bims-malgli 2022-11-20 papers

bims-malgli

Biomed News

on Biology of malignant gliomas

Issue of 2022–11–20
twenty papers selected by
Oltea Sampetrean, Keio University

Clinical utility of plasma cell-free DNA in gliomas.
RAGE Ablation Attenuates Glioma Progression and Enhances Tumor Immune Responses by Suppressing Galectin-3 Expression.
SLFN11 negatively regulates non-canonical NFkB signaling to promote glioblastoma progression.
The diagnostic and prognostic potential of the EGFR/MUC4/MMP9 axis in glioma patients.
Noninvasive approaches to detect methylation-based markers to monitor gliomas.
Superenhancer-activation of KLHDC8A drives glioma ciliation and hedgehog signaling.
Advances in molecular biomarkers and liquid biopsy in gliomas.
Single-cell image analysis reveals over-expression of organic anion transporting polypeptides (OATPs) in human glioblastoma tissue.
STINGing the immune system: lessons learned through a model of G34-mutant pediatric high-grade glioma.
Phase I dose escalation and expansion trial of single agent ONC201 in pediatric diffuse midline gliomas following radiotherapy.
Decoding vesicle-based precision oncology in gliomas.
Transmembrane water-efflux rate measured by magnetic resonance imaging as a biomarker of the expression of aquaporin-4 in gliomas.
Leveraging the CSF proteome toward minimally-invasive diagnostics surveillance of brain malignancies.
Revealing de novo pyrimidine synthesis as a key vulnerability in brain tumors.
Hypoxia-induced circADAMTS6 in a TDP43-dependent manner accelerates glioblastoma progression via ANXA2/ NF-κB pathway.
Association of Autologous Tumor Lysate-Loaded Dendritic Cell Vaccination With Extension of Survival Among Patients With Newly Diagnosed and Recurrent Glioblastoma: A Phase 3 Prospective Externally Controlled Cohort Trial.
Circulating tumor cells and extracellular vesicles as liquid biopsy markers in neuro-oncology: prospects and limitations.
Neuro-oncology at the American Society for Clinical Oncology 2022 Annual Meeting.
An armed oncolytic virus for GBM Destruction.
Tapping into the genome: the role of CSF ctDNA liquid biopsy in glioma.

Neurooncol Adv. 2022 Nov;4(Suppl 2): ii41-ii44

Clinical utility of plasma cell-free DNA in gliomas.

Erica L Carpenter, Stephen J Bagley.

  Noninvasive molecular profiling of tumors using plasma-based next-generation sequencing (NGS) is increasingly used to aid in diagnosis, treatment selection, and disease monitoring in oncology. In patients with glioma, however, the plasma cell-free DNA (cfDNA) tumor fraction, defined as the fractional proportion of circulating tumor-derived DNA (ctDNA) relative to total cfDNA, is especially low, in large part due to the blood-brain barrier. As a result, commercial plasma-based NGS assays, designed to screen for a small number of actionable genomic alterations, are not sensitive enough to guide the management of patients with glioma. As this has been long recognized in neuro-oncology, significant research efforts have been undertaken to improve the sensitivity of plasma ctDNA detection in patients with glioma and to understand the biology and clinical relevance of non-tumor-derived cfDNA, which makes up most of the total cfDNA pool. Here, we review key recent advances in the field of plasma cfDNA analysis in patients with glioma, including (1) the prognostic impact of pre-treatment and on-treatment total plasma cfDNA concentrations, (2) use of tumor-guided sequencing approaches to improve the sensitivity of ctDNA detection in the plasma, and (3) the emergence of plasma cfDNA methylomics for detection and discrimination of glioma from other primary intracranial tumors.

Keywords:  DNA methylation; biomarker; cfDNA; glioblastoma; liquid biopsy

DOI:  https://doi.org/10.1093/noajnl/vdac014
Neuro Oncol. 2022 Nov 17. pii: noac250. [Epub ahead of print]

RAGE Ablation Attenuates Glioma Progression and Enhances Tumor Immune Responses by Suppressing Galectin-3 Expression.

Ian Y Zhang, Shunan Liu, Leying Zhang, Rongrui Liang, Qinxiao Fang, Jie Zhao, Lyuzhi Ren, Eric F Medina, Aleksandr Filippov, Kimberley-Jane Bonjoc, Ammar Chaudhry, Mojtaba Dayyani, Andrea H Bild, Behnam Badie.

