bims-malgli 2021-07-11 papers

bims-malgli

Biomed News

on Biology of malignant gliomas

Issue of 2021–07–11
eleven papers selected by
Oltea Sampetrean, Keio University

Sensitizing glioblastoma to radiotherapy.
Temozolomide nano enabled medicine: promises made by the nanocarriers in glioblastoma therapy.
A novel patient stratification strategy to enhance the therapeutic efficacy of dasatinib in glioblastoma.
Chitinase-3-like-1 protein complexes modulate macrophage-mediated immune suppression in glioblastoma.
Key molecular alterations in endothelial cells in human glioblastoma uncovered through single-cell RNA sequencing.
The drug development pipeline for glioblastoma-A cross sectional assessment of the FDA Orphan Drug Product designation database.
Novel Post-Translational Modifications and Molecular Substrates in Glioma Identified by Bioinformatics.
Preclinical modeling in GBM PDX xenografts to guide clinical development of lisavanbulin - a novel tumor checkpoint controller targeting microtubules.
Agonistic CD40 therapy induces tertiary lymphoid structures but impairs responses to checkpoint blockade in glioma.
Chloride intracellular channel protein 2 is secreted and inhibits MMP14 activity, while preventing tumor cell invasion and metastasis.
Feasibility and Biological Activity of a Ketogenic/Intermittent-Fasting Diet in Patients With Glioma.

Nat Rev Drug Discov. 2021 Jul 07.

Sensitizing glioblastoma to radiotherapy.

Sarah Crunkhorn.

DOI: https://doi.org/10.1038/d41573-021-00117-4
J Control Release. 2021 Jul 03. pii: S0168-3659(21)00346-1. [Epub ahead of print]

Temozolomide nano enabled medicine: promises made by the nanocarriers in glioblastoma therapy.

Soma Yasaswi, Karishma Shetty, Khushwant S Yadav.

  Glioblastoma multiforme (GBM) is abnormal cell proliferation of glial cells. GBM is the grade IV glioma brain cancer which is life-threatening to many individuals affected by this cancer. The DNA alkylating agent Temozolomide (TMZ) has the distinctiveness of being FDA approved anticancer drug for the first line treatment for GBM. However, treatment of GBM still remains a challenge. This is attributed to TMZ's toxic nature, severe side effects, and fast degradation in vivo. In addition, the lack of targeting ability increases the chances of systemic toxicities. A nano enabled targeted delivery system not only improves the efficiency of TMZ by making it cross the blood brain barrier, have specificity to target, but also reduces toxicity to healthy tissues. Over the last decade the significant advances in the area of nanotechnology applied to medicine have developed many multifunctional therapeutics. In this context, the present review article comprehends the significant progress in the field of TMZ loaded nanocarriers showing promise for futuristic nanomedicine therapies in treating GBM.

Keywords:  BBB; Dendrimers; Gene delivery; Glioblastoma multiforme; Liposomes; Nanocarriers; Quantum dots; Temozolomide

DOI:  https://doi.org/10.1016/j.jconrel.2021.07.003
Neuro Oncol. 2021 Jul 07. pii: noab158. [Epub ahead of print]

A novel patient stratification strategy to enhance the therapeutic efficacy of dasatinib in glioblastoma.

Obada T Alhalabi, Michael N C Fletcher, Thomas Hielscher, Tobias Kessler, Tolga Lokumcu, Ulrich Baumgartner, Elena Wittmann, Silja Schlue, Mona Göttmann, Shaman Rahman, Ling Hai, Lea Hansen-Palmus, Laura Puccio, Ichiro Nakano, Christel Herold-Mende, Bryan W Day, Wolfgang Wick, Felix Sahm, Emma Phillips, Violaine Goidts.

