bims-malgli 2020-07-19 papers

bims-malgli

Biomed News

on Biology of malignant gliomas

Issue of 2020–07–19
seventeen papers selected by
Oltea Sampetrean, Keio University

Dynamic changes in glioma macrophage populations after radiotherapy reveal CSF-1R inhibition as a strategy to overcome resistance.
CCR2 of Tumor Microenvironmental Cells Is a Relevant Modulator of Glioma Biology.
Single-cell lineage analysis reveals genetic and epigenetic interplay in glioblastoma drug resistance.
"Zooming in" on Glioblastoma: Understanding Tumor Heterogeneity and its Clinical Implications in the Era of Single-Cell Ribonucleic Acid Sequencing.
Inhibition of HDAC1/2 Along with TRAP1 Causes Synthetic Lethality in Glioblastoma Model Systems.
Glioblastoma multiforme: Metabolic differences to peritumoral tissue and IDH-mutated gliomas revealed by mass spectrometry imaging.
Update on glioma biotechnology.
Global activation of oncogenic pathways underlies therapy resistance in diffuse midline glioma.
A Patient-Derived Cell Atlas Informs Precision Targeting of Glioblastoma.
Targeting the DNA Damage Response to Overcome Cancer Drug Resistance in Glioblastoma.
FTO inhibition enhances the anti-tumor effect of temozolomide by targeting MYC-miR-155/23a cluster-MXI1 feedback circuit in glioma.
Therapeutic enhancement of blood-brain and blood-tumor barriers permeability by laser interstitial thermal therapy.
Molecular and clinicopathologic features of gliomas harboring NTRK fusions.
Porf-2 Inhibits Tumor Cell Migration Through the MMP-2/9 Signaling Pathway in Neuroblastoma and Glioma.
A Potential Mechanism of Temozolomide Resistance in Glioma-Ferroptosis.
A Molecular Signature associated with prolonged survival in Glioblastoma patients treated with Regorafenib.
Hyperthermia treatment advances for brain tumors.

Sci Transl Med. 2020 Jul 15. pii: eaaw7843. [Epub ahead of print]12(552):

Dynamic changes in glioma macrophage populations after radiotherapy reveal CSF-1R inhibition as a strategy to overcome resistance.

Leila Akkari, Robert L Bowman, Jeremy Tessier, Florian Klemm, Shanna M Handgraaf, Marnix de Groot, Daniela F Quail, Lucie Tillard, Jules Gadiot, Jason T Huse, Dieta Brandsma, Johan Westerga, Colin Watts, Johanna A Joyce.

Tumor-associated macrophages (TAMs) and microglia (MG) are potent regulators of glioma development and progression. However, the dynamic alterations of distinct TAM populations during the course of therapeutic intervention, response, and recurrence have not yet been fully explored. Here, we investigated how radiotherapy changes the relative abundance and phenotypes of brain-resident MG and peripherally recruited monocyte-derived macrophages (MDMs) in glioblastoma. We identified radiation-specific, stage-dependent MG and MDM gene expression signatures in murine gliomas and confirmed altered expression of several genes and proteins in recurrent human glioblastoma. We found that targeting these TAM populations using a colony-stimulating factor-1 receptor (CSF-1R) inhibitor combined with radiotherapy substantially enhanced survival in preclinical models. Our findings reveal the dynamics and plasticity of distinct macrophage populations in the irradiated tumor microenvironment, which has translational relevance for enhancing the efficacy of standard-of-care treatment in gliomas.

DOI: https://doi.org/10.1126/scitranslmed.aaw7843
Cancers (Basel). 2020 Jul 13. pii: E1882. [Epub ahead of print]12(7):

CCR2 of Tumor Microenvironmental Cells Is a Relevant Modulator of Glioma Biology.

Matthäus Felsenstein, Anne Blank, Alexander D Bungert, Annett Mueller, Adnan Ghori, Irina Kremenetskaia, Olga Rung, Thomas Broggini, Kati Turkowski, Lea Scherschinski, Jonas Raggatz, Peter Vajkoczy, Susan Brandenburg.

