bims-malgli 2020-06-14 papers

bims-malgli

Biomed News

on Biology of malignant gliomas

Issue of 2020–06–14
thirty papers selected by
Oltea Sampetrean, Keio University

A kinase-deficient NTRK2 splice variant predominates in glioma and amplifies several oncogenic signaling pathways.
Extracellular Vesicles Induce Mesenchymal Transition and Therapeutic Resistance in Glioblastomas through NF-κB/STAT3 Signaling.
Ivosidenib in Isocitrate Dehydrogenase 1-Mutated Advanced Glioma.
Evaluation of Diagnostic Accuracy Following the Coadministration of Delta-Aminolevulinic Acid and Second Window Indocyanine Green in Rodent and Human Glioblastomas.
ARS2/MAGL signaling in glioblastoma stem cells promotes self-renewal and M2-like polarization of tumor-associated macrophages.
Patient-derived orthotopic xenografts of pediatric brain tumors: a St. Jude resource.
Rapid and Efficient Invasion Assay of Glioblastoma in Human Brain Organoids.
GBP2 enhances glioblastoma invasion through Stat3/fibronectin pathway.
Nanos3, a cancer-germline gene, promotes cell proliferation, migration, chemoresistance, and invasion of human glioblastoma.
MicroRNA-128-3p Enhances the Chemosensitivity of Temozolomide in Glioblastoma by Targeting c-Met and EMT.
Identifying Predictive Gene Expression and Signature Related to Temozolomide Sensitivity of Glioblastomas.
The enhanced treatment efficacy of invasive brain glioma by dual-targeted artemether plus paclitaxel micelles.
Lin28A promotes IRF6-regulated aerobic glycolysis in glioma cells by stabilizing SNHG14.
Expression and prognostic value of the transcription factors EGR1 and EGR3 in gliomas.
ACYP2 contributes to malignant progression of glioma through promoting Ca2+ efflux and subsequently activating c-Myc and STAT3 signals.
HOTAIR-EZH2 inhibitor AC1Q3QWB upregulates CWF19L1 and enhances cell cycle inhibition of CDK4/6 inhibitor palbociclib in glioma.
Noninvasive diffusion magnetic resonance imaging of brain tumour cell size for the early detection of therapeutic response.
ST1926 inhibits glioma progression through regulating mitochondrial complex II.
Coagulation factor 2 thrombin receptor promotes malignancy in glioma under SOX2 regulation.
Leptin and Notch Signaling Cooperate in Sustaining Glioblastoma Multiforme Progression.
DNA Methylation-based Diagnostic and Prognostic Biomarkers for Glioblastoma.
LncRNA MIR155HG Promotes Temozolomide Resistance by Activating the Wnt/β-Catenin Pathway Via Binding to PTBP1 in Glioma.
CD155 immunoregulation as a target for natural killer cell immunotherapy in glioblastoma.
Baseline Requirements for Novel Agents Being Considered for Phase II/III Brain Cancer Efficacy Trials:Conclusions from the Adult Brain Tumor Consortium's First Workshop on CNS Drug Delivery.
PD-1 inhibitors: Do they have a future in the treatment of glioblastoma?
Survival after hypofractionation in glioblastoma: a systematic review and meta-analysis.
Neuronal signatures in cancer.
Metabolic heterogeneity and adaptability in brain tumors.
Repeat radiation with bevacizumab and minocycline in bevacizumab-refractory high grade gliomas: a prospective phase 1 trial.
Consensus Recommendations for a Dynamic Susceptibility Contrast MRI Protocol for Use in High-Grade Gliomas.

Nat Commun. 2020 Jun 12. 11(1): 2977

A kinase-deficient NTRK2 splice variant predominates in glioma and amplifies several oncogenic signaling pathways.

Siobhan S Pattwell, Sonali Arora, Patrick J Cimino, Tatsuya Ozawa, Frank Szulzewsky, Pia Hoellerbauer, Tobias Bonifert, Benjamin G Hoffstrom, Norman E Boiani, Hamid Bolouri, Colin E Correnti, Barbara Oldrini, John R Silber, Massimo Squatrito, Patrick J Paddison, Eric C Holland.

Independent scientific achievements have led to the discovery of aberrant splicing patterns in oncogenesis, while more recent advances have uncovered novel gene fusions involving neurotrophic tyrosine receptor kinases (NTRKs) in gliomas. The exploration of NTRK splice variants in normal and neoplastic brain provides an intersection of these two rapidly evolving fields. Tropomyosin receptor kinase B (TrkB), encoded NTRK2, is known for critical roles in neuronal survival, differentiation, molecular properties associated with memory, and exhibits intricate splicing patterns and post-translational modifications. Here, we show a role for a truncated NTRK2 splice variant, TrkB.T1, in human glioma. TrkB.T1 enhances PDGF-driven gliomas in vivo, augments PDGF-induced Akt and STAT3 signaling in vitro, while next generation sequencing broadly implicates TrkB.T1 in the PI3K signaling cascades in a ligand-independent fashion. These TrkB.T1 findings highlight the importance of expanding upon whole gene and gene fusion analyses to include splice variants in basic and translational neuro-oncology research.

DOI: https://doi.org/10.1038/s41467-020-16786-5
Adv Biosyst. 2020 Jun 09. e1900312

Extracellular Vesicles Induce Mesenchymal Transition and Therapeutic Resistance in Glioblastomas through NF-κB/STAT3 Signaling.

Markus W Schweiger, Mao Li, Alberta Giovanazzi, Renata L Fleming, Elie I Tabet, Ichiro Nakano, Thomas Würdinger, Ennio Antonio Chiocca, Tian Tian, Bakhos A Tannous.

  Glioblastoma (GBM) is the most common primary malignant brain tumor and despite optimal treatment, long-term survival remains uncommon. GBM can be roughly divided into three different molecular subtypes, each varying in aggressiveness and treatment resistance. Recent evidence shows plasticity between these subtypes in which the proneural (PN) glioma stem-like cells (GSCs) undergo transition into the more aggressive mesenchymal (MES) subtype, leading to therapeutic resistance. Extracellular vesicles (EVs) are membranous structures secreted by nearly every cell and are shown to play a key role in GBM progression by acting as multifunctional signaling complexes. Here, it is shown that EVs derived from MES cells educate PN cells to increase stemness, invasiveness, cell proliferation, migration potential, aggressiveness, and therapeutic resistance by inducing mesenchymal transition through nuclear factor-κB/signal transducer and activator of transcription 3 signaling. The findings could potentially help explore new treatment strategies for GBM and indicate that EVs may also play a role in mesenchymal transition of different tumor types.

Keywords:  NF-κB signaling; STAT3 signaling; extracellular vesicles; glioblastoma; mesenchymal transition; treatment resistance

DOI:  https://doi.org/10.1002/adbi.201900312
J Clin Oncol. 2020 Jun 12. JCO1903327

Ivosidenib in Isocitrate Dehydrogenase 1-Mutated Advanced Glioma.

Ingo K Mellinghoff, Benjamin M Ellingson, Mehdi Touat, Elizabeth Maher, Macarena I De La Fuente, Matthias Holdhoff, Gregory M Cote, Howard Burris, Filip Janku, Robert J Young, Raymond Huang, Liewen Jiang, Sung Choe, Bin Fan, Katharine Yen, Min Lu, Chris Bowden, Lori Steelman, Shuchi S Pandya, Timothy F Cloughesy, Patrick Y Wen.