   BACKGROUND: Glioblastoma is the most common primary malignancy of the central nervous system with dismal prognosis. Genomic signatures classify isocitrate dehydrogenase 1 (IDH)-wildtype glioblastoma into three subtypes: proneural, mesenchymal and classical. Dasatinib, an inhibitor of proto-oncogene kinase Src (SRC), is one of many therapeutics which, despite promising preclinical results, has failed to improve overall survival in glioblastoma patients in clinical trials. We examined whether glioblastoma subtypes differ in their response to dasatinib and could hence be evaluated for patient enrichment strategies in clinical trials.
METHODS: We carried out in silico analyses on glioblastoma gene expression (TCGA) and single-cell RNA-Seq data. In addition, in vitro experiments using glioblastoma stem-like cells (GSCs) derived from primary patient tumors were performed, with complementary gene expression profiling and immunohistochemistry analysis of tumor samples.
RESULTS: Patients with the mesenchymal subtype of glioblastoma showed higher SRC pathway activation based on gene expression profiling. Accordingly, mesenchymal GSCs were more sensitive to SRC inhibition by dasatinib compared to proneural and classical GSCs. Notably, SRC phosphorylation status did not predict response to dasatinib treatment. Furthermore, serpin peptidase inhibitor clade H member 1 (SERPINH1), a collagen related heat-shock protein associated with cancer progression, was shown to correlate with dasatinib response and with the mesenchymal subtype.
CONCLUSION: This work highlights further molecular-based patient selection strategies in clinical trials and suggests the mesenchymal subtype as well as SERPINH1 to be associated with response to dasatinib. Our findings indicate that stratification based on gene expression subtyping should be considered in future dasatinib trials.

Keywords:  Dasatinib; Glioblastoma; Glioblastoma stem-like cells; SERPINH1; SRC

DOI:  https://doi.org/10.1093/neuonc/noab158
J Clin Invest. 2021 Jul 06. pii: 147552. [Epub ahead of print]

Chitinase-3-like-1 protein complexes modulate macrophage-mediated immune suppression in glioblastoma.

Apeng Chen, Yinan Jiang, Zhengwei Li, Lingxiang Wu, Ulises Santiago, Han Zou, Chunhui Cai, Vaibhav Sharma, Yongchang Guan, Lauren H McCarl, Jie Ma, Yijen L Wu, Joshua Michel, Yi Shi, Liza Konnikova, Nduka M Amankulor, Pascal O Zinn, Gary Kohanbash, Sameer Agnihotri, Songjian Lu, Xinghua Lu, Dandan Sun, George K Gittes, Qianghu Wang, Xiangwei Xiao, Dean Yimlamai, Ian F Pollack, Carlos J Camacho, Baoli Hu.

  Glioblastoma is a highly malignant and incurable brain tumor characterized by intrinsic and adaptive resistance to immunotherapies. However, how glioma cells induce tumor immunosuppression and escape immunosurveillance remains poorly understood. Here, we find upregulation of cancer-intrinsic Chitinase-3-like-1 (CHI3L1) signaling modulating an immunosuppressive microenvironment by reprogramming tumor-associated macrophages (TAMs). Mechanistically, CHI3L1 binding with Galectin-3 (Gal3) selectively promotes TAM migration and infiltration with a protumor M2-like but not an antitumor M1-like phenotype in vitro and in vivo, governed by a transcriptional program of NFκB/CEBPβ in the CHI3L1/Gal3-PI3K/AKT/mTOR axis. Conversely, Galectin-3-binding protein (Gal3BP) negatively regulates this process by competing with Gal3 to bind CHI3L1. Administration of a Gal3BP mimetic peptide in syngeneic glioblastoma mouse models reverses immune suppression and attenuates tumor progression. These results shed light on the role of CHI3L1 protein complexes in immune evasion by glioblastoma and as a potential immunotherapeutic target for this devastating disease.

Keywords:  Brain cancer; Cancer; Macrophages; Oncology

DOI:  https://doi.org/10.1172/JCI147552
JCI Insight. 2021 Jul 06. pii: 150861. [Epub ahead of print]

Key molecular alterations in endothelial cells in human glioblastoma uncovered through single-cell RNA sequencing.

Yuan Xie, Liqun He, Roberta Lugano, Yanyu Zhang, Haiyan Cao, Qiyuan He, Min Chao, Boxuan Liu, Qingze Cao, Jianhao Wang, Yang Jiao, Yaqin Hu, Liying Han, Yong Zhang, Hua Huang, Lene Uhrbom, Christer Betsholtz, Liang Wang, Anna Dimberg, Lei Zhang.

  Glioblastoma is the most aggressive type of brain tumor with poor therapeutic response and prognosis. Passage of systemically delivered pharmacological agents into the brain is largely blocked by the blood-brain-barrier (BBB), an organotypic specialization of brain endothelial cells (EC). Tumor vessels in GBM are abnormal and more permeable, but the heterogeneity of BBB breakdown in different parts of the tumor vasculature and at the tumor's invasive front is largely unknown. Here, through single-cell RNA sequencing (scRNA-seq) of freshly isolated ECs from human glioblastoma and paired tumor peripheral tissues, we have constructed a molecular atlas of human brain ECs providing unprecedented molecular insight into the heterogeneity of the human BBB and its molecular alteration in glioblastoma. We identified 5 distinct EC phenotypes representing different states of EC activation and BBB impairment, and associated with different anatomical locations within and around the tumor. This unique data resource provides key information for designing rational therapeutic regimens and optimizing drug delivery.