  Glioblastoma multiforme (GBM) shows a high influx of tumor-associated macrophages (TAMs). The CCR2/CCL2 pathway is considered a relevant signal for the recruitment of TAMs and has been suggested as a therapeutic target in malignant gliomas. We found that TAMs of human GBM specimens and of a syngeneic glioma model express CCR2 to varying extents. Using a Ccr2-deficient strain for glioma inoculation revealed a 30% reduction of TAMs intratumorally. This diminished immune cell infiltration occurred with augmented tumor volumes likely based on increased cell proliferation. Remaining TAMs in Ccr2-/- mice showed comparable surface marker expression patterns in comparison to wildtype mice, but expression levels of inflammatory transcription factors (Stat3, Irf7, Cox2) and cytokines (Ifnβ, Il1β, Il12α) were considerably affected. Furthermore, we demonstrated an impact on blood vessel integrity, while vascularization of tumors appeared similar between mouse strains. The higher stability and attenuated leakiness of the tumor vasculature imply improved sustenance of glioma tissue in Ccr2-/- mice. Additionally, despite TAMs residing in the perivascular niche in Ccr2-/- mice, their pro-angiogenic activity was reduced by the downregulation of Vegf. In conclusion, lacking CCR2 solely on tumor microenvironmental cells leads to enhanced tumor progression, whereby high numbers of TAMs infiltrate gliomas independently of the CCR2/CCL2 signal.

Keywords:  CCR2/CCL2 signaling; GBM; tumor angiogenesis; tumor-associated macrophages (TAMs), blood vessel integrity

DOI:  https://doi.org/10.3390/cancers12071882
Genome Biol. 2020 Jul 15. 21(1): 174

Single-cell lineage analysis reveals genetic and epigenetic interplay in glioblastoma drug resistance.

Christine E Eyler, Hironori Matsunaga, Volker Hovestadt, Samantha J Vantine, Peter van Galen, Bradley E Bernstein.

   BACKGROUND: Tumors can evolve and adapt to therapeutic pressure by acquiring genetic and epigenetic alterations that may be transient or stable. A precise understanding of how such events contribute to intratumoral heterogeneity, dynamic subpopulations, and overall tumor fitness will require experimental approaches to prospectively label, track, and characterize resistant or otherwise adaptive populations at the single-cell level. In glioblastoma, poor efficacy of receptor tyrosine kinase (RTK) therapies has been alternatively ascribed to genetic heterogeneity or to epigenetic transitions that circumvent signaling blockade.
RESULTS: We combine cell lineage barcoding and single-cell transcriptomics to trace the emergence of drug resistance in stem-like glioblastoma cells treated with RTK inhibitors. Whereas a broad variety of barcoded lineages adopt a Notch-dependent persister phenotype that sustains them through early drug exposure, rare subclones acquire genetic changes that enable their rapid outgrowth over time. Single-cell analyses reveal that these genetic subclones gain copy number amplifications of the insulin receptor substrate-1 and substrate-2 (IRS1 or IRS2) loci, which activate insulin and AKT signaling programs. Persister-like cells and genomic amplifications of IRS2 and other loci are evident in primary glioblastomas and may underlie the inefficacy of targeted therapies in this disease.
CONCLUSIONS: A method for combined lineage tracing and scRNA-seq reveals the interplay between complementary genetic and epigenetic mechanisms of resistance in a heterogeneous glioblastoma tumor model.

Keywords:  Epigenetic; Genetic; Glioma stem cells; Insulin receptor substrate/IRS; Lineage tracing; Single-cell RNA-seq; Therapy resistance; Tumor heterogeneity

DOI:  https://doi.org/10.1186/s13059-020-02085-1
Neurosurgery. 2020 Jul 16. pii: nyaa305. [Epub ahead of print]

"Zooming in" on Glioblastoma: Understanding Tumor Heterogeneity and its Clinical Implications in the Era of Single-Cell Ribonucleic Acid Sequencing.

Adham M Khalafallah, Sakibul Huq, Adrian E Jimenez, Riccardo Serra, Chetan Bettegowda, Debraj Mukherjee.

