bims-malgli 2020-11-01 papers

bims-malgli

Biomed News

on Biology of malignant gliomas

Issue of 2020–11–01
eightteen papers selected by
Oltea Sampetrean, Keio University

The HIF1α/JMY pathway promotes glioblastoma stem-like cell invasiveness after irradiation.
Temozolomide Treatment Increases Fatty Acid Uptake in Glioblastoma Stem Cells.
Metabolic plasticity of IDH1-mutant glioma cell lines is responsible for low sensitivity to glutaminase inhibition.
Microglia-Centered Combinatorial Strategies Against Glioblastoma.
Nanomechanics and Histopathology as Diagnostic Tools to Characterize Freshly Removed Human Brain Tumors.
Generating Patient-Derived Gliomas within Cerebral Organoids.
RNA-Sequencing and immunohistochemistry reveal ZFN7 as a stronger marker of survival than molecular subtypes in G-CIMP-negative glioblastoma.
Brain tumor stem cell dependence on glutaminase reveals a metabolic vulnerability through the amino acid deprivation response pathway.
Effect of 1α,25(OH)2 Vitamin D3 in Mutant P53 Glioblastoma Cells: Involvement of Neutral Sphingomyelinase1.
Neutrophil-induced ferroptosis promotes tumor necrosis in glioblastoma progression.
ATF4 links ER stress with reticulophagy in glioblastoma cells.
Distributed changes of the functional connectome in patients with glioblastoma.
Transcriptomic analysis of Diffuse Intrinsic Pontine Glioma (DIPG) identifies a targetable ALDH-positive subset of highly tumorigenic cancer stem-like cells.
A Preliminary Study on Machine Learning-Based Evaluation of Static and Dynamic FET-PET for the Detection of Pseudoprogression in Patients with IDH-Wildtype Glioblastoma.
Brain exposure of the ATM inhibitor AZD1390 in humans - a positron emission tomography (PET) study.
Organotypic Models to Study Human Glioblastoma: Studying the Beast in Its Ecosystem.
Reproducibility analysis of multi-institutional paired expert annotations and radiomic features of the Ivy Glioblastoma Atlas Project (Ivy GAP) dataset.
Immunocytokines turn up the heat in glioblastoma.

Sci Rep. 2020 Oct 30. 10(1): 18742

The HIF1α/JMY pathway promotes glioblastoma stem-like cell invasiveness after irradiation.

Laurent R Gauthier, Mahasen Saati, Hayet Bensalah-Pigeon, Karim Ben M'Barek, Oscar Gitton-Quent, Romane Bertrand, Didier Busso, Marc-André Mouthon, Ada Collura, Marie-Pierre Junier, Hervé Chneiweiss, José R Pineda, François D Boussin.

Human glioblastoma (GBM) is the most common primary malignant brain tumor. A minor subpopulation of cancer cells, known as glioma stem-like cells (GSCs), are thought to play a major role in tumor relapse due to their stem cell-like properties, their high resistance to conventional treatments and their high invasion capacity. We show that ionizing radiation specifically enhances the motility and invasiveness of human GSCs through the stabilization and nuclear accumulation of the hypoxia-inducible factor 1α (HIF1α), which in turn transcriptionally activates the Junction-mediating and regulatory protein (JMY). Finally, JMY accumulates in the cytoplasm where it stimulates GSC migration via its actin nucleation-promoting activity. Targeting JMY could thus open the way to the development of new therapeutic strategies to improve the efficacy of radiotherapy and prevent glioma recurrence.

DOI: https://doi.org/10.1038/s41598-020-75300-5
Cancers (Basel). 2020 Oct 26. pii: E3126. [Epub ahead of print]12(11):

Temozolomide Treatment Increases Fatty Acid Uptake in Glioblastoma Stem Cells.

Seamus Caragher, Jason Miska, Jack Shireman, Cheol H Park, Megan Muroski, Maciej S Lesniak, Atique U Ahmed.