Keywords:  Brain cancer; Endothelial cells; Vascular Biology

DOI:  https://doi.org/10.1172/jci.insight.150861
PLoS One. 2021 ;16(7): e0252924

The drug development pipeline for glioblastoma-A cross sectional assessment of the FDA Orphan Drug Product designation database.

Pascal Johann, Dominic Lenz, Markus Ries.

BACKGROUND: Glioblastoma (GBM) is the most common malignant brain tumour among adult patients and represents an almost universally fatal disease. Novel therapies for GBM are being developed under the orphan drug legislation and the knowledge on the molecular makeup of this disease has been increasing rapidly. However, the clinical outcomes in GBM patients with currently available therapies are still dismal. An insight into the current drug development pipeline for GBM is therefore of particular interest.
OBJECTIVES: To provide a quantitative clinical-regulatory insight into the status of FDA orphan drug designations for compounds intended to treat GBM.
METHODS: Quantitative cross-sectional analysis of the U.S. Food and Drug Administration Orphan Drug Product database between 1983 and 2020. STROBE criteria were respected.
RESULTS: Four orphan drugs out of 161 (2,4%) orphan drug designations were approved for the treatment for GBM by the FDA between 1983 and 2020. Fourteen orphan drug designations were subsequently withdrawn for unknown reasons. The number of orphan drug designations per year shows a growing trend. In the last decade, the therapeutic mechanism of action of designated compounds intended to treat glioblastoma shifted from cytotoxic drugs (median year of designation 2008) to immunotherapeutic approaches and small molecules (median year of designation 2014 and 2015 respectively) suggesting an increased focus on precision in the therapeutic mechanism of action for compounds the development pipeline.
CONCLUSION: Despite the fact that current pharmacological treatment options in GBM are sparse, the drug development pipeline is steadily growing. In particular, the surge of designated immunotherapies detected in the last years raises the hope that elaborate combination possibilities between classical therapeutic backbones (radiotherapy and chemotherapy) and novel, currently experimental therapeutics may help to provide better therapies for this deadly disease in the future.

DOI: https://doi.org/10.1371/journal.pone.0252924
OMICS. 2021 Jul 06.

Novel Post-Translational Modifications and Molecular Substrates in Glioma Identified by Bioinformatics.

Devasahayam Arokia Balaya Rex, Sumaithangi Thattai Arun Kumar, Akhila Balakrishna Rai, Chinmaya Narayana Kotimoole, Prashant Kumar Modi, Thottethodi Subrahmanya Keshava Prasad.

  Glioma is the most common type of brain cancer that originates from the glial cells. It constitutes about one-third of all brain cancers. Recently, transcriptomics, proteomics, and multiomics approaches have been harnessed to discover potential biomarkers and therapeutic targets in glioma. Moreover, post-translational modifications (PTMs) of proteins play a major role in cell biology and function and offer new avenues of research in cancer. Using unbiased multi-PTM bioinformatics analyses of two proteomic datasets of glioma available in the public domain, we identified 866 proteins with common PTMs from both studies. Out of these 866 proteins, 19 proteins were identified with the common PTMs, with the same site modifications pertaining to glioma. Importantly, the identified PTMs belonged to proteins involved in integrin PI3K/Akt/mTOR, JAK/STAT, and Ras/Raf/MAPK pathways. These pathways are essential for cell proliferation in tumor cells and thus involved in glioma progression. Taken together, these findings call for validation in larger datasets in glioma and brain cancers and with an eye to future drug discovery and diagnostic innovation. Bioinformatics-guided discovery of novel PTMs from the publicly available proteomic data can offer new avenues for innovation in cancer research.

Keywords:  diagnostics; drug targets; glioblastoma; mass spectrometry; post-translational modification; proteomics

DOI:  https://doi.org/10.1089/omi.2021.0050
Neuro Oncol. 2021 Jul 07. pii: noab162. [Epub ahead of print]

Preclinical modeling in GBM PDX xenografts to guide clinical development of lisavanbulin - a novel tumor checkpoint controller targeting microtubules.

