltea Sampetrean, Keio University

DHODH inhibition impedes glioma stem cell proliferation, induces DNA damage, and prolongs survival in orthotopic glioblastoma xenografts.
Brain Tumor Networks in Diffuse Glioma.
Pleiotropy of PP2A Phosphatases in Cancer with a Focus on Glioblastoma IDH Wildtype.
Near infrared-activatable biomimetic nanogels enabling deep tumor drug penetration inhibit orthotopic glioblastoma.
Bioinformatic Analysis of Kynurenine Pathway Enzymes and Their Relationship with Glioma Hallmarks.
Melatonin Treatment Triggers Metabolic and Intracellular pH Imbalance in Glioblastoma.
Specific targeting of glioblastoma with an oncolytic virus expressing a cetuximab-CCL5 fusion protein via innate and adaptive immunity.
Prognostic differences and implications on treatment strategies between butterfly glioblastoma and glioblastoma with unilateral corpus callosum infiltration.
α2,6 Sialylation mediated by ST6GAL1 promotes glioblastoma growth.
Expression and clinical significance of VISTA, B7-H3, and PD-L1 in glioma.
The NCI Glioblastoma Therapeutics Network (GTN).
Global survival trends for brain tumors, by histology: analysis of individual records for 556,237 adults diagnosed in 59 countries during 2000-2014 (CONCORD-3).

Oncogene. 2022 Nov 07.

DHODH inhibition impedes glioma stem cell proliferation, induces DNA damage, and prolongs survival in orthotopic glioblastoma xenografts.

Raffaella Spina, Ian Mills, Fahim Ahmad, Chixiang Chen, Heather M Ames, Jeffrey A Winkles, Graeme F Woodworth, Eli E Bar.

Glioma stem cells (GSCs) promote tumor progression and therapeutic resistance and exhibit remarkable bioenergetic and metabolic plasticity, a phenomenon that has been linked to their ability to escape standard and targeted therapies. However, specific mechanisms that promote therapeutic resistance have been somewhat elusive. We hypothesized that because GSCs proliferate continuously, they may require the salvage and de novo nucleotide synthesis pathways to satisfy their bioenergetic needs. Here, we demonstrate that GSCs lacking EGFR (or EGFRvIII) amplification are exquisitely sensitive to de novo pyrimidine synthesis perturbations, while GSCs that amplify EGFR are utterly resistant. Furthermore, we show that EGFRvIII promotes BAY2402234 resistance in otherwise BAY2402234 responsive GSCs. Remarkably, a novel, orally bioavailable, blood-brain-barrier penetrating, dihydroorotate dehydrogenase (DHODH) inhibitor BAY2402234 was found to abrogate GSC proliferation, block cell-cycle progression, and induce DNA damage and apoptosis. When dosed daily by oral gavage, BAY2402234 significantly impaired the growth of two different intracranial human glioblastoma xenograft models in mice. Given this observed efficacy and the previously established safety profiles in preclinical animal models and human clinical trials, the clinical testing of BAY2402234 in patients with primary glioblastoma that lacks EGFR amplification is warranted.

DOI: https://doi.org/10.1038/s41388-022-02517-1
Neurotherapeutics. 2022 Nov 10.

Brain Tumor Networks in Diffuse Glioma.

Yvonne Yang, Marc C Schubert, Thomas Kuner, Wolfgang Wick, Frank Winkler, Varun Venkataramani.

  Diffuse gliomas are primary brain tumors associated with a poor prognosis. Cellular and molecular mechanisms driving the invasive growth patterns and therapeutic resistance are incompletely understood. The emerging field of cancer neuroscience offers a novel approach to study these brain tumors in the context of their intricate interactions with the nervous system employing and combining methodological toolsets from neuroscience and oncology. Increasing evidence has shown how neurodevelopmental and neuronal-like mechanisms are hijacked leading to the discovery of multicellular brain tumor networks. Here, we review how gap junction-coupled tumor-tumor-astrocyte networks, as well as synaptic and paracrine neuron-tumor networks drive glioma progression. Molecular mechanisms of these malignant, homo- and heterotypic networks, and their complex interplay are reviewed. Lastly, potential clinical-translational implications and resulting therapeutic strategies are discussed.