PURPOSE: Diffuse gliomas are malignant brain tumors that include lower-grade gliomas (LGGs) and glioblastomas. Transformation of low-grade glioma into a higher tumor grade is typically associated with contrast enhancement on magnetic resonance imaging. Mutations in the isocitrate dehydrogenase 1 (IDH1) gene occur in most LGGs (> 70%). Ivosidenib is an inhibitor of mutant IDH1 (mIDH1) under evaluation in patients with solid tumors.
METHODS: We conducted a multicenter, open-label, phase I, dose escalation and expansion study of ivosidenib in patients with mIDH1 solid tumors. Ivosidenib was administered orally daily in 28-day cycles.
RESULTS: In 66 patients with advanced gliomas, ivosidenib was well tolerated, with no dose-limiting toxicities reported. The maximum tolerated dose was not reached; 500 mg once per day was selected for the expansion cohort. The grade ≥ 3 adverse event rate was 19.7%; 3% (n = 2) were considered treatment related. In patients with nonenhancing glioma (n = 35), the objective response rate was 2.9%, with 1 partial response. Thirty of 35 patients (85.7%) with nonenhancing glioma achieved stable disease compared with 14 of 31 (45.2%) with enhancing glioma. Median progression-free survival was 13.6 months (95% CI, 9.2 to 33.2 months) and 1.4 months (95% CI, 1.0 to 1.9 months) for the nonenhancing and enhancing glioma cohorts, respectively. In an exploratory analysis, ivosidenib reduced the volume and growth rates of nonenhancing tumors.
CONCLUSION: In patients with mIDH1 advanced glioma, ivosidenib 500 mg once per day was associated with a favorable safety profile, prolonged disease control, and reduced growth of nonenhancing tumors.

DOI: https://doi.org/10.1200/JCO.19.03327
Mol Imaging Biol. 2020 Jun 08.

Evaluation of Diagnostic Accuracy Following the Coadministration of Delta-Aminolevulinic Acid and Second Window Indocyanine Green in Rodent and Human Glioblastomas.

Steve S Cho, Saad Sheikh, Clare W Teng, Joseph Georges, Andrew I Yang, Emma De Ravin, Love Buch, Carrie Li, Yash Singh, Denah Appelt, Edward J Delikatny, E James Petersson, Andrew Tsourkas, Jay Dorsey, Sunil Singhal, John Y K Lee.

   PURPOSE: Fluorescence-guided-surgery offers intraoperative visualization of neoplastic tissue. Delta-aminolevulinic acid (5-ALA), which targets enzymatic abnormality in neoplastic cells, is the only approved agent for fluorescence-guided neurosurgery. More recently, we described Second Window Indocyanine Green (SWIG) which targets neoplastic tissue through enhanced vascular permeability. We hypothesized that SWIG would demonstrate similar clinical utility in identification of high-grade gliomas compared with 5-ALA.
PROCEDURES: Female C57/BL6 and nude/athymic mice underwent intracranial implantation of 300,000 GL261 and U87 cells, respectively. Tumor-bearing mice were euthanized after administration of 5-ALA (200 mg/kg intraperitoneal) and SWIG (5 mg/kg intravenous). Brain sections were imaged for protoporphyrin-IX and ICG fluorescence. Fluorescence and H&E images were registered using semi-automatic scripts for analysis. Human subjects with HGG were administered SWIG (2.5 mg/kg intravenous) and 5-ALA (20 mg/kg oral). Intraoperatively, tumors were imaged for ICG and protoporphyrin-IX fluorescence.
RESULTS: In non-necrotic tumors, 5-ALA and SWIG demonstrated 90.2 % and 89.2 % tumor accuracy (p value = 0.52) in U87 tumors and 88.1 % and 87.7 % accuracy (p value = 0.83) in GL261 tumors. The most distinct difference between 5-ALA and SWIG distribution was seen in areas of tumor-associated necrosis, which often showed weak/no protoporphyrin-IX fluorescence, but strong SWIG fluorescence. In twenty biopsy specimens from four subjects with HGG, SWIG demonstrated 100 % accuracy, while 5-ALA demonstrated 75-85 % accuracy; there was 90 % concordance between SWIG and 5-ALA fluorescence.
CONCLUSION: Our results provide the first direct comparison of the diagnostic utility of SWIG vs 5-ALA in both rodent and human HGG. Given the broader clinical utility of SWIG compared with 5-ALA, our data supports the use of SWIG in tumor surgery to improve the extent of safe resections.
CLINICAL TRIAL: NCT02710240 (US National Library of Medicine Registry; https://www.clinicaltrials.gov/ct2/show/NCT02710240?id=NCT02710240&draw=2&rank=1).

Keywords:  5-ALA; Fluorescence-guided surgery; High grade glioma; Near-infrared; Second-window ICG

DOI:  https://doi.org/10.1007/s11307-020-01504-w
Nat Commun. 2020 Jun 12. 11(1): 2978

ARS2/MAGL signaling in glioblastoma stem cells promotes self-renewal and M2-like polarization of tumor-associated macrophages.

Jinlong Yin, Sung Soo Kim, Eunji Choi, Young Taek Oh, Weiwei Lin, Tae-Hoon Kim, Jason K Sa, Jun Hee Hong, Se Hwan Park, Hyung Joon Kwon, Xiong Jin, Yeonhee You, Ji Hye Kim, Hyunggee Kim, Jaekyoung Son, Jeongwu Lee, Do-Hyun Nam, Kui Son Choi, Bingyang Shi, Ho-Shin Gwak, Heon Yoo, Antonio Iavarone, Jong Heon Kim, Jong Bae Park.

The interplay between glioblastoma stem cells (GSCs) and tumor-associated macrophages (TAMs) promotes progression of glioblastoma multiforme (GBM). However, the detailed molecular mechanisms underlying the relationship between these two cell types remain unclear. Here, we demonstrate that ARS2 (arsenite-resistance protein 2), a zinc finger protein that is essential for early mammalian development, plays critical roles in GSC maintenance and M2-like TAM polarization. ARS2 directly activates its novel transcriptional target MGLL, encoding monoacylglycerol lipase (MAGL), to regulate the self-renewal and tumorigenicity of GSCs through production of prostaglandin E2 (PGE2), which stimulates β-catenin activation of GSC and M2-like TAM polarization. We identify M2-like signature downregulated by which MAGL-specific inhibitor, JZL184, increased survival rate significantly in the mouse xenograft model by blocking PGE2 production. Taken together, our results suggest that blocking the interplay between GSCs and TAMs by targeting ARS2/MAGL signaling offers a potentially novel therapeutic option for GBM patients.

DOI: https://doi.org/10.1038/s41467-020-16789-2
Acta Neuropathol. 2020 Jun 10.

Patient-derived orthotopic xenografts of pediatric brain tumors: a St. Jude resource.

Kyle S Smith, Ke Xu, Kimberly S Mercer, Frederick Boop, Paul Klimo, Michael DeCupyere, Jose Grenet, Sarah Robinson, Paige Dunphy, Suzanne J Baker, David W Ellison, Thomas E Merchant, Santhosh A Upadayaya, Amar Gajjar, Gang Wu, Brent A Orr, Giles W Robinson, Paul A Northcott, Martine F Roussel.