Danielle M Burgenske, Surabhi Talele, Jenny L Pokorny, Ann C Mladek, Katrina K Bakken, Brett L Carlson, Mark A Schroeder, Lihong He, Zeng Hu, Gautham Gampa, Matthew L Kosel, Paul A Decker, Gaspar J Kitange, Anne Schmitt-Hoffmann, Felix Bachmann, Rachael A Vaubel, Jeanette E Eckel-Passow, Caterina Giannini, Paul McSheehy, Heidi A Lane, William F Elmquist, Jann N Sarkaria.

   BACKGROUND: Glioblastoma (GBM) is an incurable disease with few approved therapeutic interventions. Radiation therapy (RT) and temozolomide (TMZ) remain the standards of care. The efficacy and optimal deployment schedule of the orally bioavailable small-molecule tumor checkpoint controller lisavanbulin alone, and in combination with, standards of care were assessed using a panel of IDH-wildtype GBM patient-derived xenografts.
METHODS: Mice bearing intracranial tumors received lisavanbulin +/- RT +/- TMZ and followed for survival. Lisavanbulin concentrations in plasma and brain were determined by liquid chromatography with tandem mass spectrometry, while flow cytometry was used for cell cycle analysis.
RESULTS: Lisavanbulin monotherapy showed significant benefit (p<0.01) in 9 of 14 PDXs tested (median survival extension 9-84%) and brain-to-plasma ratios of 1.3 and 1.6 at 2- and 6-hours post-dose, respectively, validating previous data suggesting significant exposure in the brain. Prolonged lisavanbulin dosing from RT start until moribund was required for maximal benefit (GBM6: median survival lisavanbulin/RT 90 vs. RT alone 69 days, p=0.0001; GBM150: lisavanbulin/RT 143 days vs. RT alone 73 days, p=0.06). Similar observations were seen with RT/TMZ combinations (GBM39: RT/TMZ/lisavanbulin 502 days vs. RT/TMZ 249 days, p=0.0001; GBM26: RT/TMZ/lisavanbulin 172 days vs. RT/TMZ 121 days, p=0.04). Immunohistochemical analyses showed a significant increase in phospho-histone H3 with lisavanbulin treatment (p=0.01).
CONCLUSIONS: Lisavanbulin demonstrated excellent brain penetration, significant extension of survival alone or in RT or RT/TMZ combinations and was associated with mitotic arrest. These data provide a strong clinical rationale for testing lisavanbulin in combination with RT or RT/TMZ in GBM patients.

Keywords:  drug efficacy; glioblastoma; microtubule-targeting agents; patient-derived xenografts

DOI:  https://doi.org/10.1093/neuonc/noab162
Nat Commun. 2021 07 05. 12(1): 4127

Agonistic CD40 therapy induces tertiary lymphoid structures but impairs responses to checkpoint blockade in glioma.

Luuk van Hooren, Alessandra Vaccaro, Mohanraj Ramachandran, Konstantinos Vazaios, Sylwia Libard, Tiarne van de Walle, Maria Georganaki, Hua Huang, Ilkka Pietilä, Joey Lau, Maria H Ulvmar, Mikael C I Karlsson, Maria Zetterling, Sara M Mangsbo, Asgeir S Jakola, Thomas Olsson Bontell, Anja Smits, Magnus Essand, Anna Dimberg.

Gliomas are brain tumors characterized by an immunosuppressive microenvironment. Immunostimulatory agonistic CD40 antibodies (αCD40) are in clinical development for solid tumors, but are yet to be evaluated for glioma. Here, we demonstrate that systemic delivery of αCD40 in preclinical glioma models induces the formation of tertiary lymphoid structures (TLS) in proximity of meningeal tissue. In treatment-naïve glioma patients, the presence of TLS correlates with increased T cell infiltration. However, systemic delivery of αCD40 induces hypofunctional T cells and impairs the response to immune checkpoint inhibitors in pre-clinical glioma models. This is associated with a systemic induction of suppressive CD11b+ B cells post-αCD40 treatment, which accumulate in the tumor microenvironment. Our work unveils the pleiotropic effects of αCD40 therapy in glioma and reveals that immunotherapies can modulate TLS formation in the brain, opening up for future opportunities to regulate the immune response.

DOI: https://doi.org/10.1038/s41467-021-24347-7
Neoplasia. 2021 Jul 03. pii: S1476-5586(21)00043-9. [Epub ahead of print]23(8): 754-765

Chloride intracellular channel protein 2 is secreted and inhibits MMP14 activity, while preventing tumor cell invasion and metastasis.