  Among all cancers, glioblastoma (GBM) remains one of the least treatable. One key factor in this resistance is a subpopulation of tumor cells termed glioma stem cells (GSCs). These cells are highly resistant to current treatment modalities, possess marked self-renewal capacity, and are considered key drivers of tumor recurrence. Further complicating an understanding of GBM, evidence shows that the GSC population is not a pre-ordained and static group of cells but also includes previously differentiated GBM cells that have attained a GSC state secondary to environmental cues. The metabolic behavior of GBM cells undergoing plasticity remains incompletely understood. To that end, we probed the connection between GSCs, environmental cues, and metabolism. Using patient-derived xenograft cells, mouse models, transcriptomics, and metabolic analyses, we found that cell state changes are accompanied by sharp changes in metabolic phenotype. Further, treatment with temozolomide, the current standard of care drug for GBM, altered the metabolism of GBM cells and increased fatty acid uptake both in vitro and in vivo in the plasticity driven GSC population. These results indicate that temozolomide-induced changes in cell state are accompanied by metabolic shifts-a potentially novel target for enhancing the effectiveness of current treatment modalities.

Keywords:  chemoresistance; glioblastoma; glioma stem cell; metabolism; therapeutic stress

DOI:  https://doi.org/10.3390/cancers12113126
Cancer Metab. 2020 ;8 23

Metabolic plasticity of IDH1-mutant glioma cell lines is responsible for low sensitivity to glutaminase inhibition.

Victor Ruiz-Rodado, Adrian Lita, Tyrone Dowdy, Orieta Celiku, Alejandra Cavazos Saldana, Herui Wang, Chun Zhang Yang, Raj Chari, Aiguo Li, Wei Zhang, Hua Song, Meili Zhang, Susie Ahn, Dionne Davis, Xiang Chen, Zhengping Zhuang, Christel Herold-Mende, Kylie J Walters, Mark R Gilbert, Mioara Larion.

   Background: Targeting glutamine metabolism in cancer has become an increasingly vibrant area of research. Mutant IDH1 (IDH1 mut ) gliomas are considered good candidates for targeting this pathway because of the contribution of glutamine to their newly acquired function: synthesis of 2-hydroxyglutarate (2HG).
Methods: We have employed a combination of 13C tracers including glutamine and glucose for investigating the metabolism of patient-derived IDH1 mut glioma cell lines through NMR and LC/MS. Additionally, genetic loss-of-function (in vitro and in vivo) approaches were performed to unravel the adaptability of these cell lines to the inhibition of glutaminase activity.
Results: We report the adaptability of IDH1 mut cells' metabolism to the inhibition of glutamine/glutamate pathway. The glutaminase inhibitor CB839 generated a decrease in the production of the downstream metabolites of glutamate, including those involved in the TCA cycle and 2HG. However, this effect on metabolism was not extended to viability; rather, our patient-derived IDH1 mut cell lines display a metabolic plasticity that allows them to overcome glutaminase inhibition.
Conclusions: Major metabolic adaptations involved pathways that can generate glutamate by using alternative substrates from glutamine, such as alanine or aspartate. Indeed, asparagine synthetase was upregulated both in vivo and in vitro revealing a new potential therapeutic target for a combinatory approach with CB839 against IDH1 mut gliomas.

Keywords:  13C tracing; AGI5198; CB839; Gliomas; Glutaminase; IDH1-mutant

DOI:  https://doi.org/10.1186/s40170-020-00229-2
Front Immunol. 2020 ;11 571951

Microglia-Centered Combinatorial Strategies Against Glioblastoma.

Tomás A Martins, Philip Schmassmann, Tala Shekarian, Jean-Louis Boulay, Marie-Françoise Ritz, Steven Zanganeh, Johannes Vom Berg, Gregor Hutter.

  Tumor-associated microglia (MG) and macrophages (MΦ) are important components of the glioblastoma (GBM) immune tumor microenvironment (iTME). From the recent advances in understanding how MG and GBM cells evolve and interact during tumorigenesis, we emphasize the cooperation of MG with other immune cell types of the GBM-iTME, mainly MΦ and T cells. We provide a comprehensive overview of current immunotherapeutic clinical trials and approaches for the treatment of GBM, which in general, underestimate the counteracting contribution of immunosuppressive MG as a main factor for treatment failure. Furthermore, we summarize new developments and strategies in MG reprogramming/re-education in the GBM context, with a focus on ways to boost MG-mediated tumor cell phagocytosis and associated experimental models and methods. This ultimately converges in our proposal of novel combinatorial regimens that locally modulate MG as a central paradigm, and therefore may lead to additional, long-lasting, and effective tumoricidal responses.