  Pediatric brain tumors are the leading cause of cancer-related death in children. Patient-derived orthotopic xenografts (PDOX) of childhood brain tumors have recently emerged as a biologically faithful vehicle for testing novel and more effective therapies. Herein, we provide the histopathological and molecular analysis of 37 novel PDOX models generated from pediatric brain tumor patients treated at St. Jude Children's Research Hospital. Using a combination of histopathology, whole-genome and whole-exome sequencing, RNA-sequencing, and DNA methylation arrays, we demonstrate the overall fidelity and inter-tumoral molecular heterogeneity of pediatric brain tumor PDOX models. These models represent frequent as well as rare childhood brain tumor entities, including medulloblastoma, ependymoma, atypical teratoid rhabdoid tumor, and embryonal tumor with multi-layer rosettes. PDOX models will be valuable platforms for evaluating novel therapies and conducting pre-clinical trials to accelerate progress in the treatment of brain tumors in children. All described PDOX models and associated datasets can be explored using an interactive web-based portal and will be made freely available to the research community upon request.

Keywords:  AT/RT; ETMR; Ependymoma; Medulloblastoma; PDOX; Pediatric brain tumors

DOI:  https://doi.org/10.1007/s00401-020-02171-5
Cell Rep. 2020 Jun 09. pii: S2211-1247(20)30718-X. [Epub ahead of print]31(10): 107738

Rapid and Efficient Invasion Assay of Glioblastoma in Human Brain Organoids.

Gladiola Goranci-Buzhala, Aruljothi Mariappan, Elke Gabriel, Anand Ramani, Lucia Ricci-Vitiani, Mariachiara Buccarelli, Quintino Giorgio D'Alessandris, Roberto Pallini, Jay Gopalakrishnan.

  Glioblastoma (GBM) possesses glioma stem cells (GSCs) that exhibit aggressive invasion behavior in the brain. Current preclinical GBM invasion assays using mouse brain xenografts are time consuming and less efficient. Here, we demonstrate an array of methods that allow rapid and efficient assaying of GSCs invasion in human brain organoids. The assays are versatile to characterize various aspects of GSCs, such as invasion, integration, and interaction with mature neurons of brain organoids. Tissue clearing and quantitative 3D imaging of GSCs in host organoids reveal that invasiveness is inversely correlated with the organoids' age. Importantly, the described invasion assays can distinguish the invasive behaviors of primary and recurrent GSCs. The assays are also amenable to test pharmacological agents. As an example, we show that GI254023X, an inhibitor of ADAM10, could prevent the integration of GSCs into the organoids.

Keywords:  3D human brain organoids; ADAM10 inhibitor; GBM; NGLN3; glioma invasion; glioma stem cells; iPSCs; imaging; tissue clearing

DOI:  https://doi.org/10.1016/j.celrep.2020.107738
Oncogene. 2020 Jun 09.

GBP2 enhances glioblastoma invasion through Stat3/fibronectin pathway.

Shuye Yu, Xiaoting Yu, Lili Sun, Yanwen Zheng, Lili Chen, Hui Xu, Jing Jin, Qing Lan, Clark C Chen, Ming Li.

Guanylate-binding protein 2 (GBP2) is an interferon-inducible large GTPase which is crucial to the protective immunity against microorganisms. However, its biological function in cancer remains largely unknown. Glioblastoma multiforme (GBM) is the most common and deadly brain tumor in adults. Here we show that GBP2 expression is highly elevated in GBM tumor and cell lines, particularly in those of the mesenchymal subtype. High GBP2 expression is associated with poor prognosis. GBP2 overexpression significantly promotes GBM cell migration and invasion in vitro, and GBP2 silencing by RNA interference exhibits opposite effects. We further show that fibronectin (FN1) is dramatically induced by GBP2 expression at both mRNA and protein levels, and FN1 is essential for GBP2-promoted GBM invasiveness. Inhibition of Stat3 pathway prevents GBP2-promoted FN1 induction and cell invasion. Consistently, GBP2 dramatically promotes GBM tumor growth and invasion in mice and significantly reduces the survival time of the mice with tumor. Taken together, these findings establish the role of GBP2/Stat3/FN1 signaling cascade in GBM invasion and suggest GBP2 may serve as a potential therapeutic target for inhibiting GBM invasion.

DOI: https://doi.org/10.1038/s41388-020-1348-7
Cancer Cell Int. 2020 ;20 197

Nanos3, a cancer-germline gene, promotes cell proliferation, migration, chemoresistance, and invasion of human glioblastoma.

Fengyu Zhang, Ruilai Liu, Cheng Liu, Haishi Zhang, Yuan Lu.

   Background: Radiotherapy, chemotherapy, and surgery have made crucial strides in glioblastoma treatment, yet they often fail; thus, new treatment and new detection methods are needed. Aberrant expression of Nanos3 has been functionally associated with various cancers. Here, we sought to identify the clinical significance and potential mechanisms of Nanos3 in human glioblastoma.
Methods: Nanos3 expression was studied in nude mouse glioblastoma tissues and glioblastoma cell lines by immunohistochemistry, Western blot, and RT-PCR. Clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 gene editing assay was performed to generate the Nanos3 knockdown glioblastoma cell lines. The effects of Nanos3 on glioblastoma cells proliferation, migration, invasion, chemoresistance, germ cell characteristics, and tumor formation were analyzed by CCK8, transwell, cell survival experiments and alkaline phosphatase staining in vitro and in nude mouse models in vivo. Correlation between the expression of stemness proteins and the expression of Nanos3 was evaluated by Western blot.
Results: We found that Nanos3 was strongly expressed in both glioblastoma cell lines and tissues. Western blot and sequencing assays showed that the Nanos3 knockdown glioblastoma cell lines were established successfully, and we discovered that Nanos3 deletion reduced the proliferation, migration, and invasion of glioblastoma cells in vitro (P < 0.05). Nanos3 knockdown enhanced the sensitivity of glioblastoma cells to doxorubicin (DOX) and temozolomide (TMZ) (P < 0.05), and Nanos3+/- glioblastoma cell lines did not show the characteristics of the germline cells. In addition, Nanos3 deletion inhibited subcutaneous xenograft tumor growth in vivo (P < 0.001). Moreover, the oncogenesis germline protein levels of CD133, Oct4, Ki67, and Dazl decreased significantly in glioblastoma cells following Nanos3 knockdown.
Conclusions: Both in vitro and in vivo assays suggest that Nanos3, which is a cancer-germline gene, initiates the tumorigenesis of glioblastoma via acquiring the oncogenesis germline traits. These data demonstrate that ectopic germline traits are necessary for glioblastoma growth.

Keywords:  CRISPR/Cas9; Cancer-germline; Glioblastoma; Nanos3; Tumorigenicity

DOI:  https://doi.org/10.1186/s12935-020-01272-1
Sci Rep. 2020 Jun 11. 10(1): 9471

MicroRNA-128-3p Enhances the Chemosensitivity of Temozolomide in Glioblastoma by Targeting c-Met and EMT.

Chengbin Zhao, Ruiming Guo, Fangxia Guan, Shanshan Ma, Mu Li, Junru Wu, Xianzhi Liu, Hongwei Li, Bo Yang.

