bims-malgli 2022-01-02 papers

bims-malgli

Biomed News

on Biology of malignant gliomas

Issue of 2022–01–02
nine papers selected by
Oltea Sampetrean, Keio University

Comprehensive analysis of the expression levels and prognostic values of PRDX family genes in glioma.
Methodological Approaches for Assessing Metabolomic Changes in Glioblastomas.
Surgical resection of glioblastomas induces pleiotrophin-mediated self-renewal of glioblastoma stem cells in recurrent tumors.
In Vitro and Clinical Compassionate Use Experiences with the Drug-Repurposing Approach CUSP9v3 in Glioblastoma.
Dual IGF1R/IR inhibitors in combination with GD2-CAR T-cells display a potent anti-tumor activity in diffuse midline glioma H3K27M-mutant.
Experimental murine models of brainstem gliomas.
Recent approaches and success of liposome-based nanodrug carriers for the treatment of brain tumor.
The Impact of Tumor Treating Fields on Glioblastoma Progression Patterns.
Sex- and mutation-specific p53 gain-of-function activity in gliomagenesis.

Neurochem Int. 2021 Dec 27. pii: S0197-0186(21)00302-8. [Epub ahead of print] 105256

Comprehensive analysis of the expression levels and prognostic values of PRDX family genes in glioma.

Monika Szeliga.

  Gliomas are a histologically and molecularly heterogeneous group of neoplasms accounting for 80% of malignant primary brain tumors. Growing evidence suggests that production of reactive oxygen species (ROS) is linked to glioma pathogenesis, although it is still unclear whether it is a cause or an effect of this process. Peroxiredoxins (PRDXs), a family of six antioxidant proteins, may promote or inhibit carcinogenesis, depending on the tumor type and stage. The current knowledge on their expression, regulation and functions in glioma is scarce. In this study, a comprehensive analysis of PRDXs expression in distinct glioma subtypes and non-tumor brain tissues was conducted using gene expression data from The Cancer Genome Atlas (TCGA), REpository for Molecular BRAin NeoplasiaDaTa (REMBRANDT), The Chinese Glioma Atlas (CGGA) and Gene Expression Omnibus (GEO) datasets. The association between gene expression and patient survival was investigated. DNA methylation, mutations, copy number alterations of deregulated PRDXs as well as the correlation between gene expression and tumor-infiltrating immune cells were assessed. The analysis revealed overexpression of PRDX1, PRDX4, and PRDX6 in most histological glioma types compared to the non-tumor tissues, while PRDX2, PRDX3 and PRDX5 expression remained unaltered. The expression of PRDX4 and PRDX6 was higher in mesenchymal than proneural and classical glioma subtypes. Moreover, lower expression of PRDX1, PRDX4 and PRDX6 was observed in tumors with a glioma CpG island methylator phenotype (G-CIMP) compared to non-G-CIMP tumors, as well as in isocitrate dehydrogenase (IDH) mutant and 1p/19q co-deleted gliomas compared to the wild-type counterparts. High expression of PRDX1, PRDX4 or PRDX6 correlated with poor survival of glioma patients. PRDX1 and PRDX6 displayed a positive correlation with different immune cell population in low grade gliomas and, to a lesser extent, in glioblastoma. PRDX1 expression exhibited negative correlation with DNA methylation. These results indicate that high expression of PRDX1, PRDX4 and PRDX6 is associated with poor outcome in gliomas.

Keywords:  Gene expression; Glioblastoma; Glioma; Patient survival; Peroxiredoxin

DOI:  https://doi.org/10.1016/j.neuint.2021.105256
Methods Mol Biol. 2022 ;2445 305-328

Methodological Approaches for Assessing Metabolomic Changes in Glioblastomas.

Trang T T Nguyen, Enyuan Shang, Mike-Andrew Westhoff, Georg Karpel-Massler, Markus D Siegelin.