Keywords:  glioblastoma; glioma- associated macrophages; glioma-associated microglia; immune tumor microenvironment; immunotherapy; microglia modulation

DOI:  https://doi.org/10.3389/fimmu.2020.571951
Int J Nanomedicine. 2020 ;15 7509-7521

Nanomechanics and Histopathology as Diagnostic Tools to Characterize Freshly Removed Human Brain Tumors.

Mateusz Cieśluk, Katarzyna Pogoda, Piotr Deptuła, Paulina Werel, Alina Kułakowska, Jan Kochanowicz, Zenon Mariak, Tomasz Łysoń, Joanna Reszeć, Robert Bucki.

   Background: The tissue-mechanics environment plays a crucial role in human brain physiological development and the pathogenesis of different diseases, especially cancer. Assessment of alterations in brain mechanical properties during cancer progression might provide important information about possible tissue abnormalities with clinical relevance.
Methods: With atomic force microscopy (AFM), the stiffness of freshly removed human brain tumor tissue was determined on various regions of the sample and compared to the stiffness of healthy human brain tissue that was removed during neurosurgery to gain access to tumor mass. An advantage of indentation measurement using AFM is the small volume of tissue required and high resolution at the single-cell level.
Results: Our results showed great heterogeneity of stiffness within metastatic cancer or primary high-grade gliomas compared to healthy tissue. That effect was not clearly visible in lower-grade tumors like meningioma.
Conclusion: Collected data indicate that AFM might serve as a diagnostic tool in the assessment of human brain tissue stiffness in the process of recognizing tumors.

Keywords:  AFM; brain tumors; glioblastoma; human tissue rheology; mechanomarkers

DOI:  https://doi.org/10.2147/IJN.S270147
STAR Protoc. 2020 Jun 19. pii: 100008. [Epub ahead of print]1(1):

Generating Patient-Derived Gliomas within Cerebral Organoids.

Amanda Linkous, Howard A Fine.

Glioblastoma (GBM) remains a devastating disease with a median survival of less than two years. Current preclinical models are unable to accurately reflect the complexity of human GBM. We recently established a cerebral organoid glioma (GLICO) model to study the invasion and biology of patient-derived glioma stem cells in miniature replicas of the human brain. Through the dissemination of our detailed methodology, we aim to encourage other scientists to further build upon our existing model for studying these destructive tumors. For complete details on the use and execution of this protocol, please refer to Linkous et al. (2019).

DOI: https://doi.org/10.1016/j.xpro.2019.100008
Clin Cancer Res. 2020 Oct 26. pii: clincanres.2141.2020. [Epub ahead of print]

RNA-Sequencing and immunohistochemistry reveal ZFN7 as a stronger marker of survival than molecular subtypes in G-CIMP-negative glioblastoma.

Anna Esteve-Codina, Francesc Alameda, Cristina Carrato, Estela Pineda, Oriol Arpí, Maria Martinez Garcia, Mar Mallo, Marta Gut, Marc Dabad, Avelina Tortosa, Sonia Del Barco, Jaume Capellades, Josep Puig, Oscar Gallego, Teresa Pujol, Laura Oleaga, Miguel J Gil-Gil, Cristian de Quintana-Schmidt, Izaskun Valduvieco, Anna Martinez-Cardus, Beatriz Bellosillo, Ana Mª Muñoz-Mármol, Anna Esteve, Marta Domenech, Angels Camins, Jordi Craven-Bartle, Salvador Villa, Jordi Marruecos, Sira Domenech, Nuria de la Iglesia, Carmen Balana.

PURPOSE: Glioblastoma is the most aggressive brain tumor in adults and has few therapeutic options. The study of molecular subtype classifications may lead to improved prognostic classification and identification of new therapeutic targets. The TCGA subtype classification has mainly been applied in USA clinical trials, while the IGS has mainly been applied in European trials.
EXPERIMENTAL DESIGN: From paraffin-embedded tumor samples of 432 uniformly treated, newly diagnosed glioblastoma patients, we built tissue microarrays for immunohistochemical analysis and applied RNA-Sequencing to the best samples in order to classify them according to the TCGA and IGS subtypes.
RESULTS: We obtained transcriptomic results from 124 patients. There was a lack of agreement among the three TCGA classificatory algorithms employed, which was not solely attributable to intratumoral heterogeneity. There was overlapping of the TCGA mesenchymal subtype with IGS cluster 23 and of the TCGA classical subtype with IGS cluster 18. Molecular subtypes were not associated with prognosis, but levels of expression of 13 novel genes were identified as independent prognostic markers in G-CIMP-negative patients, independently of clinical factors and MGMT methylation. These findings were validated in at least one external database. Three of the 13 genes were selected for immunohistochemical validation. In particular, high ZNF7 RNA expression and low ZNF7 protein expression were strongly associated with longer survival, independently of molecular subtypes.
CONCLUSIONS: The TCGA and IGS molecular classifications of glioblastoma have no higher prognostic value than individual genes and should be refined before being applied to clinical trials.