Temozolomide is a first line anti-tumor drug used for the treatment of patients with Glioblastoma multiforme (GBM). However, the drug resistance to temozolomide limits its clinical application. Therefore, novel strategies to overcome chemoresistance are desperately needed for improved treatment of human GBM. Recent studies have demonstrated that miRNAs are closely related to resistance to cancer chemotherapy. This study aimed to further validate the biological role of miR-128-3p and to investigate whether miR-128-3p can enhance the chemosensitivity of glioblastoma to temozolomide (TMZ) and the underlying mechanisms. The effects of miR-128-3p and TMZ on the proliferation of glioblastoma cells were investigated by cell counting kit-8 (cck8). Transwell and intracerebral invasion assays were applied to determine the effects of the combination of miR-128-3p and TMZ on the invasion and migration of glioblastoma in vitro and in vivo. Flow cytometry was used to detect apoptosis in each group, and immunofluorescence was used to determine the expression levels of EMT-related proteins. RT-PCR and Western-blot were applied to detect EMT-transformed proteins (c-Met, PDGFRα, Notch1, and Slug) and EMT phenotype-associated proteins (Vim, CD44, and E-cadherin) at both mRNA and protein levels. Based on the microRNA.org database, we predicted the target genes of miR-128-3p. The target-relationship between miR-128-3p and c-Met and PDGFRα was verified by dual luciferase reporter gene. The tumor volume, weight and the expression levels of the proteins described above were measured in subcutaneously transplanted tumor model in nude mice. We found that the expression of miR-128-3p was down-regulated in glioblastoma tissue samples and cell lines. miR-128-3p suppressed the proliferation, migration, and invasion of GBM both in vitro and in vivo; miR-128-3p enhanced the therapeutic effect of TMZ via inhibition of proliferation, invasion and migration of glioblastoma cells and induction of apoptosis. Overexpression of miR-128-3p down-regulated the expression levels of EMT-transformed proteins (c-Met, PDGFRα, Notch1 and Slug) to enhance the effect of TMZ. In addition, we found that miR-128-3p targeted and bound c-Met. More importantly, the upregulation of c-Met significantly prompted U87 and U251 cell proliferation. This effect could be abolished when c-Met was silenced. The investigation in tumor bearing nude mice showed that miR-128-3p in combination with TMZ reduced tumor volume and the invasion extent, and increased the sensitivity of glioblastoma to TMZ. miR-128-3p is capable of enhancing the sensitivity of glioblastoma to TMZ through regulating c-Met/EMT.

DOI: https://doi.org/10.1038/s41598-020-65331-3
Front Oncol. 2020 ;10 669

Identifying Predictive Gene Expression and Signature Related to Temozolomide Sensitivity of Glioblastomas.

Hong-Qing Cai, Ang-Si Liu, Min-Jie Zhang, Hou-Jie Liu, Xiao-Li Meng, Hai-Peng Qian, Jing-Hai Wan.

  Temozolomide (TMZ) is considered a standard chemotherapeutic agent for glioblastoma (GBM). Characterizing the biological molecules and signaling pathways involved in TMZ sensitivity would be helpful for selecting therapeutic schemes and evaluating prognosis for GBM. Thus, in the present study, we selected 34 glioma cell lines paired with specific IC50 values of TMZ obtained from CancerRxGene and RNA-seq data downloaded from the Cancer Cell Line Encyclopedia to identify genes related to TMZ sensitivity. The results showed that 1,373 genes were related to the response of GBM cells to TMZ. Biological function analysis indicated that epithelial-mesenchymal transition, Wnt signaling, and immune response were the most significantly activated functions in TMZ-resistant cell lines. Additionally, negative regulation of telomere maintenance via telomerase was enriched in TMZ-sensitive glioma cell lines. We also preliminarily observed a synergistic effect of combination treatment comprising TMZ and a telomerase inhibitor in vitro. We identified six genes (MROH8, BET1, PTPRN2, STC1, NKX3-1, and ARMC10) using the random survival forests variable hunting algorithm based on the minimum error rate of the gene combination and constructed a gene expression signature. The signature was strongly related to GBM clinical characteristics and exhibited good prognosis accuracy for both The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) datasets. Patients in the high score group had a shorter survival time than those in the low score group (11.2 vs. 22.2 months, hazard ratio = 7.31, p = 4.59e-11) of the TCGA dataset. The CGGA dataset was selected as a validation group with 40 patients in the high score set and 43 patients in the low score set (12.5 vs. 28.8 months, hazard ratio = 3.42, p = 8.61e-5). Moreover, the signature showed a better prognostic value than MGMT promoter methylation in both datasets. We also developed a nomogram for clinical use that integrated the TMZ response signature and four other risk factors to individually predict patient survival after TMZ chemotherapy. Overall, our study provides promising therapeutic targets and potential guidance for adjuvant therapy of GBM.

Keywords:  gene expression signature; glioblastoma; prognosis; telomerase; temozolomide

DOI:  https://doi.org/10.3389/fonc.2020.00669
Artif Cells Nanomed Biotechnol. 2020 Dec;48(1): 983-996

The enhanced treatment efficacy of invasive brain glioma by dual-targeted artemether plus paclitaxel micelles.

Xiuying Li, Luanxia Shi, Yandong Li, Qinqing Li, Xiujun Duan, Yingli Wang, Qingshan Li.

  High grade-gliomas are highly invasive and prone to metastasis, leading to poor survival and prognosis. Currently, we urgently need a new treatment strategy to effectively inhibit glioma. In this study, artemether and paclitaxel were used as two agents for tumour suppression. Two functional materials were synthesised and modified on the surface of the micelle as targeting molecules. The addition of two functional materials confers the ability of the micelles to effectively cross the blood-brain barrier (BBB) and then target the glioma cells. Thus, this dual-targeted delivery system allows the drug to play a better role in inhibiting tumour invasion and vasculogenic mimicry (VM) channels. In this paper, the anticancer effects of dual-targeted artemether plus paclitaxel micelles on glioma U87 cells were studied in three aspects: (I) In vitro and in vivo targeting assessment, including the role of penetrating BBB and targeting glioma; (II) In vitro regulation of invasion-associated proteins; (III) Inhibition of VM channels formation and invasion in vitro; (IV) The study of pharmacodynamics in tumour-bearing mice. These results suggest that dual-targeted artemether plus paclitaxel micelle may provide a new strategy to treat glioma via inhibiting invasive and VM channels.

Keywords:  BBB; Micelles; VM channels; invasive glioma

DOI:  https://doi.org/10.1080/21691401.2020.1773489
Cell Death Dis. 2020 Jun 11. 11(6): 447

Lin28A promotes IRF6-regulated aerobic glycolysis in glioma cells by stabilizing SNHG14.

Jinjing Lu, Xiaobai Liu, Jian Zheng, Jian Song, Yunhui Liu, Xuelei Ruan, Shuyuan Shen, Lianqi Shao, Chunqing Yang, Di Wang, Heng Cai, Shuo Cao, Yixue Xue.

Warburg effect is a hallmark of cancer cells, wherein glycolysis is preferred over oxidative phosphorylation even in aerobic conditions. Reprogramming of glycometabolism is especially crucial for malignancy in glioma. RNA-binding proteins and long noncoding RNAs are important for aerobic glycolysis during malignant transformation. Thus, we determined the expression and function of RNA-binding protein Lin28A, long noncoding RNA SNHG14, and transcription factor IRF6 in human glioma cells to elucidate the mechanism(s) underlying their role in glycolysis. Quantitative real-time polymerase chain reaction and western blotting showed that Lin28A and SNHG14 were overexpressed and IRF6 was downregulated in glioma. Depleting Lin28A from cells decreased the stability and expression of SNHG14. Furthermore, depleting SNHG14 reduced IRF6 mRNA degradation by targeting its 3' untranslated region and inhibiting STAU1-mediated degradation, thereby increasing the expression of IRF6. PKM2 is an important enzyme in aerobic glycolysis, and GLUT1 is the primary transporter that facilitates glucose uptake. IRF6 inhibited the transcription of PKM2 and GLUT1, thereby impairing glycolysis and cell proliferation and inducing apoptosis in glioma. Notably, depleting Lin28A and SNHG14 and overexpressing IRF6 reduced the growth of xenograft tumors in vivo and prolonged the survival of nude mice. Taken together, our data revealed that the Lin28A/SNHG14/IRF6 axis is crucial for reprogramming glucose metabolism and stimulating tumorigenesis in glioma cells. Thus, targeting this axis might help in the development of a novel therapeutic strategy for glioma metabolism.

