bims-malgli 2022-03-13 papers

bims-malgli

Biomed News

on Biology of malignant gliomas

Issue of 2022–03–13
eleven papers selected by
Oltea Sampetrean, Keio University

Tumor-Associated Macrophages in Gliomas-Basic Insights and Treatment Opportunities.
Temozolomide and radiotherapy versus radiotherapy alone in patients with glioblastoma, IDH-wildtype: post-hoc analysis of the EORTC randomized phase 3 CATNON trial.
Anti-tumor Activity of a Mitochondrial Targeted HSP90 Inhibitor in Gliomas.
XAF1 directs glioma response to temozolomide through apoptotic transition of autophagy by activation of ATM-AMPK signaling.
Glioblastoma: The Current State of Biology and Therapeutic Strategies.
Expression of pluripotency-related genes in human glioblastoma.
Global DNA methylation profiling reveals chromosomal instability in IDH-mutant astrocytomas.
CAR T Cell Therapy in Primary Brain Tumors: Current Investigations and the Future.
Advances in local therapy for glioblastoma - taking the fight to the tumour.
The metabolomic landscape plays a critical role in glioma oncogenesis.
Increased replication stress and R-loop accumulation in EGFRvIII-expressing glioblastoma present new therapeutic opportunities.

Cancers (Basel). 2022 Mar 04. pii: 1319. [Epub ahead of print]14(5):

Tumor-Associated Macrophages in Gliomas-Basic Insights and Treatment Opportunities.

Johannes K Andersen, Hrvoje Miletic, Jubayer A Hossain.

  Glioma refers to a group of primary brain tumors which includes glioblastoma (GBM), astrocytoma and oligodendroglioma as major entities. Among these, GBM is the most frequent and most malignant one. The highly infiltrative nature of gliomas, and their intrinsic intra- and intertumoral heterogeneity, pose challenges towards developing effective treatments. The glioma microenvironment, in addition, is also thought to play a critical role during tumor development and treatment course. Unlike most other solid tumors, the glioma microenvironment is dominated by macrophages and microglia-collectively known as tumor-associated macrophages (TAMs). TAMs, like their homeostatic counterparts, are plastic in nature and can polarize to either pro-inflammatory or immunosuppressive states. Many lines of evidence suggest that immunosuppressive TAMs dominate the glioma microenvironment, which fosters tumor development, contributes to tumor aggressiveness and recurrence and, very importantly, impedes the therapeutic effect of various treatment regimens. However, through the development of new therapeutic strategies, TAMs can potentially be shifted towards a proinflammatory state which is of great therapeutic interest. In this review, we will discuss various aspects of TAMs in the context of glioma. The focus will be on the basic biology of TAMs in the central nervous system (CNS), potential biomarkers, critical evaluation of model systems for studying TAMs and finally, special attention will be given to the potential targeted therapeutic options that involve the TAM compartment in gliomas.

Keywords:  TAM biomarker; glioblastoma; glioma; immune checkpoints; immunotherapy; macrophage; microglia; targeted therapies; tumor-associated macrophages (TAMs)

DOI:  https://doi.org/10.3390/cancers14051319
Clin Cancer Res. 2022 Mar 11. pii: clincanres.4283.2021. [Epub ahead of print]

Temozolomide and radiotherapy versus radiotherapy alone in patients with glioblastoma, IDH-wildtype: post-hoc analysis of the EORTC randomized phase 3 CATNON trial.

C Mircea S Tesileanu, Marc Sanson, Wolfgang Wick, Alba A Brandes, Paul M Clement, Sara C Erridge, Michael A Vogelbaum, Anna K Nowak, Jean-Francois Baurain, Warren P Mason, Helen Wheeler, Olivier L Chinot, Sanjeev Gill, Matthew Griffin, Leland Rogers, Walter Taal, Roberta Rudà, Michael Weller, Catherine McBain, Myra E van Linde, Kenneth Aldape, Robert B Jenkins, Johan M Kros, Pieter Wesseling, Andreas von Deimling, Youri Hoogstrate, Iris de Heer, Peggy N Atmodimedjo, Hendrikus Jan J Dubbink, Rutger W W Brouwer, Wilfred F J van IJcken, Kin Jip Cheung, Vassilis Golfinopoulos, Brigitta G Baumert, Thierry Gorlia, Pim J French, Martin J van den Bent.