DOI: https://doi.org/10.1158/1078-0432.CCR-20-2141
Cancer Res. 2020 Oct 26. pii: canres.3923.2019. [Epub ahead of print]

Brain tumor stem cell dependence on glutaminase reveals a metabolic vulnerability through the amino acid deprivation response pathway.

Ian J Restall, Orsolya Cseh, Laura M Richards, Trevor J Pugh, H Artee Luchman, Samuel Weiss.

Cancer cells can metabolize glutamine to replenish TCA cycle intermediates, leading to a dependence on glutaminolysis for cell survival. However, a mechanistic understanding of the role that glutamine metabolism has on the survival of glioblastoma (GBM) brain tumor stem cells (BTSC) has not yet been elucidated. Here we report that, across a panel of 19 glioblastoma BTSC lines, inhibition of glutaminase (GLS) showed a variable response from complete blockade of cell growth to absolute resistance. Surprisingly, BTSC sensitivity to GLS inhibition was a result of reduced intracellular glutamate triggering the amino acid deprivation response (AADR) and not due to the contribution of glutaminolysis to the TCA cycle. Moreover, BTSC sensitivity to GLS inhibition negatively correlated with expression of the astrocytic glutamate transporters EAAT1 and EAAT2. Blocking glutamate transport in BTSCs with high EAAT1/EAAT2 expression rendered cells susceptible to GLS inhibition, triggering the AADR and limiting cell growth. These findings uncover a unique metabolic vulnerability in BTSCs and support the therapeutic targeting of upstream activators and downstream effectors of the AADR pathway in GBM. Moreover, they demonstrate that gene expression patterns reflecting the cellular hierarchy of the tissue of origin can alter the metabolic requirements of the cancer stem cell population.

DOI: https://doi.org/10.1158/0008-5472.CAN-19-3923
Cancers (Basel). 2020 Oct 28. pii: E3163. [Epub ahead of print]12(11):

Effect of 1α,25(OH)2 Vitamin D3 in Mutant P53 Glioblastoma Cells: Involvement of Neutral Sphingomyelinase1.

Samuela Cataldi, Cataldo Arcuri, Andrea Lazzarini, Irina Nakashidze, Francesco Ragonese, Bernard Fioretti, Ivana Ferri, Carmela Conte, Michela Codini, Tommaso Beccari, Francesco Curcio, Elisabetta Albi.

  Glioblastoma is one the most aggressive primary brain tumors in adults, and, despite the fact that radiation and chemotherapy after surgical approaches have been the treatments increasing the survival rates, the prognosis of patients remains poor. Today, the attention is focused on highlighting complementary treatments that can be helpful in improving the classic therapeutic approaches. It is known that 1α,25(OH)2 vitamin D3, a molecule involved in bone metabolism, has many serendipidy effects in cells. It targets normal and cancer cells via genomic pathway by vitamin D3 receptor or via non-genomic pathways. To interrogate possible functions of 1α,25(OH)2 vitamin D3 in multiforme glioblastoma, we used three cell lines, wild-type p53 GL15 and mutant p53 U251 and LN18 cells. We demonstrated that 1α,25(OH)2 vitamin D3 acts via vitamin D receptor in GL15 cells and via neutral sphingomyelinase1, with an enrichment of ceramide pool, in U251 and LN18 cells. Changes in sphingomyelin/ceramide content were considered to be possibly responsible for the differentiating and antiproliferative effect of 1α,25(OH)2 vitamin D in U251 and LN18 cells, as shown, respectively, in vitro by immunofluorescence and in vivo by experiments of xenotransplantation in eggs. This is the first time 1α,25(OH)2 vitamin D3 is interrogated for the response of multiforme glioblastoma cells in dependence on the p53 mutation, and the results define neutral sphingomyelinase1 as a signaling effector.