DOI: https://doi.org/10.1038/s41419-020-2650-6
Sci Rep. 2020 Jun 09. 10(1): 9285

Expression and prognostic value of the transcription factors EGR1 and EGR3 in gliomas.

Arnon Møldrup Knudsen, Ida Eilertsen, Susanne Kielland, Mikkel Warming Pedersen, Mia Dahl Sørensen, Rikke Hedegaard Dahlrot, Henning Bünsow Boldt, Sune Munthe, Frantz Rom Poulsen, Bjarne Winther Kristensen.

Most glioblastoma patients have a dismal prognosis, although some survive several years. However, only few biomarkers are available to predict the disease course. EGR1 and EGR3 have been linked to glioblastoma stemness and tumour progression, and this study aimed to investigate their spatial expression and prognostic value in gliomas. Overall 207 gliomas including 190 glioblastomas were EGR1/EGR3 immunostained and quantified. A cohort of 21 glioblastomas with high P53 expression and available tissue from core and periphery was stained with double-immunofluorescence (P53-EGR1 and P53-EGR3) and quantified.EGR1 expression increased with WHO-grade, and declined by 18.9% in the tumour periphery vs. core (P = 0.01), while EGR3 expression increased by 13.8% in the periphery vs. core (P = 0.04). In patients with high EGR1 expression, 83% had methylated MGMT-promoters, while all patients with low EGR1 expression had un-methylated MGMT-promoters. High EGR3 expression in MGMT-methylated patients was associated with poor survival (HR = 1.98; 95%CI 1.22-3.22; P = 0.006), while EGR1 high/EGR3 high, was associated with poor survival vs. EGR1 high/EGR3 low (HR = 2.11; 95%CI 1.25-3.56; P = 0.005). EGR1 did not show prognostic value, but could be involved in MGMT-methylation. Importantly, EGR3 may be implicated in cell migration, while its expression levels seem to be prognostic in MGMT-methylated patients.

DOI: https://doi.org/10.1038/s41598-020-66236-x
J Exp Clin Cancer Res. 2020 Jun 09. 39(1): 106

ACYP2 contributes to malignant progression of glioma through promoting Ca2+ efflux and subsequently activating c-Myc and STAT3 signals.

Mengdan Li, Banjun Ruan, Jing Wei, Qi Yang, Mingwei Chen, Meiju Ji, Peng Hou.

   BACKGROUND: Acylphosphatase 2 (ACYP2) is involved in cell differentiation, energy metabolism and hydrolysis of intracellular ion pump. It has been reported as a negative regulator in leukemia and a positive regulator in colon cancer, respectively. However, its biological role in glioma remains totally unclear.
METHODS: We performed quantitative RT-PCR (qRT-PCR), immunohistochemistry (IHC) and western blot assays to evaluate ACYP2 expression. The functions of ACYP2 in glioma cells were determined by a series of in vitro and in vivo experiments, including cell proliferation, colony formation, cell cycle, apoptosis, migration, invasion and nude mouse tumorigenicity assays. In addition, western blot and co-immunoprecipitation (Co-IP) assays were used to identify its downstream targets.
RESULTS: Knocking down ACYP2 in glioma cells significantly inhibited cell proliferation, colony formation, migration, invasion and tumorigenic potential in nude mice, and induced cell cycle arrest and apoptosis. Conversely, ectopic expression of ACYP2 in glioma cells dramatically promoted malignant phenotypes of glioma cells. Mechanistically, ACYP2 promoted malignant progression of glioma cells through regulating intracellular Ca2+ homeostasis via its interaction with PMCA4, thereby activating c-Myc and PTP1B/STAT3 signals. This could be effectively reversed by Ca2+ chelator BAPTA-AM or calpain inhibitor calpeptin.
CONCLUSIONS: Our data demonstrate that ACYP2 functions as an oncogene in glioma through activating c-Myc and STAT3 signals via the regulation of intracellular Ca2+ homeostasis, and indicate that ACYP2 may be a potential therapeutic target and prognostic biomarker in gliomas.

Keywords:  Acylphosphatase 2 (ACYP2); C-Myc; Calcium homeostasis; Glioma; STAT3

DOI:  https://doi.org/10.1186/s13046-020-01607-w
Clin Transl Med. 2020 Jan;10(1): 182-198

HOTAIR-EZH2 inhibitor AC1Q3QWB upregulates CWF19L1 and enhances cell cycle inhibition of CDK4/6 inhibitor palbociclib in glioma.

Jin Shi, Shigang Lv, Miaojing Wu, Xianggan Wang, Yan Deng, Yansheng Li, Kuanxun Li, Hongyu Zhao, Xingen Zhu, Minhua Ye.

   BACKGROUND: Glioblastoma (GBM) is the most common primary tumor in the brain, and the median survival time for GBM patients is only about 14 months; therefore, there is an urgent need for new and more effective strategies. Since cell cycle disorder is a key factor in tumor progression and immortalization, there is great potential for controlling cell cycle disorders in tumor cells in GBM patients. We began to study a novel combination of AQB and palbociclib to evaluate its potential as a new therapeutic target.
METHODS: Protein mass spectrometry was used to identify the tumor suppressor genes up-regulated by AQB.The effects of HOTAIR - EZH2 inhibitor AQB and CDK4/6 inhibitor Palbociclib on glioma cells lines were examined in vitro and in vivo experiments.
RESULTS: The combination of AQB and palbociclib inhibitors has a more pronounced suppression effect on the cell cycle, especially gliomas with high expression of HOTAIR and EZH2 and low expression of CWF19L1. We performed protein mass spectrometry to identify AQB upregulated tumor suppressor genes and confirmed that CWF19L1 is regulated by H3K27ac through chromatin immunoprecipitation-quantitative PCR results. Univariate and multivariate Cox regression analysis and database analysis were performed to suggest CWF19L1 is a good prognostic factor. Our experimental results suggested that CWF19L1 can be significantly upregulated by AQB and lead to degradation of CDK4/6, resulting in G1 arrest. The combination of AQB and CDK4/6 inhibitor palbociclib is more effective in inhibiting the growth of glioma than in the single drug, both in vivo and in vitro. Similarly, we found that both AQB and palbociclib can inhibit Wnt/β-catenin signaling, and the combined use of the two inhibitors has a stronger inhibitory effect on tumor metastasis.
CONCLUSIONS: The combination of AQB and CDK4/6 inhibitor palbociclib has been found to have significant antitumor effects, which is likely to become a new strategy for glioma treatment.

Keywords:  AQB; CDK4; CDK6; cell cycle, CWF19L1; palbociclib; β-catenin

DOI:  https://doi.org/10.1002/ctm2.21
Sci Rep. 2020 Jun 08. 10(1): 9223

Noninvasive diffusion magnetic resonance imaging of brain tumour cell size for the early detection of therapeutic response.

Thomas A Roberts, Harpreet Hyare, Giulia Agliardi, Ben Hipwell, Angela d'Esposito, Andrada Ianus, James O Breen-Norris, Rajiv Ramasawmy, Valerie Taylor, David Atkinson, Shonit Punwani, Mark F Lythgoe, Bernard Siow, Sebastian Brandner, Jeremy Rees, Eleftheria Panagiotaki, Daniel C Alexander, Simon Walker-Samuel.