Keywords:  Cancer neuroscience; Diffuse glioma; Glioblastoma; Neuron-glioma synapse; Neuron-tumor networks; Tumor-tumor networks

DOI:  https://doi.org/10.1007/s13311-022-01320-w
Cancers (Basel). 2022 Oct 25. pii: 5227. [Epub ahead of print]14(21):

Pleiotropy of PP2A Phosphatases in Cancer with a Focus on Glioblastoma IDH Wildtype.

Elham Kashani, Erik Vassella.

  Serine/Threonine protein phosphatase 2A (PP2A) is a heterotrimeric (or occasionally, heterodimeric) phosphatase with pleiotropic functions and ubiquitous expression. Despite the fact that they all contribute to protein dephosphorylation, multiple PP2A complexes exist which differ considerably by their subcellular localization and their substrate specificity, suggesting diverse PP2A functions. PP2A complex formation is tightly regulated by means of gene expression regulation by transcription factors, microRNAs, and post-translational modifications. Furthermore, a constant competition between PP2A regulatory subunits is taking place dynamically and depending on the spatiotemporal circumstance; many of the integral subunits can outcompete the rest, subjecting them to proteolysis. PP2A modulation is especially important in the context of brain tumors due to its ability to modulate distinct glioma-promoting signal transduction pathways, such as PI3K/Akt, Wnt, Ras, NF-κb, etc. Furthermore, PP2A is also implicated in DNA repair and survival pathways that are activated upon treatment of glioma cells with chemo-radiation. Depending on the cancer cell type, preclinical studies have shown some promise in utilising PP2A activator or PP2A inhibitors to overcome therapy resistance. This review has a special focus on "glioblastoma, IDH wild-type" (GBM) tumors, for which the therapy options have limited efficacy, and tumor relapse is inevitable.

Keywords:  Ser/Thr phosphatase; brain tumors; glioblastoma; signaling pathway; therapy

DOI:  https://doi.org/10.3390/cancers14215227
Nat Commun. 2022 Nov 11. 13(1): 6835

Near infrared-activatable biomimetic nanogels enabling deep tumor drug penetration inhibit orthotopic glioblastoma.

Dongya Zhang, Sidan Tian, Yanjie Liu, Meng Zheng, Xiangliang Yang, Yan Zou, Bingyang Shi, Liang Luo.

Glioblastoma multiforme (GBM) is one of the most fatal malignancies due to the existence of blood-brain barrier (BBB) and the difficulty to maintain an effective drug accumulation in deep GBM lesions. Here we present a biomimetic nanogel system that can be precisely activated by near infrared (NIR) irradiation to achieve BBB crossing and deep tumor penetration of drugs. Synthesized by crosslinking pullulan and poly(deca-4,6-diynedioic acid) (PDDA) and loaded with temozolomide and indocyanine green (ICG), the nanogels are inert to endogenous oxidative conditions but can be selectively disintegrated by ICG-generated reactive oxygen species upon NIR irradiation. Camouflaging the nanogels with apolipoprotein E peptide-decorated erythrocyte membrane further allows prolonged blood circulation and active tumor targeting. The precisely controlled NIR irradiation on tumor lesions excites ICG and deforms the cumulated nanogels to trigger burst drug release for facilitated BBB permeation and infiltration into distal tumor cells. These NIR-activatable biomimetic nanogels suppress the tumor growth in orthotopic GBM and GBM stem cells-bearing mouse models with significantly extended survival.

DOI: https://doi.org/10.1038/s41467-022-34462-8
Metabolites. 2022 Nov 02. pii: 1054. [Epub ahead of print]12(11):

Bioinformatic Analysis of Kynurenine Pathway Enzymes and Their Relationship with Glioma Hallmarks.

Gustavo Ignacio Vázquez Cervantes, Javier Ángel Navarro Cossio, Gonzalo Pérez de la Cruz, Aleli Salazar, Verónica Pérez de la Cruz, Benjamin Pineda.