Saya Ozaki, Akihiro Umakoshi, Hajime Yano, Shota Ohsumi, Yutaro Sumida, Erika Hayase, Eika Usa, Afsana Islam, Mohammed E Choudhury, Yusuke Nishi, Daisuke Yamashita, Yoshihiro Ohtsuka, Masahiro Nishikawa, Akihiro Inoue, Satoshi Suehiro, Jun Kuwabara, Hideaki Watanabe, Yasutsugu Takada, Yuji Watanabe, Ichiro Nakano, Takeharu Kunieda, Junya Tanaka.

  The abilities to invade surrounding tissues and metastasize to distant organs are the most outstanding features that distinguish malignant from benign tumors. However, the mechanisms preventing the invasion and metastasis of benign tumor cells remain unclear. By using our own rat distant metastasis model, gene expression of cells in primary tumors was compared with that in metastasized tumors. Among many distinct gene expressions, we have focused on chloride intracellular channel protein 2 (CLIC2), an ion channel protein of as-yet unknown function, which was predominantly expressed in the primary tumors. We created CLIC2 overexpressing rat glioma cell line and utilized benign human meningioma cells with naturally high CLIC2 expression. CLIC2 was expressed at higher levels in benign human brain tumors than in their malignant counterparts. Moreover, its high expression was associated with prolonged survival in the rat metastasis and brain tumor models as well as with progression-free survival in patients with brain tumors. CLIC2 was also correlated with the decreased blood vessel permeability likely by increased contents of cell adhesion molecules. We found that CLIC2 was secreted extracellularly, and bound to matrix metalloproteinase (MMP) 14. Furthermore, CLIC2 prevented the localization of MMP14 in the plasma membrane, and inhibited its enzymatic activity. Indeed, overexpressing CLIC2 and recombinant CLIC2 protein effectively suppressed malignant cell invasion, whereas CLIC2 knockdown reversed these effects. Thus, CLIC2 suppress invasion and metastasis of benign tumors at least partly by inhibiting MMP14 activity.

Keywords:  Benign; Brain tumor; Distant metastasis; Invasion; Malignant

DOI:  https://doi.org/10.1016/j.neo.2021.06.001
Neurology. 2021 Jul 07. pii: 10.1212/WNL.0000000000012386. [Epub ahead of print]

Feasibility and Biological Activity of a Ketogenic/Intermittent-Fasting Diet in Patients With Glioma.

Karisa C Schreck, Fang-Chi Hsu, Adam Berrington, Bobbie Henry-Barron, Diane Vizthum, Lindsay Blair, Eric H Kossoff, Linda Easter, Christopher T Whitlow, Peter B Barker, Mackenzie C Cervenka, Jaishri O Blakeley, Roy E Strowd.

OBJECTIVE: To examine the feasibility, safety, systemic biological activity, and cerebral activity of a ketogenic dietary intervention in patients with glioma.
METHODS: 25 patients with biopsy-confirmed WHO Grade 2-4 astrocytoma with stable disease following adjuvant chemotherapy were enrolled in an 8-week GLioma Atkins-based Diet (GLAD). GLAD consisted of 2 fasting days (calories<20% calculated estimated needs) interleaved between 5 modified Atkins diet days (net carbohydrates≤20 gm/day) each week. The primary outcome was dietary adherence by food records. Markers of systemic and cerebral activity included weekly urine ketones, serum insulin, glucose, hemoglobin A1c, IGF-1, and MR spectroscopy at baseline and week 8.
RESULTS: 21 patients completed the study (84%). 80% of patients reached ≥40 mg/dL urine acetoacetate during the study. 48% of patients were adherent by food record. The diet was well-tolerated with two grade 3 adverse events (neutropenia, seizure). Measures of systemic activity including hemoglobin A1c, insulin, and fat body mass decreased significantly, while lean body mass increased. MR spectroscopy demonstrated increased ketone concentrations (β-hydroxybutyrate (bHB) and acetone (Ace)) in both lesional and contralateral brain, compared to baseline. Average ketonuria correlated with cerebral ketones in lesional (tumor) and contralateral brain (bHB Rs 0.52, p=0.05). Sub-group analysis of IDH-mutant glioma showed no differences in cerebral metabolites after controlling for ketonuria.
CONCLUSIONS: The GLAD dietary intervention, while demanding, produced meaningful ketonuria, and significant systemic and cerebral metabolic changes in participants. Ketonuria in participants correlated with cerebral ketone concentration and appear to be a better indicator of systemic activity than patient-reported food records.

DOI: https://doi.org/10.1212/WNL.0000000000012386