Cancer cells differ in size from those of their host tissue and are known to change in size during the processes of cell death. A noninvasive method for monitoring cell size would be highly advantageous as a potential biomarker of malignancy and early therapeutic response. This need is particularly acute in brain tumours where biopsy is a highly invasive procedure. Here, diffusion MRI data were acquired in a GL261 glioma mouse model before and during treatment with Temozolomide. The biophysical model VERDICT (Vascular Extracellular and Restricted Diffusion for Cytometry in Tumours) was applied to the MRI data to quantify multi-compartmental parameters connected to the underlying tissue microstructure, which could potentially be useful clinical biomarkers. These parameters were compared to ADC and kurtosis diffusion models, and, measures from histology and optical projection tomography. MRI data was also acquired in patients to assess the feasibility of applying VERDICT in a range of different glioma subtypes. In the GL261 gliomas, cellular changes were detected according to the VERDICT model in advance of gross tumour volume changes as well as ADC and kurtosis models. VERDICT parameters in glioblastoma patients were most consistent with the GL261 mouse model, whilst displaying additional regions of localised tissue heterogeneity. The present VERDICT model was less appropriate for modelling more diffuse astrocytomas and oligodendrogliomas, but could be tuned to improve the representation of these tumour types. Biophysical modelling of the diffusion MRI signal permits monitoring of brain tumours without invasive intervention. VERDICT responds to microstructural changes induced by chemotherapy, is feasible within clinical scan times and could provide useful biomarkers of treatment response.

DOI: https://doi.org/10.1038/s41598-020-65956-4
Biomed Pharmacother. 2020 Jun 08. pii: S0753-3322(20)30483-2. [Epub ahead of print]128 110291

ST1926 inhibits glioma progression through regulating mitochondrial complex II.

Liu De, Tang Yuan, Zheng Yong.

  The antitumor activity of atypical adamantyl retinoid ST1926 has been frequently reported in cancer studies; nevertheless, its effect on glioma has not been fully understood. Mitochondria are critical in regulating tumorigenesis and are defined as a promising target for anti-tumor therapy. In the present study, we found that ST1926 might be a mitochondria-targeting anti-glioma drug. ST1926 showed significantly inhibitory role in the viability of glioma cells mainly through inducing apoptosis and autophagy. The results showed that ST1926 alleviated mitochondria-regulated bioenergetics in glioma cells via reducing ATP production and promoting reactive oxygen species production. Importantly, ST1926 significantly impaired complex II (CII) function, which was associated with the inhibition of succinate dehydrogenase (SDH) activity. In addition, the effects of ST1926 on the induction of apoptosis and ROS were further promoted by the treatment of CII inhibitors, including TTFA and 3-NPA. Furthermore, the in vivo experiments confirmed the role of ST1926 in suppressing xenograft tumor growth with few toxicity. Therefore, ST1926 might be an effective anti-glioma drug through targeting CII.

Keywords:  Apoptosis; Complex II; Glioma; Mitochondria; ST1926

DOI:  https://doi.org/10.1016/j.biopha.2020.110291
Aging (Albany NY). 2020 Jun 07. 12

Coagulation factor 2 thrombin receptor promotes malignancy in glioma under SOX2 regulation.

Guojun Gao, Ming Yang, Fan Wang, Ge Dang, Xiaoling Zhang, Jing Zhao, Xiangyang Wang, Baozhe Jin.

  Glioma is the most common human primary brain cancer with high mortality and unfavorable clinical outcome. Coagulation factor 2 thrombin receptor (F2R), is a key component in the thrombosis process and has been demonstrated upregulated in various cancers. However, the effect and molecular mechanisms of F2R in glioma remains unclear. In our study, we confirmed that the expression of F2R was upregulated in glioma and predicted poor prognosis. Gene Set Enrichment Analysis (GSEA) and function assays demonstrated that F2R overexpression promoted glioma cell proliferation, metastasis and epithelial-mesenchymal transition (EMT) in vitro and tumor growth in vivo. Then, we identified and validated F2R was the target gene of SRY-box 2 (SOX2) by dual luciferase reporter assay and chromatin immunoprecipitation assay. Besides, High expression of F2R in malignant glioma was associated with β-catenint signaling pathway activation. Our findings conclude that F2R promotes glioma cell proliferation and metastasis under SOX2 and actives WNT/β-catenin Signaling pathway, which provides novel insight to the therapeutic regimen in glioma.

Keywords:  F2R; SOX2; glioma; metastasis; proliferation

DOI:  https://doi.org/10.18632/aging.103281
Biomolecules. 2020 Jun 09. pii: E886. [Epub ahead of print]10(6):

Leptin and Notch Signaling Cooperate in Sustaining Glioblastoma Multiforme Progression.

Salvatore Panza, Umberto Russo, Francesca Giordano, Antonella Leggio, Ines Barone, Daniela Bonofiglio, Luca Gelsomino, Rocco Malivindi, Francesca Luisa Conforti, Giuseppina Daniela Naimo, Cinzia Giordano, Stefania Catalano, Sebastiano Andò.

  Glioblastoma multiforme (GBM) is the most malignant form of glioma, which represents one of the commonly occurring tumors of the central nervous system. Despite the continuous development of new clinical therapies against this malignancy, it still remains a deadly disease with very poor prognosis. Here, we demonstrated the existence of a biologically active interaction between leptin and Notch signaling pathways that sustains GBM development and progression. We found that the expression of leptin and its receptors was significantly higher in human glioblastoma cells, U-87 MG and T98G, than in a normal human glial cell line, SVG p12, and that activation of leptin signaling induced growth and motility in GBM cells. Interestingly, flow cytometry and real-time RT-PCR assays revealed that GBM cells, grown as neurospheres, displayed stem cell-like properties (CD133+) along with an enhanced expression of leptin receptors. Leptin treatment significantly increased the neurosphere forming efficiency, self-renewal capacity, and mRNA expression levels of the stemness markers CD133, Nestin, SOX2, and GFAP. Mechanistically, we evidenced a leptin-mediated upregulation of Notch 1 receptor and the activation of its downstream effectors and target molecules. Leptin-induced effects on U-87 MG and T98G cells were abrogated by the selective leptin antagonist, the peptide LDFI (Leu-Asp-Phe-Ile), as well as by the specific Notch signaling inhibitor, GSI (Gamma Secretase Inhibitor) and in the presence of a dominant-negative of mastermind-like-1. Overall, these findings demonstrate, for the first time, a functional interaction between leptin and Notch signaling in GBM, highlighting leptin/Notch crosstalk as a potential novel therapeutic target for GBM treatment.

Keywords:  Notch; glioblastoma multiforme; leptin

DOI:  https://doi.org/10.3390/biom10060886
Cell Transplant. 2020 Jan-Dec;29:29 963689720933241

DNA Methylation-based Diagnostic and Prognostic Biomarkers for Glioblastoma.

Yunliang Tang, Cheng Qing, Jiao Wang, Zhenguo Zeng.