  Glioblastoma (GBM) is the most common primary brain malignancy in adults and one of the most aggressive of all human cancers. It is highly recurrent and treatment-resistant, in large part due to its infiltrative nature and inter- and intratumoral heterogeneity. This heterogeneity entails varying genomic landscapes and cell types within and between tumors and the tumor microenvironment (TME). In GBM, heterogeneity is a driver of treatment resistance, recurrence, and poor prognosis, representing a substantial impediment to personalized medicine. Over the last decade, sequencing technologies have facilitated deeper understanding of GBM heterogeneity by "zooming in" progressively further on tumor genomics and transcriptomics. Initial efforts employed bulk ribonucleic acid (RNA) sequencing, which examines composite gene expression of whole tumor specimens. While groundbreaking at the time, this bulk RNAseq masks the crucial contributions of distinct tumor subpopulations to overall gene expression. This work progressed to the use of bulk RNA sequencing in anatomically and spatially distinct tumor subsections, which demonstrated previously underappreciated genomic complexity of GBM. A revolutionary next step forward has been the advent of single-cell RNA sequencing (scRNAseq), which examines gene expression at the single-cell level. scRNAseq has enabled us to understand GBM heterogeneity in unprecedented detail. We review seminal studies in our progression of understanding GBM heterogeneity, with a focus on scRNAseq and the insights that it has provided into understanding the GBM tumor mass, peritumoral space, and TME. We highlight preclinical and clinical implications of this work and consider its potential to impact neuro-oncology and to improve patient outcomes via personalized medicine.

Keywords:  Glioblastoma; RNA sequencing; Single-cell RNA sequencing

DOI:  https://doi.org/10.1093/neuros/nyaa305
Cells. 2020 Jul 10. pii: E1661. [Epub ahead of print]9(7):

Inhibition of HDAC1/2 Along with TRAP1 Causes Synthetic Lethality in Glioblastoma Model Systems.

Trang T T Nguyen, Yiru Zhang, Enyuan Shang, Chang Shu, Catarina M Quinzii, Mike-Andrew Westhoff, Georg Karpel-Massler, Markus D Siegelin.

  The heterogeneity of glioblastomas, the most common primary malignant brain tumor, remains a significant challenge for the treatment of these devastating tumors. Therefore, novel combination treatments are warranted. Here, we showed that the combined inhibition of TRAP1 by gamitrinib and histone deacetylases (HDAC1/HDAC2) through romidepsin or panobinostat caused synergistic growth reduction of established and patient-derived xenograft (PDX) glioblastoma cells. This was accompanied by enhanced cell death with features of apoptosis and activation of caspases. The combination treatment modulated the levels of pro- and anti-apoptotic Bcl-2 family members, including BIM and Noxa, Mcl-1, Bcl-2 and Bcl-xL. Silencing of Noxa, BAK and BAX attenuated the effects of the combination treatment. At the metabolic level, the combination treatment led to an enhanced reduction of oxygen consumption rate and elicited an unfolded stress response. Finally, we tested whether the combination treatment of gamitrinib and panobinostat exerted therapeutic efficacy in PDX models of glioblastoma (GBM) in mice. While single treatments led to mild to moderate reduction in tumor growth, the combination treatment suppressed tumor growth significantly stronger than single treatments without induction of toxicity. Taken together, we have provided evidence that simultaneous targeting of TRAP1 and HDAC1/2 is efficacious to reduce tumor growth in model systems of glioblastoma.

Keywords:  Bcl-2 family; HDAC inhibitors; electron transport chain; gamitrinib; glioblastoma; tumor metabolism

DOI:  https://doi.org/10.3390/cells9071661
Neuropathology. 2020 Jul 13.

Glioblastoma multiforme: Metabolic differences to peritumoral tissue and IDH-mutated gliomas revealed by mass spectrometry imaging.

Judith M Kampa, Udo Kellner, Christian Marsching, Carina Ramallo Guevara, Ulrich J Knappe, Mikail Sahin, Marco Giampà, Karsten Niehaus, Hanna Bednarz.

  Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor. High infiltration rates and poor therapy responses make it the deadliest glioma. The tumor metabolism is known to differ from normal one and is influenced through various factors which can lead to longer survival. Metabolites are small molecules (< 1500 Da) that display the metabolic pathways in the tissue. To determine the metabolic alterations between tumor and peritumoral tissue in human GBMs, mass spectrometry imaging (MSI) was performed on thin sections from 25 resected tumors. In addition, the GBMs were compared with six gliomas harboring a mutation in the isocitrate dehydrogenase (IDH1) gene (IDH1). With this technique, a manifold of analytes can be easily visualized on a single tissue section. Metabolites were annotated based on their accurate mass using high resolution MSI. Differences in their mean intensities in the tumor and peritumoral areas were statistically evaluated and abundances were visualized on the tissue. Enhanced levels of the antioxidants ascorbic acid, taurine, and glutathione in tumor areas suggest protective effects on the tumor. Increased levels of purine and pyrimidine metabolism compounds in GBM areas indicate the high energy demand. In accordance with these results, enhanced abundances of lactate and glutamine were detected. Moreover, decreased abundance of N-acetylaspartate, a marker for neuronal health, was measured in tumor areas. Obtained metabolic information could potentially support and personalize therapeutic approaches, hence emphasizing the suitability of MSI for GBM research.

Keywords:  MALDI mass spectrometry imaging; antioxidants; glioblastoma multiforme; spatial localization of metabolites; tumor metabolism

DOI:  https://doi.org/10.1111/neup.12671
Clin Neurol Neurosurg. 2020 Jul 07. pii: S0303-8467(20)30418-2. [Epub ahead of print]195 106075

Update on glioma biotechnology.

Madeline Abrams, Noah Reichman, Deepak Khatri, Nitesh V Patel, Randy S D'Amico, Tamika Wong, Sherese Fralin, Mona Li, Marc Symons, David Langer, Christopher G Filippi, John A Boockvar.

  Neuro-oncological research is at the forefront of the rising cancer therapy market, as evidenced by its growing revenue and the multitude of clinical trials investigating innovative treatment approaches. The Feinstein Institute for Medical Research, in conjunction with the Department of Neurosurgery at Lenox Hill Hospital and the Zucker School of Medicine at Hofstra / Northwell, sponsored The Brain Tumor Biotech Summit in New York City in June 2019. The aim of the Summit was to provide a forum that encourages collaboration between cancer specialists, biotechnology and pharmaceutical industry leaders, and the investment community in order to promote innovation and advance emerging therapies for brain tumors. Areas highlighted during the Summit included immunotherapy, precision medicine, and novel applications and experimental treatments such as receptor targeting, methods for improved drug delivery, and innovative intraoperative techniques and technologies. This review synthesizes the recent breakthroughs in brain tumor research as presented at The Brain Tumor Biotech Summit.

Keywords:  Biotechnology; Brain tumor; Glioblastoma; Glioma; Industry

DOI:  https://doi.org/10.1016/j.clineuro.2020.106075
Acta Neuropathol Commun. 2020 Jul 17. 8(1): 111

Global activation of oncogenic pathways underlies therapy resistance in diffuse midline glioma.

M-M Georgescu, M Z Islam, Y Li, M L Circu, J Traylor, C M Notarianni, C N Kline, D K Burns.

  Diffuse midline gliomas (DMGs) are aggressive pediatric brain tumors with dismal prognosis due to therapy-resistant tumor growth and invasion. We performed the first integrated histologic/genomic/proteomic analysis of 21 foci from three pontine DMG cases with supratentorial dissemination. Histone H3.3-K27M was the driver mutation, usually at high variant allele fraction due to recurrent chromosome 1q copy number gain, in combination with germline variants in ATM, FANCM and MYCN genes. Both previously reported and novel recurrent copy number variations and somatic pathogenic mutations in chromatin remodeling, DNA damage response and PI3K/MAPK growth pathways were variably detected, either in multiple or isolated foci. Proteomic analysis showed global upregulation of histone H3, lack of H3-K27 trimethylation, and further impairment of polycomb repressive complex 2 by ASXL1 downregulation. Activation of oncogenic pathways resulted from combined upregulation of N-MYC, SOX2, p65/p50 NF-κB and STAT3 transcription factors, EGFR, FGFR2, PDGFRα/β receptor tyrosine kinases, and downregulation of PHLPP1/2, PTEN and p16/INK4A tumor suppressors. Upregulation of SMAD4, PAI-1, CD44, and c-SRC in multiple foci most likely contributed to invasiveness. This integrated comprehensive analysis revealed a complex spatiotemporal evolution in diffuse intrisic pontine glioma, recommending pontine and cerebellar biopsies for accurate populational genetic characterization, and delineated common signaling pathways and potential therapeutic targets. It also revealed an unsuspected activation of a multitude of oncogenic pathways, including cancer cell reprogramming, explaining the resistance of DMG to current therapies.