  Glioblastoma (GBM), a highly malignant primary brain tumor, inevitably leads to death. In the last decade, a variety of novel molecular characteristics of GBMs were unraveled. The identification of the mutation in the IDH1 and less commonly IDH2 gene was surprising and ever since has nurtured research in the field of GBM metabolism. While initially thought that mutated IDH1 were to act as a loss of function mutation it became clear that it conferred the production of an oncometabolite that in turn substantially reprograms GBM metabolism. While mutated IDH1 represents truly the tip of the iceberg, there are numerous other related observations in GBM that are of significant interest to the field, including the notion that oxidative metabolism appears to play a more critical role than believed earlier. Metabolic zoning is another important hallmark of GBM since it was found that the infiltrative margin that drives GBM progression reveals enrichment of fatty acid derivatives. Consistently, fatty acid metabolism appears to be a novel therapeutic target for GBM. How metabolism in GBM intersects is another pivotal issue that appears to be important for its progression and response and resistance to therapies. In this review, we will summarize some of the most relevant findings related to GBM metabolism and cell death and how these observations are influencing the field. We will provide current approaches that are applied in the field to measure metabolomic changes in GBM models, including the detection of unlabeled and labeled metabolites as well as extracellular flux analysis.

Keywords:  Cell death; Glioblastoma; IDH1; Metabolic reprogramming; Metabolism

DOI:  https://doi.org/10.1007/978-1-0716-2071-7_19
Neuro Oncol. 2021 Dec 29. pii: noab302. [Epub ahead of print]

Surgical resection of glioblastomas induces pleiotrophin-mediated self-renewal of glioblastoma stem cells in recurrent tumors.

Arnon Møldrup Knudsen, Bo Halle, Oriane Cédile, Mark Burton, Christina Baun, Helge Thisgaard, Atul Anand, Christopher Hubert, Mads Thomassen, Signe Regner Michaelsen, Birgitte Brinkmann Olsen, Rikke Hedegaard Dahlrot, Rolf Bjerkvig, Justin Durla Lathia, Bjarne Winther Kristensen.

   BACKGROUND: Glioblastomas are highly resistant to therapy, and virtually all patients experience tumor recurrence after standard-of-care treatment. Surgical tumor resection is a cornerstone in glioblastoma therapy, but its impact on cellular phenotypes in the local post-surgical microenvironment has yet to be fully elucidated.
METHODS: We developed a preclinical orthotopic xenograft tumor resection model in rats with integrated 18F-FET PET/CT imaging. Primary and recurrent tumors were subject to bulk and single cell RNA sequencing. Differentially expressed genes and pathways were investigated and validated using tissue specimens from the xenograft model, 23 patients with matched primary/recurrent tumors, and a cohort including 190 glioblastoma patients. Functional investigations were performed in vitro with multiple patient-derived cell cultures.
RESULTS: Tumor resection induced microglia/macrophage infiltration, angiogenesis as well as proliferation and upregulation of several stem cell related genes in recurrent tumor cells. Expression changes of selected genes SOX2, POU3F2, OLIG2 and NOTCH1 were validated at the protein level in xenografts and early recurrent patient tumors. Single cell transcriptomics revealed presence of distinct phenotypic cell clusters in recurrent tumors which deviated from clusters found in primary tumors. Recurrent tumors expressed elevated levels of pleiotrophin (PTN), secreted by both tumor cells and tumor-associated microglia/macrophages. Mechanistically, PTN could induce tumor cell proliferation, self-renewal and the stem cell program. In glioblastoma patients, high PTN expression was associated with poor overall survival, and identified as an independent prognostic factor.
CONCLUSION: Surgical tumor resection is an iatrogenic driver of PTN-mediated self-renewal in glioblastoma tumor cells that promotes therapeutic resistance and tumor recurrence.