  Glioblastomas are the most common primary central nervous system malignancy tumor in adults. Glioblastoma patients have poor prognosis, with an average survival period of approximately 14 mo after diagnosis. To date, there are a limited number of effective treatment methods for glioblastoma, and its molecular mechanisms remain elusive. In this article, we analyzed the key biomarkers and pathways in glioblastoma patients based on gene expression and DNA methylation datasets. The 60 hypomethylated/upregulated genes and 110 hypermethylated/downregulated genes were identified in GSE50923, GSE50161, and GSE116520 microarrays. Functional enrichment analyses indicated that these methylated-differentially expressed genes were primarily involved in collagen fibril organization, chemical synaptic transmission, extracellular matrix-receptor interaction, and GABAergic synapse. The hub genes were screened from a protein-protein interaction network; in selected genes, increased NMB mRNA level was associated with favorable overall survival, while elevated CHI3L1, POSTN, S100A4, LOX, S100A11, IGFBP2, SLC12A5, VSNL1, and RGS4 mRNA levels were associated with poor overall survival in glioblastoma patients. Additionally, CHI3L1, S100A4, LOX, and S100A11 expressions were negatively correlated with their corresponding methylation status. Furthermore, the receiver-operator characteristic curve analysis indicated that CHI3L1, S100A4, LOX, and S100A11 can also serve as highly specific and sensitive diagnostic biomarkers for glioblastoma patients. Collectively, our study revealed the possible methylated-differentially expressed genes and associated pathways in glioblastoma and identified four DNA methylation-based biomarkers of glioblastoma. These results may provide insight on diagnostic and prognostic biomarkers, and therapeutic targets in glioblastoma.

Keywords:  DNA methylation; biological markers; glioblastomas

DOI:  https://doi.org/10.1177/0963689720933241
Cell Mol Neurobiol. 2020 Jun 11.

LncRNA MIR155HG Promotes Temozolomide Resistance by Activating the Wnt/β-Catenin Pathway Via Binding to PTBP1 in Glioma.

Xin He, Jie Sheng, Wei Yu, Kejian Wang, Shujuan Zhu, Qian Liu.

  Temozolomide (TMZ) is widely used for glioma therapy in the clinic. Currently, the development of TMZ resistance has largely led to poor prognosis. However, very little is understood about the role of MIR155HG, as a long noncoding RNA, in TMZ resistance. In our study, MIR155HG level was markedly higher in glioma patients than in normal controls and that poor survival was positively correlated with MIR155HG expression. It was apparent that TMZ sensitivity was promoted by downregulation of MIR155HG, and this could be reversed by MIR155HG overexpression in vivo and in vitro. Furthermore, polypyrimidine tract binding protein 1 (PTBP1) was proven to bind with MIR155HG and to regulate MIR155HG-related TMZ resistance. Mechanistic investigation showed that the expression levels of both MIR155HG and PTBP1 influenced the expression of relevant proteins in the Wnt/β-catenin pathway. Collectively, the study demonstrated that the knockdown of MIR155HG increased glioma sensitivity to TMZ by inhibiting Wnt/β-catenin pathway activation via potently downregulating PTBP1.

Keywords:  Drug resistance; Glioma; MIR155HG; PTBP1; Wnt/β-catenin

DOI:  https://doi.org/10.1007/s10571-020-00898-z
J Hematol Oncol. 2020 Jun 12. 13(1): 76

CD155 immunoregulation as a target for natural killer cell immunotherapy in glioblastoma.

Kyle B Lupo, Sandro Matosevic.

  Natural killer (NK) cells are powerful immune effectors, modulating their anti-tumor function through a balance activating and inhibitor ligands on their cell surface. Though still emerging, cancer immunotherapies utilizing NK cells are proving promising as a modality for the treatment of a number of solid tumors, including glioblastoma (GBM) and other gliomas, but are often limited due to complex immunosuppression associated with the GBM tumor microenvironment which includes overexpression of inhibitory receptors on GBM cells. CD155, or poliovirus receptor (PVR), has recently emerged as a pro-tumorigenic antigen, overexpressed on GBM and contributing to increased GBM migration and aggressiveness. CD155 has also been established as an immunomodulatory receptor, able to both activate NK cells through interactions with CD226 (DNAM-1) and CD96 and inhibit them through interaction with TIGIT. However, NK cell TIGIT expression has been shown to be upregulated in cancer, establishing CD155 as a predominantly inhibitory receptor within the context of GBM and other solid tumors, and rendering it of interest as a potential target for antigen-specific NK cell-based immunotherapy. This review will explore the function of CD155 within GBM as it relates to tumor migration and NK cell immunoregulation, as well as pre-clinical and clinical targeting of CD155/TIGIT and the potential that this pathway holds for the development of emerging NK cell-based immunotherapies.

Keywords:  CD155; Glioblastoma; Immunotherapy; Natural killer cells; TIGIT

DOI:  https://doi.org/10.1186/s13045-020-00913-2
Neuro Oncol. 2020 Jun 07. pii: noaa142. [Epub ahead of print]

Baseline Requirements for Novel Agents Being Considered for Phase II/III Brain Cancer Efficacy Trials:Conclusions from the Adult Brain Tumor Consortium's First Workshop on CNS Drug Delivery.

Adult Brain Tumor Consortium

DOI: https://doi.org/10.1093/neuonc/noaa142
Clin Cancer Res. 2020 Jun 11. pii: clincanres.1135.2020. [Epub ahead of print]

PD-1 inhibitors: Do they have a future in the treatment of glioblastoma?

Mustafa Khasraw, David A Reardon, Michael Weller, John H Sampson.

Glioblastoma (WHO grade IV glioma) is the most common malignant primary brain tumor in adults. Survival has remained largely static for decades, despite significant efforts to develop new effective therapies. Immunotherapy, and especially immune checkpoint inhibitors and programmed cell death (PD)-1/PD-L1 inhibitors have transformed the landscape of cancer treatment and improved patient survival in a number of different cancer types. With the exception of few select cases (e.g., patients with Lynch syndrome) the neuro-oncology community is still awaiting evidence that PD-1 blockade can lead to meaningful clinical benefit in glioblastoma. This lack of progress in the field is likely to be due to multiple reasons, including inherent challenges in brain tumor drug development, the blood-brain barrier, the unique immune environment in the brain, the impact of corticosteroids, as well as inter- and intra-tumoral heterogeneity. Here we critically review the clinical literature, address the unique aspects of glioma immunobiology and potential immunobiological barriers to progress, and contextualize new approaches to increase the efficacy of PD-1/PD-L1 inhibitors in glioblastoma that may identify gaps and testable relevant hypotheses for future basic and clinical research and to provide a novel perspective to further stimulate pre-clinical and clinical research to ultimately help patients with glioma, including glioblastoma, which is arguably one of the greatest areas of unmet need in cancer. Moving forward, we need to build on our existing knowledge by conducting further fundamental glioma immunobiology research in parallel with innovative and methodologically sound clinical trials.

DOI: https://doi.org/10.1158/1078-0432.CCR-20-1135
Radiat Oncol. 2020 Jun 08. 15(1): 145

Survival after hypofractionation in glioblastoma: a systematic review and meta-analysis.

Jane-Chloe Trone, Alexis Vallard, Sandrine Sotton, Majed Ben Mrad, Omar Jmour, Nicolas Magné, Benjamin Pommier, Silvy Laporte, Edouard Ollier.