Keywords:  Diffuse midline glioma, Autopsy, Next generation sequencing (NGS), Copy number variation (CNV), Proteomics

DOI:  https://doi.org/10.1186/s40478-020-00992-9
Cell Rep. 2020 Jul 14. pii: S2211-1247(20)30878-0. [Epub ahead of print]32(2): 107897

A Patient-Derived Cell Atlas Informs Precision Targeting of Glioblastoma.

Patrik Johansson, Cecilia Krona, Soumi Kundu, Milena Doroszko, Sathishkumar Baskaran, Linnéa Schmidt, Claire Vinel, Elin Almstedt, Ramy Elgendy, Ludmila Elfineh, Caroline Gallant, Sara Lundsten, Fernando J Ferrer Gago, Aleksi Hakkarainen, Petra Sipilä, Maria Häggblad, Ulf Martens, Bo Lundgren, Melanie M Frigault, David P Lane, Fredrik J Swartling, Lene Uhrbom, Marika Nestor, Silvia Marino, Sven Nelander.

  Glioblastoma (GBM) is a malignant brain tumor with few therapeutic options. The disease presents with a complex spectrum of genomic aberrations, but the pharmacological consequences of these aberrations are partly unknown. Here, we report an integrated pharmacogenomic analysis of 100 patient-derived GBM cell cultures from the human glioma cell culture (HGCC) cohort. Exploring 1,544 drugs, we find that GBM has two main pharmacological subgroups, marked by differential response to proteasome inhibitors and mutually exclusive aberrations in TP53 and CDKN2A/B. We confirm this trend in cell and in xenotransplantation models, and identify both Bcl-2 family inhibitors and p53 activators as potentiators of proteasome inhibitors in GBM cells. We can further predict the responses of individual cell cultures to several existing drug classes, presenting opportunities for drug repurposing and design of stratified trials. Our functionally profiled biobank provides a valuable resource for the discovery of new treatments for GBM.

Keywords:  biobank; combination therapy; data integration; glioblastoma; multi-omics; p53 reactivators; patient-derived cells; primary cells; proteasome

DOI:  https://doi.org/10.1016/j.celrep.2020.107897
Int J Mol Sci. 2020 Jul 11. pii: E4910. [Epub ahead of print]21(14):

Targeting the DNA Damage Response to Overcome Cancer Drug Resistance in Glioblastoma.

Alessandra Ferri, Venturina Stagni, Daniela Barilà.

  Glioblastoma multiforme (GBM) is a severe brain tumor whose ability to mutate and adapt to therapies is at the base for the extremely poor survival rate of patients. Despite multiple efforts to develop alternative forms of treatment, advances have been disappointing and GBM remains an arduous tumor to treat. One of the leading causes for its strong resistance is the innate upregulation of DNA repair mechanisms. Since standard therapy consists of a combinatory use of ionizing radiation and alkylating drugs, which both damage DNA, targeting the DNA damage response (DDR) is proving to be a beneficial strategy to sensitize tumor cells to treatment. In this review, we will discuss how recent progress in the availability of the DDR kinase inhibitors will be key for future therapy development. Further, we will examine the principal existing DDR inhibitors, with special focus on those currently in use for GBM clinical trials.

Keywords:  DDR inhibitors; DNA damage response; glioblastoma

DOI:  https://doi.org/10.3390/ijms21144910
Cancer Res. 2020 Jul 17. pii: canres.0132.2020. [Epub ahead of print]

FTO inhibition enhances the anti-tumor effect of temozolomide by targeting MYC-miR-155/23a cluster-MXI1 feedback circuit in glioma.

Li Xiao, Xiaodi Li, Zekun Mu, Jianwen Zhou, Peng Zhou, Chen Xie, Songshan Jiang.