Keywords:  Glioblastoma; Pleiotrophin; Recurrence; Self-renewal; Tumor resection

DOI:  https://doi.org/10.1093/neuonc/noab302
Pharmaceuticals (Basel). 2021 Nov 29. pii: 1241. [Epub ahead of print]14(12):

In Vitro and Clinical Compassionate Use Experiences with the Drug-Repurposing Approach CUSP9v3 in Glioblastoma.

Marc-Eric Halatsch, Annika Dwucet, Carl Julius Schmidt, Julius Mühlnickel, Tim Heiland, Katharina Zeiler, Markus D Siegelin, Richard Eric Kast, Georg Karpel-Massler.

   BACKGROUND: Glioblastoma represents the most common primary brain tumor in adults. Despite technological advances, patients with this disease typically die within 1-2 years after diagnosis. In the search for novel therapeutics, drug repurposing has emerged as an alternative to traditional drug development pipelines, potentially facilitating and expediting the transition from drug discovery to clinical application. In a drug repurposing effort, the original CUSP9 and its derivatives CUSP9* and CUSP9v3 were developed as combinations of nine non-oncological drugs combined with metronomic low-dose temozolomide.
METHODS: In this work, we performed pre-clinical testing of CUSP9v3 in different established, primary cultured and stem-like glioblastoma models. In addition, eight patients with heavily pre-treated recurrent glioblastoma received the CUSP9v3 regime on a compassionate use basis in a last-ditch effort.
RESULTS: CUSP9v3 had profound antiproliferative and pro-apoptotic effects across all tested glioblastoma models. Moreover, the cells' migratory capacity and ability to form tumor spheres was drastically reduced. In vitro, additional treatment with temozolomide did not significantly enhance the antineoplastic activity of CUSP9v3. CUSP9v3 was well-tolerated with the most frequent grade 3 or 4 adverse events being increased hepatic enzyme levels.
CONCLUSIONS: CUSP9v3 displays a strong anti-proliferative and anti-migratory activity in vitro and seems to be safe to apply to patients. These data have prompted further investigation of CUSP9v3 in a phase Ib/IIa clinical trial (NCT02770378).

Keywords:  CUSP9*; CUSP9v3; compassionate use; drug repurposing; glioblastoma

DOI:  https://doi.org/10.3390/ph14121241
Neuro Oncol. 2021 Dec 29. pii: noab300. [Epub ahead of print]

Dual IGF1R/IR inhibitors in combination with GD2-CAR T-cells display a potent anti-tumor activity in diffuse midline glioma H3K27M-mutant.

Emmanuel de Billy, Marsha Pellegrino, Domenico Orlando, Giulia Pericoli, Roberta Ferretti, Pietro Businaro, Maria Antonietta Ajmone-Cat, Sabrina Rossi, Lucia Lisa Petrilli, Nicola Maestro, Francesca Diomedi-Camassei, Marco Pezzullo, Cristiano De Stefanis, Paola Bencivenga, Alessia Palma, Rossella Rota, Francesca Del Bufalo, Luca Massimi, Gerrit Weber, Chris Jones, Andrea Carai, Simona Caruso, Biagio De Angelis, Ignazio Caruana, Concetta Quintarelli, Angela Mastronuzzi, Franco Locatelli, Maria Vinci.