Keywords:  U251; glioblastoma; neutral sphingomyelinase; vitamin D receptor; vitamin D3

DOI:  https://doi.org/10.3390/cancers12113163
Nat Commun. 2020 10 27. 11(1): 5424

Neutrophil-induced ferroptosis promotes tumor necrosis in glioblastoma progression.

Patricia P Yee, Yiju Wei, Soo-Yeon Kim, Tong Lu, Stephen Y Chih, Cynthia Lawson, Miaolu Tang, Zhijun Liu, Benjamin Anderson, Krishnamoorthy Thamburaj, Megan M Young, Dawit G Aregawi, Michael J Glantz, Brad E Zacharia, Charles S Specht, Hong-Gang Wang, Wei Li.

Tumor necrosis commonly exists and predicts poor prognoses in many cancers. Although it is thought to result from chronic ischemia, the underlying nature and mechanisms driving the involved cell death remain obscure. Here, we show that necrosis in glioblastoma (GBM) involves neutrophil-triggered ferroptosis. In a hyperactivated transcriptional coactivator with PDZ-binding motif-driven GBM mouse model, neutrophils coincide with necrosis temporally and spatially. Neutrophil depletion dampens necrosis. Neutrophils isolated from mouse brain tumors kill cocultured tumor cells. Mechanistically, neutrophils induce iron-dependent accumulation of lipid peroxides within tumor cells by transferring myeloperoxidase-containing granules into tumor cells. Inhibition or depletion of myeloperoxidase suppresses neutrophil-induced tumor cell cytotoxicity. Intratumoral glutathione peroxidase 4 overexpression or acyl-CoA synthetase long chain family member 4 depletion diminishes necrosis and aggressiveness of tumors. Furthermore, analyses of human GBMs support that neutrophils and ferroptosis are associated with necrosis and predict poor survival. Thus, our study identifies ferroptosis as the underlying nature of necrosis in GBMs and reveals a pro-tumorigenic role of ferroptosis. Together, we propose that certain tumor damage(s) occurring during early tumor progression (i.e. ischemia) recruits neutrophils to the site of tissue damage and thereby results in a positive feedback loop, amplifying GBM necrosis development to its fullest extent.

DOI: https://doi.org/10.1038/s41467-020-19193-y
Autophagy. 2020 Oct 28. 1-17

ATF4 links ER stress with reticulophagy in glioblastoma cells.

Svenja Zielke, Simon Kardo, Laura Zein, Muriel Mari, Adriana Covarrubias-Pinto, Maximilian N Kinzler, Nina Meyer, Alexandra Stolz, Simone Fulda, Fulvio Reggiori, Donat Kögel, Sjoerd J L van Wijk.

  Selective degradation of the endoplasmic reticulum (ER; reticulophagy) is a type of autophagy involved in the removal of ER fragments. So far, amino acid starvation as well as ER stress have been described as inducers of reticulophagy, which in turn restores cellular energy levels and ER homeostasis. Here, we explored the autophagy-inducing mechanisms that underlie the autophagic cell death (ACD)-triggering compound loperamide (LOP) in glioblastoma cells. Interestingly, LOP triggers upregulation of the transcription factor ATF4, which is accompanied by the induction of additional ER stress markers. Notably, knockout of ATF4 significantly attenuated LOP-induced autophagy and ACD. Functionally, LOP also specifically induces the engulfment of large ER fragments within autophagosomes and lysosomes as determined by electron and fluorescence microscopy. LOP-induced reticulophagy and cell death are predominantly mediated through the reticulophagy receptor RETREG1/FAM134B and, to a lesser extent, TEX264, confirming that reticulophagy receptors can promote ACD. Strikingly, apart from triggering LOP-induced autophagy and ACD, ATF4 is also required for LOP-induced reticulophagy. These observations highlight a key role for ATF4, RETREG1 and TEX264 in response to LOP-induced ER stress, reticulophagy and ACD, and establish a novel mechanistic link between ER stress and reticulophagy, with possible implications for additional models of drug-induced ER stress. Abbreviations: ACD: autophagic cell death; ATF6: activating transcription factor 6; ATL3: atlastin 3; BafA1: bafilomycin A1; CCPG1: cell cycle progression gene 1; co-IP: co-immunoprecipitation; DDIT3/CHOP: DNA damage inducible transcript 3; ER: endoplasmic reticulum; EIF2A/eIF2α: eukaryotic translation initiation factor 2A; EIF2AK3/PERK: eukaryotic translation initiation factor 2 alpha kinase 3; ERN1/IRE1α: endoplasmic reticulum to nucleus signaling 1; GABARAP: GABA type A receptor-associated protein; GBM: glioblastoma multiforme; HSPA5/BiP: heat shock protein family (Hsp70) member 5; LOP: loperamide; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; RETREG1/FAM134B: reticulophagy regulator 1; RTN3L: reticulon 3 long; SEC62: SEC62 homolog, protein translocation factor; TEX264: testis-expressed 264, reticulophagy receptor; UPR: unfolded protein response.