Malignant glioma constitutes one of the fatal primary brain tumors in adults. Such poor prognosis calls for a better understanding of cancer-related signaling pathways of this disease. Here we elucidate a MYC-miRNA-MXI1 feedback loop that regulates proliferation and tumorigenesis in glioma. MYC suppressed MXI1 expression via microRNA-155 (miR-155) and the microRNA-23a~27a~24-2 cluster (miR-23a cluster), whereas MXI1, in turn, inhibited MYC expression by binding to its promoter. Overexpression of miR-155 and the miR-23a cluster promoted tumorigenesis in U87 glioma cells. Furthermore, FTO, an N6-methyladenosine (m6A) RNA demethylase, regulated the loop by targeting MYC. The ethyl ester form of meclofenamic acid (MA2) inhibited FTO and enhanced the effect of the chemotherapy drug temozolomide (TMZ) on suppressing proliferation of glioma cells and negatively regulated the loop. These data collectively highlight a key regulatory circuit in glioma and provide potential targets for clinical treatment.

DOI: https://doi.org/10.1158/0008-5472.CAN-20-0132
Neurooncol Adv. 2020 Jan-Dec;2(1):2(1): vdaa071

Therapeutic enhancement of blood-brain and blood-tumor barriers permeability by laser interstitial thermal therapy.

Afshin Salehi, Mounica R Paturu, Bhuvic Patel, Matthew D Cain, Tatenda Mahlokozera, Alicia B Yang, Tsen-Hsuan Lin, Eric C Leuthardt, Hiroko Yano, Sheng-Kwei Song, Robyn S Klein, Robert Schmidt, Albert H Kim.

   Background: The blood-brain and blood-tumor barriers (BBB and BTB), which restrict the entry of most drugs into the brain and tumor, respectively, are a significant challenge in the treatment of glioblastoma. Laser interstitial thermal therapy (LITT) is a minimally invasive surgical technique increasingly used clinically for tumor cell ablation. Recent evidence suggests that LITT might locally disrupt BBB integrity, creating a potential therapeutic window of opportunity to deliver otherwise brain-impermeant agents.
Methods: We established a LITT mouse model to test if laser therapy can increase BBB/BTB permeability in vivo. Mice underwent orthotopic glioblastoma tumor implantation followed by LITT in combination with BBB tracers or the anticancer drug doxorubicin. BBB/BTB permeability was measured using fluorimetry, microscopy, and immunofluorescence. An in vitro endothelial cell model was also used to corroborate findings.
Results: LITT substantially disrupted the BBB and BTB locally, with increased permeability up to 30 days after the intervention. Remarkably, molecules as large as human immunoglobulin extravasated through blood vessels and permeated laser-treated brain tissue and tumors. Mechanistically, LITT decreased tight junction integrity and increased brain endothelial cell transcytosis. Treatment of mice bearing glioblastoma tumors with LITT and adjuvant doxorubicin, which is typically brain-impermeant, significantly increased animal survival.
Conclusions: Together, these results suggest that LITT can locally disrupt the BBB and BTB, enabling the targeted delivery of systemic therapies, including, potentially, antibody-based agents.

Keywords:  blood–brain barrier; blood–tumor barrier; central nervous system tumors; glioblastoma; laser interstitial thermal therapy

DOI:  https://doi.org/10.1093/noajnl/vdaa071
Acta Neuropathol Commun. 2020 Jul 14. 8(1): 107

Molecular and clinicopathologic features of gliomas harboring NTRK fusions.

Matthew Torre, Varshini Vasudevaraja, Jonathan Serrano, Michael DeLorenzo, Seth Malinowski, Anne-Florence Blandin, Melanie Pages, Azra H Ligon, Fei Dong, David M Meredith, MacLean P Nasrallah, Craig Horbinski, Sonika Dahiya, Keith L Ligon, Mariarita Santi, Shakti H Ramkissoon, Mariella G Filbin, Matija Snuderl, Sanda Alexandrescu.