  Indoleamine dioxygenase (IDO), a rate limiting enzyme of the tryptophan catabolism through the kynurenine pathway (KP), has been related with a lower survival and a poor patient prognosis on several solid tumors, including gliomas. However, the use of IDO inhibitors as a therapeutic strategy for tumor treatment remains controversial in clinical trials and the role of other KP enzymes on tumor progression has remained poorly understood so far. Recently, different studies on different types of cancer have pointed out the importance of KP enzymes downstream IDO. Because of this, we conducted a bioinformatic analysis of the expression of different KP enzymes and their correlation with the gene expression of molecules related to the hallmarks of cancer in transcriptomic datasets from patients with different types of brain tumors including low grade gliomas, glioblastoma multiforme, neuroblastoma, and paraganglioma and pheochromocytoma. We found that KP enzymes that drive to NAD+ synthesis are overexpressed on different brain tumors compared to brain cortex data. Moreover, these enzymes presented positive correlations with the expression of genes related to immune response modulation, angiogenesis, Signal Transducer and Activator of Transcription (STAT) signaling, and Rho GTPase expression. These correlations suggest the relevance of the expression of the KP enzymes in brain tumor pathogenesis.

Keywords:  glioma; immune response; tryptophan catabolism

DOI:  https://doi.org/10.3390/metabo12111054
Cells. 2022 Nov 02. pii: 3467. [Epub ahead of print]11(21):

Melatonin Treatment Triggers Metabolic and Intracellular pH Imbalance in Glioblastoma.

Beatriz I Fernandez-Gil, Andrea Otamendi-Lopez, Alexandra Bechtle, Carla A Vazquez-Ramos, Neda Qosja, Paola Suarez-Meade, Rachel Sarabia-Estrada, Mark E Jentoft, Hugo Guerrero-Cázares, Germaine Escames, Paula Schiapparelli, Alfredo Quiñones-Hinojosa.

  Metabolic rewiring in glioblastoma (GBM) is linked to intra- and extracellular pH regulation. In this study, we sought to characterize the role of melatonin on intracellular pH modulation and metabolic consequences to identify the mechanisms of action underlying melatonin oncostatic effects on GBM tumor initiating cells. GBM tumor initiating cells were treated at different times with melatonin (1.5 and 3.0 mM). We analyzed melatonin's functional effects on GBM proliferation, cell cycle, viability, stemness, and chemo-radiosensitivity. We then assessed the effects of melatonin on GBM metabolism by analyzing the mitochondrial and glycolytic parameters. We also measured the intracellular and extracellular pH. Finally, we tested the effects of melatonin on a mouse subcutaneous xenograft model. We found that melatonin downregulated LDHA and MCT4, decreasing lactate production and inducing a decrease in intracellular pH that was associated with an increase in ROS and ATP depletion. These changes blocked cell cycle progression and induced cellular death and we observed similar results in vivo. Melatonin's cytotoxic effects on GBM were due, at least in part, to intracellular pH modulation, which has emerged as a newly identified mechanism, providing new insights into the oncostatic effect of melatonin on GBM.

Keywords:  GBM; LDHA; MCT4; OXPHOS; ROS; cancer metabolism; glycolysis; intracellular acidity; lactate

DOI:  https://doi.org/10.3390/cells11213467
Nat Cancer. 2022 Nov 10.

Specific targeting of glioblastoma with an oncolytic virus expressing a cetuximab-CCL5 fusion protein via innate and adaptive immunity.

Lei Tian, Bo Xu, Yuqing Chen, Zhenlong Li, Jing Wang, Jianying Zhang, Rui Ma, Shuai Cao, Weidong Hu, E Antonio Chiocca, Balveen Kaur, Michael A Caligiuri, Jianhua Yu.

Chemokines such as C-C motif ligand 5 (CCL5) regulate immune cell trafficking in the tumor microenvironment (TME) and govern tumor development, making them promising targets for cancer therapy. However, short half-lives and toxic off-target effects limit their application. Oncolytic viruses (OVs) have become attractive therapeutic agents. Here, we generate an oncolytic herpes simplex virus type 1 (oHSV) expressing a secretable single-chain variable fragment of the epidermal growth factor receptor (EGFR) antibody cetuximab linked to CCL5 by an Fc knob-into-hole strategy that produces heterodimers (OV-Cmab-CCL5). OV-Cmab-CCL5 permits continuous production of CCL5 in the TME, as it is redirected to EGFR+ glioblastoma (GBM) tumor cells. OV-Cmab-CCL5 infection of GBM significantly enhances the migration and activation of natural killer cells, macrophages and T cells; inhibits tumor EGFR signaling; reduces tumor size; and prolongs survival of GBM-bearing mice. Collectively, our data demonstrate that OV-Cmab-CCL5 offers a promising approach to improve OV therapy for solid tumors.