PURPOSE: In a post-hoc analysis of the CATNON trial (NCT00626990), we explored whether adding temozolomide to radiotherapy improves outcome in patients with IDH1/2wt anaplastic astrocytomas with molecular features of glioblastoma (redesignated as glioblastoma, IDH-wildtype in the 2021 WHO classification of CNS tumors).
EXPERIMENTAL DESIGN: From the randomized phase 3 CATNON study examining the addition of adjuvant and concurrent temozolomide to radiotherapy in anaplastic astrocytomas, we selected a subgroup of IDH1/2wt and H3F3Awt tumors with presence of TERT promoter mutations and/or EGFR amplifications and/or combined gain of chromosome 7 and loss of chromosome 10. Molecular abnormalities including MGMT promoter methylation status were determined by next-generation sequencing, DNA methylation profiling, and SNaPshot analysis.
RESULTS: Of the 751 patients entered in the CATNON study, 670 had fully molecularly characterized tumors. 159 of these tumors met the WHO 2021 molecular criteria for glioblastoma, IDH-wildtype. Of these patients, 47 received radiotherapy only and 112 received a combination of radiotherapy and temozolomide. There was no added effect of temozolomide on either overall survival (HR 1.19, 95%CI 0.82-1.71) or progression-free survival (HR 0.87, 95%CI 0.61-1.24). MGMT promoter methylation was prognostic for overall survival, but was not predictive for outcome to temozolomide treatment either with respect to overall survival or progression-free survival.
CONCLUSIONS: In this cohort of patients with glioblastoma, IDH-wildtype temozolomide treatment did not add benefit beyond that observed from radiotherapy, regardless of MGMT promoter status. These findings require a new well-powered prospective clinical study to explore the efficacy of temozolomide treatment in this patient population.

DOI: https://doi.org/10.1158/1078-0432.CCR-21-4283
Clin Cancer Res. 2022 Mar 04. pii: clincanres.0833.2021. [Epub ahead of print]

Anti-tumor Activity of a Mitochondrial Targeted HSP90 Inhibitor in Gliomas.

Shiyou Wei, Delong Yin, Shengnan Yu, Xiang Lin, Milan R Savani, Kuang Du, Yin Ku, Di Wu, Shasha Li, Hao Liu, Meng Tian, Yaohui Chen, Michelle Bowie, Seethalakshmi Hariharan, Matthew Waitkus, Stephen T Keir, Eric T Sugarman, Rebecca A Deek, Marilyne Labrie, Mustafa Khasraw, Yiling Lu, Gordon B Mills, Meenhard Herlyn, Kongming Wu, Lunxu Liu, Zhi Wei, Keith T Flaherty, Kalil Abdullah, Gao Zhang, David M Ashley.

PURPOSE: To investigate the anti-tumor activity of a mitochondrial-localized HSP90 inhibitor, Gamitrinib, in multiple glioma models, and to elucidate the anti-tumor mechanisms of Gamitrinib in gliomas.
EXPERIMENTAL DESIGN: A broad panel of primary and temozolomide (TMZ)-resistant human glioma cell lines were screened by cell viability assays, flow cytometry and crystal violet assays to investigate the therapeutic efficacy of Gamitrinib. Seahorse assays were used to measure the mitochondrial respiration of glioma cells. Integrated analyses of RNA sequencing (RNAseq) and reverse phase protein array (RPPA) data were performed to reveal the potential anti-tumor mechanisms of Gamitrinib. Neurospheres, patient-derived organoids (PDOs), cell line-derived xenografts (CDX) and patient-derived xenografts (PDX) models were generated to further evaluate the therapeutic efficacy of Gamitrinib.
RESULTS: Gamitrinib inhibited cell proliferation and induced cell apoptosis and death in 17 primary glioma cells, 6 TMZ-resistant glioma cells, 4 neurospheres and 3 PDOs. Importantly, Gamitrinib significantly delayed the tumor growth and improved survival of mice in both CDX and PDX models in which tumors were either subcutaneously or intracranially implanted. Integrated computational analyses of RNAseq and RPPA data revealed that Gamitrinib exhibited its anti-tumor activity via (1) suppressing mitochondrial biogenesis, OXPHOS and cell cycle progression and (2) activating the energy-sensing AMP-activated kinase, DNA damage and stress response.
CONCLUSIONS: These preclinical findings established the therapeutic role of Gamitrinib in gliomas and revealed the inhibition of mitochondrial biogenesis and tumor bioenergetics as the primary anti-tumor mechanisms in gliomas.