  Fusions involving neurotrophic tyrosine receptor kinase (NTRK) genes are detected in ≤2% of gliomas and can promote gliomagenesis. The remarkable therapeutic efficacy of TRK inhibitors, which are among the first Food and Drug Administration-approved targeted therapies for NTRK-fused gliomas, has generated significant clinical interest in characterizing these tumors. In this multi-institutional retrospective study of 42 gliomas with NTRK fusions, next generation DNA sequencing (n = 41), next generation RNA sequencing (n = 1), RNA-sequencing fusion panel (n = 16), methylation profile analysis (n = 18), and histologic evaluation (n = 42) were performed. All infantile NTRK-fused gliomas (n = 7) had high-grade histology and, with one exception, no other significant genetic alterations. Pediatric NTRK-fused gliomas (n = 13) typically involved NTRK2, ranged from low- to high-histologic grade, and demonstrated histologic overlap with desmoplastic infantile ganglioglioma, pilocytic astrocytoma, ganglioglioma, and glioblastoma, among other entities, but they rarely matched with high confidence to known methylation class families or with each other; alterations involving ATRX, PTEN, and CDKN2A/2B were present in a subset of cases. Adult NTRK-fused gliomas (n = 22) typically involved NTRK1 and had predominantly high-grade histology; genetic alterations involving IDH1, ATRX, TP53, PTEN, TERT promoter, RB1, CDKN2A/2B, NF1, and polysomy 7 were common. Unsupervised principal component analysis of methylation profiles demonstrated no obvious grouping by histologic grade, NTRK gene involved, or age group. KEGG pathway analysis detected methylation differences in genes involved in PI3K/AKT, MAPK, and other pathways. In summary, the study highlights the clinical, histologic, and molecular heterogeneity of NTRK-fused gliomas, particularly when stratified by age group.

Keywords:  Glioma; Methylation; NGS sequencing; NTRK

DOI:  https://doi.org/10.1186/s40478-020-00980-z
Front Oncol. 2020 ;10 975

Porf-2 Inhibits Tumor Cell Migration Through the MMP-2/9 Signaling Pathway in Neuroblastoma and Glioma.

Xue-Yuan Li, Guo-Hui Huang, Qian-Kun Liu, Xi-Tao Yang, Kang Wang, Wen-Zheng Luo, Tian-Song Liang, Shan-Peng Yuan, Ying-Wei Zhen, Dong-Ming Yan.

  Tumor migration and invasion are key pathological processes that contribute to cell metastasis as well as treatment failure in patients with malignant tumors. However, the mechanisms governing tumor cell migration remain poorly understood. By analyzing the tumor-related database and tumor cell lines, we found that preoptic regulatory factor-2 (Porf-2) is downexpressed in both neuroblastoma and glioma. Using in vitro assays, our data demonstrated that the expression of Porf-2 inhibits tumor cell migration both in neuroblastoma and glioma cell lines. Domain-mutated Porf-2 plasmids were then constructed, and it was found that the GAP domain, which plays a role in the inactivation of Rac1, is the functional domain for inhibiting tumor cell migration. Furthermore, by screening potential downstream effectors, we found that Porf-2 can reduce MMP-2 and MMP-9 expression. Overexpression of MMP-2 blocked the inhibitory effect of Porf-2 in tumor cell migration both in vitro and in vivo. Taken together, we show for the first time that Porf-2 is capable of suppressing tumor cell migration via its GAP domain and the downregulation of MMP-2/9, suggesting that targeting Porf-2 could be a promising therapeutic strategy for nervous system tumors.

Keywords:  MMP-2/9; Porf-2; glioma; neuroblastoma; tumor migration

DOI:  https://doi.org/10.3389/fonc.2020.00975
Front Oncol. 2020 ;10 897

A Potential Mechanism of Temozolomide Resistance in Glioma-Ferroptosis.

Zhifang Hu, Yajing Mi, Huiming Qian, Na Guo, Aili Yan, Yuelin Zhang, Xingchun Gao.

  Temozolomide (TMZ) is the first-line chemotherapy drug that has been used to treat glioma for over a decade, but the benefits are limited by half of the treated patients who acquired resistance. Studies have shown that glioma TMZ resistance is a complex process with multiple factors, which has not been fully elucidated. Ferroptosis, which is a new type of cell death discovered in recent years, has been reported to play an important role in tumor drug resistance. The present study reviews the relationship between ferroptosis and glioma TMZ resistance, and highlights the role of ferroptosis in glioma TMZ resistance. Finally, the investigators discussed the future orientation for ferroptosis in glioma TMZ resistance, in order to promote the clinical use of ferroptosis induction in glioma treatment.