   BACKGROUND: Diffuse midline gliomas (DMG) H3K27M-mutant, including diffuse intrinsic pontine glioma (DIPG), are pediatric brain tumors associated with grim prognosis. Although GD2-CAR T-cells demonstrated significant anti-tumor activity against DMG H3K27M-mutant in vivo, a multimodal approach may be needed to more effectively treat patients. We investigated GD2 expression in DMG/DIPG and other pediatric high-grade gliomas (pHGG) and sought to identify chemical compounds that would enhance GD2-CAR T-cell anti-tumor efficacy.
METHODS: Immunohistochemistry in tumor tissue samples and immunofluorescence in primary patient-derived cell lines were performed to study GD2 expression. We developed a high-throughput cell-based assay to screen 42 kinase inhibitors in combination with GD2-CAR T-cells. Cell viability, western blots, flow-cytometry, real time PCR experiments, DIPG 3D culture models and orthotopic xenograft model were applied to investigate the effect of selected compounds on DIPG cell death and CAR T-cell function.
RESULTS: GD2 was heterogeneously, but widely, expressed in the tissue tested, while its expression was homogeneous and restricted to DMG/DIPG H3K27M-mutant cell lines. We identified dual IGF1R/IR antagonists, BMS-754807 and linsitinib, able to inhibit tumor cell viability at concentrations that do not affect CAR T-cells. Linsitinib, but not BMS-754807, decreases activation/exhaustion of GD2-CAR T-cells and increases their central memory profile. The enhanced anti-tumor activity of linsitinib/GD2-CAR T-cell combination was confirmed in DIPG models in vitro, ex vivo and in vivo.
CONCLUSION: Our study supports the development of IGF1R/IR inhibitors to be used in combination with GD2-CAR T-cells for treating patients affected by DMG/DIPG and, potentially, by pHGG.

Keywords:  CAR T-cells; DIPG; DMG; IGF1R/IR; immunotherapy

DOI:  https://doi.org/10.1093/neuonc/noab300
Drug Discov Today. 2021 Dec 23. pii: S1359-6446(21)00567-5. [Epub ahead of print]

Experimental murine models of brainstem gliomas.

Shuting Ni, Rujing Chen, Kaili Hu.

  As an intractable central nervous system (CNS) tumor, brainstem gliomas (BGs) are one of the leading causes of pediatric death by brain tumors. Owing to the risk of surgical resection and the little improvement in survival time after radiotherapy and chemotherapy, there is an urgent need to find reliable model systems to better understand the regional pathogenesis of the brainstem and improve treatment strategies. In this review, we outline the evolution of BG murine models, and discuss both their advantages and limitations in drug discovery.

Keywords:  Brainstem glioma; Diffuse intrinsic pontine glioma; Experimental murine model

DOI:  https://doi.org/10.1016/j.drudis.2021.12.016
Curr Drug Deliv. 2021 Dec 12.

Recent approaches and success of liposome-based nanodrug carriers for the treatment of brain tumor.

Tapan K Shaw, Paramita Paul.

  Brain tumors are nothing but a collection of neoplasms originated either from areas within the brain or from systemic metastasized tumors of other organs that have spread to the brain. It is a leading cause of death worldwide. The presence of the blood-brain barrier (BBB), blood-brain tumor barrier (BBTB), and some other factors may limit the entry of many potential therapeutics into the brain tissues in tumor area at the therapeutic concentration required for satisfying effectiveness. Liposomes are taking an active role in delivering many drugs through the BBB into the tumor due to their nanosize and their physiological compatibility. Further, this colloidal carrier can encapsulate both lipophilic and hydrophilic drugs due to its unique structure. The surface of the liposomes can be modified with various ligands that are very specific to the numerous receptors overexpressed onto the BBB as well as onto the diseased tumor surface site (i.e., BBTB) to deliver selective drugs into the tumor site. Moreover, the enhanced permeability and retention (EPR) effect can be an added advantage for nanosize liposomes to concentrate into the tumor microenvironment through relatively leaky vasculature of solid tumor in the brain where no restriction of penetration applies compared to normal BBB. Here in this review, we have tried to compilethe recent advancement along with the associated challenges of liposomes containing different anticancer chemotherapeutics across the BBB/BBTB for the treatment of gliomas that will be very helpful for the readers for better understanding of different trends of brain tumor targeted liposomes-based drug delivery and for pursuing fruitful research on the similar research domain.

Keywords:  Blood brain barrier; Brain targeting; Brain tumor; Enhanced permeability; Glioma; Liposomes; Treatment of brain tumor; retention effect

DOI:  https://doi.org/10.2174/1567201818666211213102308
Int J Radiat Oncol Biol Phys. 2021 Dec 26. pii: S0360-3016(21)03424-6. [Epub ahead of print]

The Impact of Tumor Treating Fields on Glioblastoma Progression Patterns.