DOI: https://doi.org/10.1158/1078-0432.CCR-21-0833
Neurooncol Adv. 2022 Jan-Dec;4(1):4(1): vdac013

XAF1 directs glioma response to temozolomide through apoptotic transition of autophagy by activation of ATM-AMPK signaling.

Min-Goo Lee, Zisun Choi, Na-Jung Lim, Ji-Sun Lim, Kyung-Woo Lee, Kyung-Phil Ko, Byung-Kyu Ryu, Shin-Hyuk Kang, Sung-Gil Chi.

   Background: X-linked inhibitor of apoptosis-associated factor 1 (XAF1) is a tumor suppressor that is commonly inactivated in multiple human cancers. However, its role in the pathogenesis and therapeutic response of glioma is poorly characterized.
Methods: XAF1 activation by temozolomide (TMZ) and its effect on TMZ cytotoxicity were defined using luciferase reporter, flow cytometry, and immunofluorescence assays. Signaling mechanism was analyzed using genetic and pharmacologic experiments. In vivo studies were performed in mice to validate the role of XAF1 in TMZ therapy.
Results: Epigenetic alteration of XAF1 is frequent in cell lines and primary tumors and contributes to cancer cell growth. XAF1 transcription is activated by TMZ via JNK-IRF-1 signaling to promote apoptosis while it is impaired by promoter hypermethylation. In tumor cells expressing high O 6-methylguanine-DNA methyltransferase (MGMT), XAF1 response to TMZ is debilitated. XAF1 facilitates TMZ-mediated autophagic flux to direct an apoptotic transition of protective autophagy. Mechanistically, XAF1 is translocated into the mitochondria to stimulate reactive oxygen species (ROS) production and ataxia telangiectasia mutated (ATM)-AMP-activated protein kinase (AMPK) signaling. A mutant XAF1 lacking the zinc finger 6 domain fails to localize in the mitochondria and activate ROS-ATM-AMPK signaling and autophagy-mediated apoptosis. XAF1-restored xenograft tumors display a reduced growth rate and enhanced therapeutic response to TMZ, which is accompanied with activation of ATM-AMPK signaling. XAF1 expression is associated with overall survival of TMZ treatment patients, particularly with low MGMT cancer.
Conclusions: This study uncovers an important role for the XAF1-ATM-AMPK axis as a linchpin to govern glioma response to TMZ therapy.

Keywords:  AMPK; XAF1; apoptosis; glioblastoma; temozolomide

DOI:  https://doi.org/10.1093/noajnl/vdac013
Cancer Res. 2022 Mar 01. 82(5): 769-772

Glioblastoma: The Current State of Biology and Therapeutic Strategies.

Zev A Binder, Donald M O'Rourke.

Over the past two decades, there have been advances in surgical technologies and chemoradiation strategies for glioblastoma, yet durable remissions are rarely seen. As the biological challenges and genetic basis of glioblastoma have become more understood, new therapeutic strategies may lead to more durable clinical responses and long-term remissions. We believe specialized academic centers that form meaningful corporate partnerships to complement basic science infrastructure and use adaptive clinical trial designs will achieve more rapid translation of innovative approaches to glioblastoma. Here we outline the core biological challenges to be overcome in the management of glioblastoma.

DOI: https://doi.org/10.1158/0008-5472.CAN-21-3534
Neurooncol Adv. 2022 Jan-Dec;4(1):4(1): vdab163

Expression of pluripotency-related genes in human glioblastoma.

Álvaro Fabrício Lopes Rios, Daniela Pretti da Cunha Tirapelli, Mucio Luiz de Assis Cirino, Andressa Romualdo Rodrigues, Ester S Ramos, Carlos Gilberto Carlotti.

   Background: Cancer is a group of heterogeneous diseases characterized by several disruptions of the genetic and epigenetic components of cell biology. Some types of cancer have been shown to be constituted by a mosaic of cells with variable differentiation states, with more aggressive tumors being more undifferentiated. In most cases, undifferentiated tumor cells express associated embryonic markers such as the OCT4, NANOG, SOX2, and CARM1 genes. The ectopic or reminiscent expression of some master regulator genes of pluripotency has been indicated as the cause of the poorly differentiated state of tumors, and based on the evidence of some reports, can be used as a possible therapeutic target. Considering this information, a more detailed investigation of the expression of pluripotency-associated genes is necessary to evaluate the roles of these genes in the etiology of some tumors and their use targets of therapy.
Methods: The expression of four pluripotency-related genes was investigated (OCT4, NANOG, SOX2, and CARM1) in the most malignant primary human brain tumor, glioblastoma (GBM).
Results and Conclusion: The results demonstrated a signature of OCT4/SOX2/CARM1 genes and a significant increase of CARM1 expression in GBM cases.