DOI: https://doi.org/10.1038/s43018-022-00448-0
Sci Rep. 2022 Nov 10. 12(1): 19208

Prognostic differences and implications on treatment strategies between butterfly glioblastoma and glioblastoma with unilateral corpus callosum infiltration.

Mohammad Hazaymeh, Ronja Löber-Handwerker, Katja Döring, Tammam Abboud, Dorothee Mielke, Veit Rohde, Vesna Malinova.

Approximately 25% of glioblastomas show at diagnosis a corpus callosum infiltration, which is associated with poor prognosis. The extent of corpus callosum involvement, however, ranges from partial unilateral to complete bilateral infiltration. The role of surgery in glioblastoma with corpus callosum involvement is controversial. In this study, we aimed to examine prognostic differences between glioblastoma with unilateral and glioblastoma with bilateral corpus callosum infiltration, and to evaluate possible treatment strategy implications. Patients with newly diagnosed glioblastoma from 2010 to 2019 were included. Corpus callosum infiltration was assessed in contrast-enhanced T1-weighted preoperative magnetic resonance imaging. Extent of resection, adjuvant treatments and overall survival were evaluated. Corpus callosum involvement was found in 96 (26.4%) out of 363 patients with newly diagnosed glioblastoma. Bilateral corpus callosum infiltration was found in 27 out of 96 patients (28%), and 69 patients had unilateral corpus callosum infiltration. Glioblastoma with corpus callosum affection had significantly lower median overall survival compared to glioblastoma without corpus callosum involvement (9 vs. 11 months, p = 0.02). A subgroup analysis of glioblastoma with unilateral corpus callosum infiltration revealed a significant difference in median overall survival dependent on extent of resection (6.5 without gross total resection vs. 11 months with gross total resection, Log-rank test p = 0.02). Our data confirms a shorter overall survival in glioblastoma subpopulation with corpus callosum involvement, especially for glioblastoma with bilateral corpus callosum infiltration. However, patients with partial corpus callosum infiltration undergoing gross total resection exhibited a significant survival benefit compared to their counterparts without gross total resection. Whenever reasonably achievable gross total resection should be considered as an integral part of the treatment strategy in glioblastoma with partial corpus callosum infiltration.

DOI: https://doi.org/10.1038/s41598-022-23794-6
JCI Insight. 2022 Nov 08. pii: e158799. [Epub ahead of print]7(21):

α2,6 Sialylation mediated by ST6GAL1 promotes glioblastoma growth.

Sajina Gc, Kaysaw Tuy, Lucas Rickenbacker, Robert Jones, Asmi Chakraborty, C Ryan Miller, Elizabeth A Beierle, Vidya Sagar Hanumanthu, Anh N Tran, James A Mobley, Susan L Bellis, Anita B Hjelmeland.

  One of the least-investigated areas of brain pathology research is glycosylation, which is a critical regulator of cell surface protein structure and function. β-Galactoside α2,6-sialyltransferase (ST6GAL1) is the primary enzyme that α2,6 sialylates N-glycosylated proteins destined for the plasma membrane or secretion, thereby modulating cell signaling and behavior. We demonstrate a potentially novel, protumorigenic role for α2,6 sialylation and ST6GAL1 in the deadly brain tumor glioblastoma (GBM). GBM cells with high α2,6 sialylation exhibited increased in vitro growth and self-renewal capacity and decreased mouse survival when orthotopically injected. α2,6 Sialylation was regulated by ST6GAL1 in GBM, and ST6GAL1 was elevated in brain tumor-initiating cells (BTICs). Knockdown of ST6GAL1 in BTICs decreased in vitro growth, self-renewal capacity, and tumorigenic potential. ST6GAL1 regulates levels of the known BTIC regulators PDGF Receptor β (PDGFRB), Activated Leukocyte Cell Adhesion Molecule, and Neuropilin, which were confirmed to bind to a lectin-recognizing α2,6 sialic acid. Loss of ST6GAL1 was confirmed to decrease PDGFRB α2,6 sialylation, total protein levels, and the induction of phosphorylation by PDGF-BB. Thus, ST6GAL1-mediated α2,6 sialylation of a select subset of cell surface receptors, including PDGFRB, increases GBM growth.