Keywords:  GPX4; drug resistance; ferroptosis; glioma; temozolomide

DOI:  https://doi.org/10.3389/fonc.2020.00897
Neuro Oncol. 2020 Jul 14. pii: noaa156. [Epub ahead of print]

A Molecular Signature associated with prolonged survival in Glioblastoma patients treated with Regorafenib.

Alessandra Santangelo, Marzia Rossato, Giuseppe Lombardi, Salvatore Benfatto, Denise Lavezzari, Gian Luca De Salvo, Stefano Indraccolo, Maria Cristina Dechecchi, Paola Prandini, Roberto Gambari, Chiara Scapoli, Gianfranco Di Gennaro, Mario Caccese, Marica Eoli, Roberta Rudà, Alba Ariela Brandes, Toni Ibrahim, Simona Rizzato, Ivan Lolli, Giuseppe Lippi, Massimo Delledonne, Vittorina Zagonel, Giulio Cabrini.

   BACKGROUND: Patients with glioblastoma (GBM) have a dramatically poor prognosis. The recent REGOMA trial suggested an overall survival benefit of regorafenib in recurrent GBM patients. Considering the extreme genetic heterogeneity of GBMs, we aimed to identify molecular biomarkers predictive of differential response to the drug.
METHODS: Total RNA was extracted from tumor samples of patients enrolled in the REGOMA trial. Genome-wide transcriptome and miRNA profiles were associated with patients' Overall Survival (OS) and Progression Free Survival (PFS).
RESULTS: At first step, a set of 11 gene transcripts (HIF1A, CTSK, SLC2A1, KLHL12, CDKN1A, CA12, WDR1, CD53, CBR4, NIFK-AS1, RAB30-DT) and 10 miRNAs (miR-93-5p, miR-203a-3p, miR-17-5p, let-7c-3p, miR-101-3p, miR-3607-3p, miR-6516-3p, miR-301a-3p, miR-23b-3p, miR-222-3p) was filtered by comparing survival between regorafenib and lomustine arms. As second step, a minisignature of two gene transcripts (HIF1A, CDKN1A) and three miRNAs (miR-3607-3p, miR-301a-3p, miR-93-5p) identified a subgroup of patients showing prolonged survival after regorafenib administration (median OS range 10.6 - 20.8 months).
CONCLUSIONS: The study provides evidence that a signature based on the expression of five biomarkers could help identifying a subgroup of GBM patients exhibiting a striking survival advantage when treated with regorafenib. Despite the presented results must be confirmed in larger replication cohorts, the study highlights potential biomarker options to help guiding the clinical decision among regorafenib and other treatments in patients with relapsing GBM.

Keywords:   CDKN1A ; HIF1A ; glioblastoma; miR-93-5p; regorafenib

DOI:  https://doi.org/10.1093/neuonc/noaa156
Int J Hyperthermia. 2020 Jul;37(2): 3-19

Hyperthermia treatment advances for brain tumors.

Georgios P Skandalakis, Daniel R Rivera, Caroline D Rizea, Alexandros Bouras, Joe Gerald Jesu Raj, Dominique Bozec, Constantinos G Hadjipanayis.

  Hyperthermia therapy (HT) of cancer is a well-known treatment approach. With the advent of new technologies, HT approaches are now important for the treatment of brain tumors. We review current clinical applications of HT in neuro-oncology and ongoing preclinical research aiming to advance HT approaches to clinical practice. Laser interstitial thermal therapy (LITT) is currently the most widely utilized thermal ablation approach in clinical practice mainly for the treatment of recurrent or deep-seated tumors in the brain. Magnetic hyperthermia therapy (MHT), which relies on the use of magnetic nanoparticles (MNPs) and alternating magnetic fields (AMFs), is a new quite promising HT treatment approach for brain tumors. Initial MHT clinical studies in combination with fractionated radiation therapy (RT) in patients have been completed in Europe with encouraging results. Another combination treatment with HT that warrants further investigation is immunotherapy. HT approaches for brain tumors will continue to a play an important role in neuro-oncology.

Keywords:  Brain tumor; hyperthermia therapy; laser interstitial thermal therapy; magnetic hyperthermia therapy; photothermal therapy

DOI:  https://doi.org/10.1080/02656736.2020.1772512