Keywords:  cancer; gene expression; pluripotency; stem cell

DOI:  https://doi.org/10.1093/noajnl/vdab163
Acta Neuropathol Commun. 2022 Mar 09. 10(1): 32

Global DNA methylation profiling reveals chromosomal instability in IDH-mutant astrocytomas.

Yan Liu, Adwait Amod Sathe, Kalil G Abdullah, Samuel K McBrayer, Steven H Adams, Andrew J Brenner, Kimmo J Hatanpaa, Mariano S Viapiano, Chao Xing, Jamie M Walker, Timothy E Richardson.

  Diffusely infiltrating gliomas are among the most common central nervous system tumors in adults. Over the past decade, the subcategorization of these tumors has changed to include both traditional histologic features and more recently identified molecular factors. However, one molecular feature that has yet to be integrated is the presence/absence of chromosomal instability (CIN). Herein, we use global methylation profiling to evaluate a reference cohort of IDH-mutant astrocytomas with and without prior evidence of CIN (n = 42), and apply the resulting methylation-based characteristics to a larger test cohort of publicly-available IDH-mutant astrocytomas (n = 245). We demonstrate that IDH-mutant astrocytomas with evidence of CIN cluster separately from their chromosomally-stable counterparts. CIN cases were associated with higher initial histologic grade, altered expression patterns of genes related to CIN in other cancers, elevated initial total copy number burden, and significantly worse progression-free and overall survival. In addition, in a grade-for-grade analysis, patients with CIN-positive WHO grade 2 and 3 tumors had significantly worse survival. These results suggest that global methylation profiling can be used to discriminate between chromosomally stable and unstable IDH-mutant astrocytomas, and may therefore provide a reliable and cost-effective method for identifying gliomas with chromosomal instability and resultant poor clinical outcome.

Keywords:  Astrocytoma; Chromosomal instability; Copy number variation; Glioblastoma; Glioma; IDH-mutation; Methylation profiling

DOI:  https://doi.org/10.1186/s40478-022-01339-2
Front Immunol. 2022 ;13 817296

CAR T Cell Therapy in Primary Brain Tumors: Current Investigations and the Future.

Ya-Jui Lin, Leila A Mashouf, Michael Lim.

  Chimeric antigen receptor T cells (CAR T cells) are engineered cells expressing a chimeric antigen receptor (CAR) against a specific tumor antigen (TA) that allows for the identification and elimination of cancer cells. The remarkable clinical effect seen with CAR T cell therapies against hematological malignancies have attracted interest in developing such therapies for solid tumors, including brain tumors. Glioblastoma (GBM) is the most common primary brain tumor in adults and is associated with poor prognosis due to its highly aggressive nature. Pediatric brain cancers are similarly aggressive and thus are a major cause of pediatric cancer-related death. CAR T cell therapy represents a promising avenue for therapy against these malignancies. Several specific TAs, such as EGFR/EGFRvIII, IL13Rα2, B7-H3, and HER2, have been targeted in preclinical studies and clinical trials. Unfortunately, CAR T cells against brain tumors have showed limited efficacy due to TA heterogeneity, difficulty trafficking from blood to tumor sites, and the immunosuppressive tumor microenvironment. Here, we review current CAR T cell approaches in treating cancers, with particular focus on brain cancers. We also describe a novel technique of focused ultrasound controlling the activation of engineered CAR T cells to achieve the safer cell therapies. Finally, we summarize the development of combinational strategies to improve the efficacy and overcome historical limitations of CAR T cell therapy.

Keywords:  CAR T cell; brain tumor; focus ultrasound; glioma; immunotherapy

DOI:  https://doi.org/10.3389/fimmu.2022.817296
Nat Rev Neurol. 2022 Mar 11.

Advances in local therapy for glioblastoma - taking the fight to the tumour.

Thomas S van Solinge, Lisa Nieland, E Antonio Chiocca, Marike L D Broekman.

Despite advances in neurosurgery, chemotherapy and radiotherapy, glioblastoma remains one of the most treatment-resistant CNS malignancies, and the tumour inevitably recurs. The majority of recurrences appear in or near the resection cavity, usually within the area that received the highest dose of radiation. Many new therapies focus on combatting these local recurrences by implementing treatments directly in or near the tumour bed. In this Review, we discuss the latest developments in local therapy for glioblastoma, focusing on recent preclinical and clinical trials. The approaches that we discuss include novel intraoperative techniques, various treatments of the surgical cavity, stereotactic injections directly into the tumour, and new developments in convection-enhanced delivery and intra-arterial treatments.