   BACKGROUND: Glioblastoma multiforme (GBM) has a poor prognosis despite a multi modal treatment that includes normofractionated radiotherapy. So, various hypofractionated alternatives to normofractionated RT have been tested to improve such prognosis. There is need of systematic review and meta-analysis to analyse the literature properly and maybe generalised the use of hypofractionation. The aim of this study was first, to perform a meta-analysis of all controlled trials testing the impact of hypofractionation on survival without age restriction and secondly, to analyse data from all non-comparative trials testing the impact of hypofractionation, radiosurgery and hypofractionated stereotactic RT in first line.
MATERIALS/METHODS: We searched Medline, Embase and Cochrane databases to identify all publications testing the impact of hypofractionation in glioblastoma between 1985 and March 2020. Combined hazard ratio from comparative studies was calculated for overall survival. The impact of study design, age and use of adjuvant temozolomide was explored by stratification. Meta-regressions were performed to determine the impact of prognostic factors.
RESULTS: 2283 publications were identified. Eleven comparative trials were included. No impact on overall survival was evidenced (HR: 1.07, 95%CI: 0.89-1.28) without age restriction. The analysis of non-comparative literature revealed heterogeneous outcomes with limited quality of reporting. Concurrent chemotherapy, completion of surgery, immobilization device, isodose of prescription, and prescribed dose (depending on tumour volume) were poorly described. However, results on survival are encouraging and were correlated with the percentage of resected patients and with patients age but not with median dose.
CONCLUSIONS: Because few trials were randomized and because the limited quality of reporting, it is difficult to define the place of hypofactionation in glioblastoma. In first line, hypofractionation resulted in comparable survival outcome with the benefit of a shortened duration. The method used to assess hypofractionation needs to be improved.

Keywords:  glioblastoma; hypofractionation; meta-analysis, review; methodology; radiotherapy; survival outcome

DOI:  https://doi.org/10.1186/s13014-020-01584-6
Int J Cancer. 2020 Jun 08.

Neuronal signatures in cancer.

Erik Jung, Julieta Alfonso, Hannah Monyer, Wolfgang Wick, Frank Winkler.

  Despite advances in the treatment of solid tumors, the prognosis of patients with many cancers remain poor, particularly of those with primary and metastatic brain tumors. In the last years, "Cancer Neuroscience" emerged as novel field of research at the crossroads of oncology and classical neuroscience. In primary brain tumors, including glioblastoma, communicating networks that render tumor cells resistant against cytotoxic therapies were identified. To build these networks, glioblastoma cells extend neurite-like protrusions called tumor microtubes (TMs). Synapses on TMs allow tumor cells to retrieve neuronal input that fosters growth. Single cell sequencing further revealed that primary brain tumors recapitulate many steps of neurodevelopment. Interestingly, neuronal characteristics, including the ability to extend neurite-like protrusions, neuronal gene expression signatures and interactions with neurons, have now been found not only in brain and neuroendocrine tumors but also in some cancers of epithelial origin. In this review, we will provide an overview about neurite-like protrusions as well as neurodevelopmental origins, hierarchies and gene expression signatures in cancer. We will also discuss how "Cancer Neuroscience" might provide a framework for the development of novel therapies. This article is protected by copyright. All rights reserved.

Keywords:  cancer neuroscience; glioma neuroscience; neurobiology; neurodevelopment; tumor microtubes

DOI:  https://doi.org/10.1002/ijc.33138
Cell Mol Life Sci. 2020 Jun 06.

Metabolic heterogeneity and adaptability in brain tumors.

Christian E Badr, Daniel J Silver, Florian A Siebzehnrubl, Loic P Deleyrolle.

  The metabolic complexity and flexibility commonly observed in brain tumors, especially glioblastoma, is fundamental for their development and progression. The ability of tumor cells to modify their genetic landscape and adapt metabolically, subverts therapeutic efficacy, and inevitably instigates therapeutic resistance. To overcome these challenges and develop effective therapeutic strategies targeting essential metabolic processes, it is necessary to identify the mechanisms underlying heterogeneity and define metabolic preferences and liabilities of malignant cells. In this review, we will discuss metabolic diversity in brain cancer and highlight the role of cancer stem cells in regulating metabolic heterogeneity. We will also highlight potential therapeutic modalities targeting metabolic vulnerabilities and examine how intercellular metabolic signaling can shape the tumor microenvironment.

Keywords:  Cell communication; Glioma; Immune cells; Metabolism; Slow-cycling cells; Tumor initiating cells; Tumor microenvironment (TME)

DOI:  https://doi.org/10.1007/s00018-020-03569-w
J Neurooncol. 2020 Jun 06.

Repeat radiation with bevacizumab and minocycline in bevacizumab-refractory high grade gliomas: a prospective phase 1 trial.

Adam L Cohen, Christopher J Anker, Brett Johnson, Lindsay M Burt, Dennis C Shrieve, Karen Salzman, Randy Jensen, Ken Boucher, Howard Colman.

   INTRODUCTION: There are no effective treatments for gliomas after progression on radiation, temozolomide, and bevacizumab. Microglia activation may be involved in radiation resistance and can be inhibited by the brain penetrating antibiotic minocycline. In this phase 1 trial, we examined the safety and effect on survival, symptom burden, and neurocognitive function of reirradiation, minocycline, and bevacizumab.
METHODS: The trial used a 3 + 3 design for dose escalation followed by a ten person dose expansion. Patients received reirradiation with dosing based on radiation oncologist judgment, bevacizumab 10 mg/kg IV every two weeks, and oral minocycline twice a day. Symptom burden was measured using MDASI-BT. Neurocognitive function was measured using the COGSTATE battery.
RESULTS: The maximum tolerated dose of minocycline was 400 mg twice a day with no unexpected toxicities. The PFS3 was 64.6%, and median overall survival was 6.4 months. Symptom burden and neurocognitive function did not decline in the interval between treatment completion and tumor progression.
CONCLUSIONS: Minocycline 400 mg orally twice a day with bevacizumab and reirradiation is well tolerated by physician and patient reported outcomes in people with gliomas that progress on bevacizumab.

Keywords:  Bevacizumab; Glioma; Minocycline; Reirradiation

DOI:  https://doi.org/10.1007/s11060-020-03551-3
Neuro Oncol. 2020 Jun 09. pii: noaa141. [Epub ahead of print]

Consensus Recommendations for a Dynamic Susceptibility Contrast MRI Protocol for Use in High-Grade Gliomas.

Jumpstarting Brain Tumor Drug Development Coalition Imaging Standardization Steering Committee

  Despite the widespread clinical use of dynamic susceptibility contrast (DSC) MRI, DSC-MRI methodology has not been standardized, hindering its utilization for response assessment in multi-center trials. Recently, the DSC-MRI Standardization Subcommittee of the Jumpstarting Brain Tumor Drug Development Coalition issued an updated consensus DSC-MRI protocol compatible with BTIP, the standardized brain tumor imaging protocol for high-grade gliomas that is increasingly used in the clinical setting and is the default MRI protocol for the National Clinical Trials Network. After reviewing the basis for controversy over DSC-MRI protocols, this manuscript provides evidence-based best practices for clinical DSC-MRI as determined by the Committee, including pulse sequence (gradient echo vs. spin echo), BTIP-compliant contrast agent dosing (preload and bolus), flip angle (FA), echo time (TE), and post-processing leakage correction. In summary, full-dose preload, full-dose bolus dosing using intermediate (60°) FA and field strength-dependent TE (40-50ms at 1.5T, 20-35ms at 3T) provides overall best accuracy and precision for cerebral blood volume estimates. When single-dose contrast agent usage is desired, no-preload, full-dose bolus dosing using low FA (30°) and field strength-dependent TE provides excellent performance, with reduced contrast agent usage and elimination of potential systematic errors introduced by variations in preload dose and incubation time.

Keywords:  DSC-MRI; cerebral blood volume; clinical trial; consensus protocol; high-grade glioma

DOI:  https://doi.org/10.1093/neuonc/noaa141