Keywords:  HSPA5/BiP; MEFs; MZ-54; RETREG1/FAM134B; TEX264; autophagic cell death; loperamide; p-eIF2α; selective autophagy

DOI:  https://doi.org/10.1080/15548627.2020.1827780
Sci Rep. 2020 Oct 27. 10(1): 18312

Distributed changes of the functional connectome in patients with glioblastoma.

Karl-Heinz Nenning, Julia Furtner, Barbara Kiesel, Ernst Schwartz, Thomas Roetzer, Nikolaus Fortelny, Christoph Bock, Anna Grisold, Martha Marko, Fritz Leutmezer, Hesheng Liu, Polina Golland, Sophia Stoecklein, Johannes A Hainfellner, Gregor Kasprian, Daniela Prayer, Christine Marosi, Georg Widhalm, Adelheid Woehrer, Georg Langs.

Glioblastoma might have widespread effects on the neural organization and cognitive function, and even focal lesions may be associated with distributed functional alterations. However, functional changes do not necessarily follow obvious anatomical patterns and the current understanding of this interrelation is limited. In this study, we used resting-state functional magnetic resonance imaging to evaluate changes in global functional connectivity patterns in 15 patients with glioblastoma. For six patients we followed longitudinal trajectories of their functional connectome and structural tumour evolution using bi-monthly follow-up scans throughout treatment and disease progression. In all patients, unilateral tumour lesions were associated with inter-hemispherically symmetric network alterations, and functional proximity of tumour location was stronger linked to distributed network deterioration than anatomical distance. In the longitudinal subcohort of six patients, we observed patterns of network alterations with initial transient deterioration followed by recovery at first follow-up, and local network deterioration to precede structural tumour recurrence by two months. In summary, the impact of focal glioblastoma lesions on the functional connectome is global and linked to functional proximity rather than anatomical distance to tumour regions. Our findings further suggest a relevance for functional network trajectories as a possible means supporting early detection of tumour recurrence.

DOI: https://doi.org/10.1038/s41598-020-74726-1
Mol Cancer Res. 2020 Oct 26. pii: molcanres.0464.2020. [Epub ahead of print]

Transcriptomic analysis of Diffuse Intrinsic Pontine Glioma (DIPG) identifies a targetable ALDH-positive subset of highly tumorigenic cancer stem-like cells.

Rachel K Surowiec, Sarah F Ferris, April Apfelbaum, Carlos Espinoza, Ranjit K Mehta, Karamoja Monchamp, Veerin R Sirihorachai, Karan Bedi, Mats Ljungman, Stefanie Galban.

Understanding the cancer stem-cell (CSC) landscape in diffuse intrinsic pontine glioma (DIPG) is desperately needed to address treatment resistance and identify novel therapeutic approaches. Patient derived DIPG cells demonstrated heterogeneous expression of aldehyde dehydrogenase (ALDH) and CD133 by flow cytometry. Transcriptome-level characterization identified elevated mRNA levels of MYC, E2F, DNA damage repair (DDR) genes, glycolytic metabolism and mTOR signaling in ALDH+ compared to ALDH- supporting a stem-like phenotype and indicating a druggable target. ALDH+ cells demonstrated increased proliferation, neurosphere formation and initiated tumors that resulted in decreased survival when orthotopically implanted. Pharmacological MAPK/PI3K/mTOR targeting downregulated MYC, E2F and DDR mRNAs and reduced glycolytic metabolism. In vivo PI3K/mTOR targeting inhibited tumor growth in both flank and an ALDH+ orthotopic tumor model likely by reducing cancer stemness. In summary, we describe existence of ALDH+ DIPGs with proliferative properties due to increased metabolism, which may be regulated by the microenvironment and likely contributing to drug resistance and tumor recurrence. Implications: Characterization of ALDH+ DIPGs coupled with targeting MAPK/PI3K/mTOR signaling provides an impetus for molecularly targeted therapy aimed at addressing the CSC phenotype in DIPG.