DOI: https://doi.org/10.1038/s41582-022-00621-0
Cancer Sci. 2022 Mar 10.

The metabolomic landscape plays a critical role in glioma oncogenesis.

Kenta Masui, Webster K Cavenee, Paul S Mischel, Noriyuki Shibata.

  Cancer cells depend on metabolic reprogramming for survival, undergoing profound shifts in nutrient-sensing, nutrient uptake and flux through anabolic pathways, in order to drive nucleotide, lipid, and protein synthesis and provide key intermediates needed for those pathways. Although metabolic enzymes themselves can be mutated, including to generate oncometabolites, this is a relatively rare event in cancer. Usually, gene amplification, overexpression, and/or downstream signal transduction upregulate rate-limiting metabolic enzymes and limit feedback loops, to drive persistent tumor growth. Recent molecular genetic advances revealed discrete links between oncogenotypes and the resultant metabolic phenotypes. However, more comprehensive approaches are needed to unravel the dynamic spatio-temporal regulatory map of enzymes and metabolites that enable cancer cells to adapt to their microenvironment to maximize tumor growth. Proteomic and metabolomic analyses are powerful tools for analyzing a repertoire of metabolic enzymes as well as intermediary metabolites, and in conjunction with other omic approaches could provide critical information in this regard. Here, we provide an overview of cancer metabolism, especially from an "omics" perspective and with a particular focus on the genomically well-characterized malignant tumor, glioblastoma. We further discuss how metabolomics could be leveraged to improve the management of patients, by linking cancer cell genotype, epigenotype and phenotype through metabolic reprogramming.

Keywords:  OMICS; epigenetics; glioblastoma; mTOR complex; metabolome

DOI:  https://doi.org/10.1111/cas.15325
Neurooncol Adv. 2022 Jan-Dec;4(1):4(1): vdab180

Increased replication stress and R-loop accumulation in EGFRvIII-expressing glioblastoma present new therapeutic opportunities.

Nina Struve, Konstantin Hoffer, Anna-Sophie Weik, Britta Riepen, Leonie Krug, Meryem H Cetin, Jasmin Burmester, Leonie Ott, Jana Liebing, Fruzsina Gatzemeier, Justus Müller-Goebel, Mirja Gerbach, Lara Bußmann, Ann Christin Parplys, Kristian Unger, Wael Y Mansour, Ulrich Schüller, Thorsten Rieckmann, Cordula Petersen, Kai Rothkamm, Susan C Short, Malte Kriegs.

   Background: The oncogene epidermal growth factor receptor variant III (EGFRvIII) is expressed in approximately one-third of all glioblastomas (GBMs). So far it is not clear if EGFRvIII expression induces replication stress in GBM cells, which might serve as a therapeutical target.
Methods: Isogenetic EGFRvIII- and EGFRvIII+ cell lines with endogenous EGFRvIII expression were used. Markers of oncogenic and replication stress such as γH2AX, RPA, 53BP1, ATR, and CHK1 were analyzed using western blot, immunofluorescence, and flow cytometry. The DNA fiber assay was performed to analyze replication, transcription was measured by incorporation of EU, and genomic instability was investigated by micronuclei and CGH-Array analysis. Immunohistochemistry staining was used to detect replication stress markers and R-loops in human GBM samples.
Results: EGFRvIII+ cells exhibit an activated replication stress response, increased spontaneous DNA damage, elevated levels of single-stranded DNA, and reduced DNA replication velocity, which are all indicative characteristics of replication stress. Furthermore, we show here that EGFRvIII expression is linked to increased genomic instability. EGFRvIII-expressing cells display elevated RNA synthesis and R-loop formation, which could also be confirmed in EGFRvIII-positive GBM patient samples. Targeting replication stress by irinotecan resulted in increased sensitivity of EGFRvIII+ cells.
Conclusion: This study demonstrates that EGFRvIII expression is associated with increased replication stress, R-loop accumulation, and genomic instability. This might contribute to intratumoral heterogeneity but may also be exploited for individualized therapy approaches.

Keywords:  EGFRvIII; R-loops; genomic instability; glioblastoma; irinotecan sensitivity; replication stress

DOI:  https://doi.org/10.1093/noajnl/vdab180