Keywords:  Brain cancer; Cell Biology; Glycobiology; Oncology

DOI:  https://doi.org/10.1172/jci.insight.158799
Clin Immunol. 2022 Nov 08. pii: S1521-6616(22)00259-5. [Epub ahead of print] 109178

Expression and clinical significance of VISTA, B7-H3, and PD-L1 in glioma.

Li-Chong Wang, Yue-Long Wang, Bin He, Yan-Jiang Zheng, Hong-Chi Yu, Zhi-Yong Liu, Rang-Rang Fan, Xin Zan, Rui-Chao Liang, Ze-Pei Wu, Xin Tang, Guo-Qing Wang, Jian-Guo Xu, Liang-Xue Zhou.

  Immune checkpoint (IC) therapy has led to a breakthrough in cancer treatment. However, the interaction of ICs is controversial in glioma. We detected features of ICs using transcriptome data and a multicolor immunofluorescence assay. We discovered that B7-H3 increased with grade and age and predicted worse overall survival (OS) at the transcriptional and proteomic levels. VISTA and PD-L1 were associated with OS and grade at the RNA level. At the protein level, VISTA was primarily expressed in tumor cells and TAMs. B7-H3 and VISTA were positively correlated with PD-L1. There was a strong correlation between PD-L1 and CD3 and between VISTA and IBA-1. PD-L1 was coexpressed with T cells. VISTA was coexpressed with TAMs. In T cells, we found a strong correlation in ICs, which worsened in TAMs and tumor cells. In conclusion, B7-H3 is a vital prognostic target for immunotherapy. We provided a potential mechanism for the immunosuppressive microenvironment in glioma.

Keywords:  B7-H3; Glioma; PD-L1; VISTA; mIF

DOI:  https://doi.org/10.1016/j.clim.2022.109178
Neuro Oncol. 2022 Nov 11. pii: noac247. [Epub ahead of print]

The NCI Glioblastoma Therapeutics Network (GTN).

Suzanne Forry, Leah Hubbard, Michael G Espey, Bhadrasain Vikram, Bhupinder Mann, Abdul Tawab-Amiri, Toby Hecht.

DOI: https://doi.org/10.1093/neuonc/noac247
Neuro Oncol. 2022 Nov 10. pii: noac217. [Epub ahead of print]

Global survival trends for brain tumors, by histology: analysis of individual records for 556,237 adults diagnosed in 59 countries during 2000-2014 (CONCORD-3).

CONCORD Working Group

   BACKGROUND: Survival is a key metric of the effectiveness of a health system in managing cancer. We set out to provide a comprehensive examination of worldwide variation and trends in survival from brain tumors in adults, by histology.
METHODS: We analyzed individual data for adults (15-99 years) diagnosed with a brain tumor (ICD-O-3 topography code C71) during 2000-2014, regardless of tumor behavior. Data underwent a 3-phase quality control as part of CONCORD-3. We estimated net survival for 11 histology groups, using the unbiased nonparametric Pohar Perme estimator.
RESULTS: The study included 556,237 adults. In 2010-2014, the global range in age-standardized 5-year net survival for the most common sub-types was broad: in the range 20%-38% for diffuse and anaplastic astrocytoma, from 4% to 17% for glioblastoma, and between 32% and 69% for oligodendroglioma. For patients with glioblastoma, the largest gains in survival occurred between 2000-2004 and 2005-2009. These improvements were more noticeable among adults diagnosed aged 40-70 years than among younger adults.
CONCLUSIONS: To the best of our knowledge, this study provides the largest account to date of global trends in population-based survival for brain tumors by histology in adults. We have highlighted remarkable gains in 5-year survival from glioblastoma since 2005, providing large-scale empirical evidence on the uptake of chemoradiation at population level. Worldwide, survival improvements have been extensive, but some countries still lag behind. Our findings may help clinicians involved in national and international tumor pathway boards to promote initiatives aimed at more extensive implementation of clinical guidelines.

Keywords:  brain tumor; international comparisons; net survival; population-based cancer registries

DOI:  https://doi.org/10.1093/neuonc/noac217