DOI: https://doi.org/10.1158/1541-7786.MCR-20-0464
Cancers (Basel). 2020 Oct 22. pii: E3080. [Epub ahead of print]12(11):

A Preliminary Study on Machine Learning-Based Evaluation of Static and Dynamic FET-PET for the Detection of Pseudoprogression in Patients with IDH-Wildtype Glioblastoma.

Sied Kebir, Teresa Schmidt, Matthias Weber, Lazaros Lazaridis, Norbert Galldiks, Karl-Josef Langen, Christoph Kleinschnitz, Elke Hattingen, Ulrich Herrlinger, Philipp Lohmann, Martin Glas.

  Pseudoprogression (PSP) detection in glioblastoma remains challenging and has important clinical implications. We investigated the potential of machine learning (ML) in improving the performance of PET using O-(2-[18F]-fluoroethyl)-L-tyrosine (FET) for differentiation of tumor progression from PSP in IDH-wildtype glioblastoma. We retrospectively evaluated the PET data of patients with newly diagnosed IDH-wildtype glioblastoma following chemoradiation. Contrast-enhanced MRI suspected PSP/TP and all patients underwent subsequently an additional dynamic FET-PET scan. The modified Response Assessment in Neuro-Oncology (RANO) criteria served to diagnose PSP. We trained a Linear Discriminant Analysis (LDA)-based classifier using FET-PET derived features on a hold-out validation set. The results of the ML model were compared with a conventional FET-PET analysis using the receiver-operating-characteristic (ROC) curve. Of the 44 patients included in this preliminary study, 14 patients were diagnosed with PSP. The mean (TBRmean) and maximum tumor-to-brain ratios (TBRmax) were significantly higher in the TP group as compared to the PSP group (p = 0.014 and p = 0.033, respectively). The area under the ROC curve (AUC) for TBRmax and TBRmean was 0.68 and 0.74, respectively. Using the LDA-based algorithm, the AUC (0.93) was significantly higher than the AUC for TBRmax. This preliminary study shows that in IDH-wildtype glioblastoma, ML-based PSP detection leads to better diagnostic performance.

Keywords:  amino acid PET; artificial intelligence; glioma; treatment-related changes; tumor progression

DOI:  https://doi.org/10.3390/cancers12113080
Neuro Oncol. 2020 Oct 30. pii: noaa238. [Epub ahead of print]

Brain exposure of the ATM inhibitor AZD1390 in humans - a positron emission tomography (PET) study.

Aurelija Jucaite, Per Stenkrona, Zsolt Cselényi, Serena De Vita, Nuria Buil-Bruna, Katarina Varnäs, Alicia Savage, Andrea Varrone, Peter Johnström, Magnus Schou, Chris Davison, Andy Sykes, Venkatesh Pilla Reddy, Matthias Hoch, Ana Vazquez-Romero, Mohammad Mahdi Moein, Christer Halldin, Melinda S Merchant, Martin Pass, Lars Farde.

   BACKGROUND: The protein kinase ATM (ataxia telangiectasia mutated) mediates cellular response to DNA damage induced by radiation. ATM inhibition decreases DNA damage repair in tumor cells and affects tumor growth. AZD1390 is a novel, highly potent, selective ATM inhibitor designed to cross the blood-brain barrier (BBB) and currently evaluated with radiotherapy in a Phase 1 study in patients with brain malignancies. In the present study, PET was used to measure brain exposure of 11C-labelled AZD1390 after intravenous (i.v.) bolus administration in healthy subjects with an intact BBB.
METHODS: AZD1390 was radiolabeled with carbon-11 and a microdose (mean injected mass 1.21µg) was injected in 8 male subjects (21-65 years). The radioactivity concentration of [ 11C]AZD1390 in brain was measured using a high-resolution PET system. Radioactivity in arterial blood was measured to obtain a metabolite corrected arterial input function for quantitative image analysis. Participants were monitored by laboratory examinations, vital signs, ECG, adverse events (AEs).
RESULTS: The brain radioactivity concentration of [ 11C]AZD1390 was 0.64 SUV (standard uptake value) and reached maximum 1.00 %ID (percent of injected dose) at Tmax[brain] of 21 min (time of maximum brain radioactivity concentration) after i.v. injection. The whole brain total distribution volume was 5.20 mL*cm -3. No AEs related to [ 11C]AZD1390 were reported.
CONCLUSIONS: This study demonstrates that [ 11C]AZD1390 crosses the intact BBB and supports development of AZD1390 for the treatment of glioblastoma multiforme (GBM) or other brain malignancies. Moreover, it illustrates the potential of PET microdosing in predicting and guiding dose range and schedule for subsequent clinical studies.