Martin Glas, Matthew T Ballo, Ze'ev Bomzon, Noa Urman, Shay Levi, Gitit Lavy-Shahaf, Suriya Jeyapalan, Terence T Sio, Paul M DeRose, Martin Misch, Sophie Taillibert, Zvi Ram, Andreas F Hottinger, Jacob Easaw, Chae-Yong Kim, Suyash Mohan, Roger Stupp.

   BACKGROUND: Tumor-treating fields (TTFields) is an antimitotic treatment modality that interferes with glioblastoma cell division and organelle assembly by delivering low-intensity alternating electric fields to the tumor. A previous analysis from the pivotal EF-14 trial demonstrated a clear correlation between TTFields dose-density at the tumor bed and survival in patients treated with TTFields. This study tests the hypothesis that the antimitotic effects of TTFields result in measurable changes in the location and patterns of progression of newly diagnosed glioblastoma (nGBM) patients.
METHODS: MRI images of 428 nGBM patients that participated in the pivotal EF-14 trial were reviewed and the rates at which distant progression occurred in the TTFields treatment and control arm were compared. Realistic head models of 252 TTFields treated patients were created and TTFields intensity distributions were calculated using a Finite Elements Method. TTFields dose was calculated within regions of the tumor bed and normal brain and its relationship with progression determined.
RESULTS: Distant progression was frequently observed in the TTFields-treated arm, and distant lesions in the TTFields-treated arm appeared at larger distances from the primary lesion than in the control arm. Distant progression correlated with improved clinical outcome in the TTFields patients, with no such correlation observed in the controls. Areas of normal brain that remained normal were exposed to higher TTFields doses compared to normal brain that subsequently exhibited neoplastic progression. Additionally, the average dose to areas of enhancing tumor that returned to normal was significantly higher than in the areas of normal brain that progressed to enhancing tumor.
CONCLUSIONS: There was a direct correlation between TTFields dose distribution and tumor response, confirming the therapeutic activity of TTFields and the rationale for optimizing array placement to maximize TTFields dose in areas at highest risk of progression, as well as array layout adaptation after progression.

Keywords:  Glioblastoma; MRI; TTFields; TTFields dose; Tumor progression

DOI:  https://doi.org/10.1016/j.ijrobp.2021.12.152
Cancer Res Commun. 2021 Dec;1(3): 148-163

Sex- and mutation-specific p53 gain-of-function activity in gliomagenesis.

Nathan C Rockwell, Wei Yang, Nicole M Warrington, Max V Staller, Malachi Griffith, Obi L Griffith, Christina A Gurnett, Barak A Cohen, Dustin Baldridge, Joshua B Rubin.

  In cancer, missense mutations in the DNA-binding domain of TP53 are common. They abrogate canonical p53 activity and frequently confer gain-of-oncogenic function (GOF) through localization of transcriptionally active mutant p53 to non-canonical genes. We found that several recurring p53 mutations exhibit a sex difference in frequency in patients with glioblastoma (GBM). In vitro and in vivo analysis of three mutations, p53R172H, p53Y202C, and p53Y217C revealed unique interactions between cellular sex and p53 GOF mutations that determined each mutation's ability to transform male versus female primary mouse astrocytes. These phenotypic differences were correlated with sex- and p53 mutation- specific patterns of genomic localization to the transcriptional start sites of upregulated genes belonging to core cancer pathways. The promoter regions of these genes exhibited a sex difference in enrichment for different transcription factor DNA-binding motifs. Together, our data establish a novel mechanism for sex specific mutant p53 GOF activity in GBM with implications for all cancer.

Keywords:  gain-of-function; glioblastoma; p53; sex differences; transcription

DOI:  https://doi.org/10.1158/2767-9764.crc-21-0026