Keywords:  AZD1390; ataxia telangiectasia mutated; blood-brain barrier; glioblastoma; positron emission tomography

DOI:  https://doi.org/10.1093/neuonc/noaa238
iScience. 2020 Oct 23. 23(10): 101633

Organotypic Models to Study Human Glioblastoma: Studying the Beast in Its Ecosystem.

David Pamies, Marie-Gabrielle Zurich, Thomas Hartung.

  Glioblastoma is a very aggressive primary brain tumor in adults, with very low survival rates and no curative treatments. The high failure rate of drug development for this cancer is linked to the high-cost, time-consuming, and inefficient models used to study the disease. Advances in stem cell and in vitro cultures technologies are promising, however, and here we present the advantages and limitations of available organotypic culture models and discuss their possible applications for studying glioblastoma.

Keywords:  Bioengineering; Cancer; Clinical Neuroscience; Tissue Engineering

DOI:  https://doi.org/10.1016/j.isci.2020.101633
Med Phys. 2020 Oct 28.

Reproducibility analysis of multi-institutional paired expert annotations and radiomic features of the Ivy Glioblastoma Atlas Project (Ivy GAP) dataset.

Sarthak Pati, Ruchika Verma, Hamed Akbari, Michel Bilello, Virginia B Hill, Chiharu Sako, Ramon Correa, Niha Beig, Ludovic Venet, Siddhesh Thakur, Prashant Serai, Sung Min Ha, Geri D Blake, Russell Taki Shinohara, Pallavi Tiwari, Spyridon Bakas.

PURPOSE: The availability of radiographic MRI scans for the Ivy Glioblastoma Atlas Project (Ivy GAP) has opened up opportunities for development of radiomic markers for prognostic/predictive applications in Glioblastoma (GBM). In this work, we address two critical challenges with regard to developing robust radiomic approaches: (1) the lack of availability of reliable segmentation labels for GBM tumor sub-compartments (i.e., enhancing tumor, non-enhancing tumor core, peritumoral edematous/infiltrated tissue), and (2) identifying \reproducible" radiomic features that are robust to segmentation variability across readers/sites.
ACQUISITION AND VALIDATION METHODS: From TCIA's Ivy GAP cohort, we obtained a paired set (n=31) of expert annotations approved by two board-certified neuro-radiologists at the Hospital of the University of Pennsylvania (UPenn) and at CaseWestern Reserve University (CWRU). For these studies, we performed a reproducibility study that assessed the variability in (a) segmentation labels, and (b) radiomic features, between these paired annotations. The radiomic variability was assessed on a comprehensive panel of 11,700 radiomic features including intensity, volumetric, morphologic, histogram-based, and textural parameters, extracted for each of the paired sets of annotations. Our results demonstrated (a) a high level of inter-rater agreement (median value of DICE ≥ 0:8 for all sub-compartments), and (b) ≈ 24% of the extracted radiomic features being highly correlated (based on Spearman's rank correlation coefficient) to annotation variations. These robust features largely belonged to morphology (describing shape characteristics), intensity (capturing intensity profile statistics), and COLLAGE (capturing heterogeneity in gradient orientations) feature families.
DATA FORMAT AND USAGE NOTES: We make publicly available on TCIA's Analysis Results Directory, the complete set of (a) multi-institutional expert annotations for the tumor sub-compartments, (b) 11,700 radiomic features, and (c) the associated reproducibility meta-analysis.
POTENTIAL APPLICATIONS: The annotations and the associated meta-data for Ivy GAP is released with the purpose of enabling researchers towards developing image-based biomarkers for prognostic/predictive applications in GBM.

DOI: https://doi.org/10.1002/mp.14556
Nat Rev Drug Discov. 2020 Oct 27.

Immunocytokines turn up the heat in glioblastoma.

M Teresa Villanueva.



Keywords:  Biotechnology; Cancer; Drug discovery; Immunology; Therapeutics

DOI:  https://doi.org/10.1038/d41573-020-00188-9