   BACKGROUND: Malignant gliomas consist of heterogenous cellular components that have adopted multiple overlapping escape mechanisms that overcome both targeted and immune-based therapies. The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily that is activated by diverse proinflammatory ligands present in the tumor microenvironment. Activation of RAGE by its ligands stimulates multiple signaling pathways that are important in tumor growth and invasion. However, treatment strategies that only target the interaction of RAGE with its ligands are ineffective as cancer therapies due to the abundance and diversity of exogenous RAGE ligands in gliomas.
METHODS: As an alternative approach to RAGE ligand inhibition, we evaluated genetic ablation of RAGE on the tumorigenicity of two syngeneic murine glioma models. RAGE expression was inhibited in the GL261 and K-Luc gliomas by shRNA and CRSPR/Cas9 techniques prior to intracranial implantation. Tumor growth, invasion, and inflammatory responses were examined by histology, survival, Nanostring, and flow cytometry.
RESULTS: Intracellular RAGE ablation abrogated glioma growth and invasion by suppressing AKT and ERK1/2 activities and by downregulating MMP9 expression. Interestingly, RAGE inhibition in both glioma models enhanced tumor inflammatory responses by downregulating the expression of galectin-3 and potentiated immunotherapy responses to immune checkpoint blockade.
CONCLUSIONS: We demonstrated that intracellular RAGE ablation suppresses multiple cellular pathways that are important in glioma progression, invasion, and immune escape. These findings strongly support the development of RAGE ablation as a treatment strategy for malignant gliomas.

Keywords:  Brain tumor; Glioblastoma; Macrophage; Microglia

DOI:  https://doi.org/10.1093/neuonc/noac250
Cancer Res Commun. 2022 Sep;2(9): 966-978

SLFN11 negatively regulates non-canonical NFkB signaling to promote glioblastoma progression.

Mariafausta Fischietti, Frank Eckerdt, Ricardo E Perez, Jamie N Guillen Magaña, Candice Mazewski, Sang Ho, Christopher Gonzalez, Lukas D Streich, Elspeth M Beauchamp, Amy B Heimberger, Aneta H Baran, Feng Yue, C David James, Leonidas C Platanias.

  Glioblastoma (GBM) is an aggressive and incurable brain tumor in nearly all instances, whose disease progression is driven in part by the glioma stem cell (GSC) subpopulation. Here, we explored the effects of Schlafen family member 11 (SLFN11) in the molecular, cellular and tumor biology of GBM. CRISPR/Cas9 mediated knockout (KO) of SLFN11 inhibited GBM cell proliferation and neurosphere growth and was associated with reduced expression of progenitor/stem cell marker genes, such as NES, SOX2 and CD44. Loss of SLFN11 stimulated expression of NF-κB target genes, consistent with a negative regulatory role for SLFN11 on the NF-κB pathway. Further, our studies identify p21 as a direct transcriptional target of NF-κB2 in GBM whose expression was stimulated by loss of SLFN11. Genetic disruption of SLFN11 blocked GBM growth and significantly extended survival in an orthotopic patient-derived xenograft model. Together, our results identify SLFN11 as a novel component of signaling pathways that contribute to GBM and GSC with implications for future diagnostic and therapeutic strategies.

Keywords:  CDKN1A/p21; Glioblastoma (GBM); Schlafen 11 (SLFN11); glioma stem cell (GSC); nuclear factor-κB (NF-κB)

DOI:  https://doi.org/10.1158/2767-9764.crc-22-0192
Sci Rep. 2022 Nov 18. 12(1): 19868

The diagnostic and prognostic potential of the EGFR/MUC4/MMP9 axis in glioma patients.

Agathe Quesnel, Nathan Coles, Tuomo M Polvikoski, George S Karagiannis, Claudio Angione, Meez Islam, Ahmad A Khundakar, Panagiota S Filippou.

Glioblastoma is the most aggressive form of brain cancer, presenting poor prognosis despite current advances in treatment. There is therefore an urgent need for novel biomarkers and therapeutic targets. Interactions between mucin 4 (MUC4) and the epidermal growth factor receptor (EGFR) are involved in carcinogenesis, and may lead to matrix metalloproteinase-9 (MMP9) overexpression, exacerbating cancer cell invasiveness. In this study, the role of MUC4, MMP9, and EGFR in the progression and clinical outcome of glioma patients was investigated. Immunohistochemistry (IHC) and immunofluorescence (IF) in fixed tissue samples of glioma patients were used to evaluate the expression and localization of EGFR, MMP9, and MUC4. Kaplan-Meier survival analysis was also performed to test the prognostic utility of the proteins for glioma patients. The protein levels were assessed with enzyme-linked immunosorbent assay (ELISA) in serum of glioma patients, to further investigate their potential as non-invasive serum biomarkers. We demonstrated that MUC4 and MMP9 are both significantly upregulated during glioma progression. Moreover, MUC4 is co-expressed with MMP9 and EGFR in the proliferative microvasculature of glioblastoma, suggesting a potential role for MUC4 in microvascular proliferation and angiogenesis. The combined high expression of MUC4/MMP9, and MUC4/MMP9/EGFR was associated with poor overall survival (OS). Finally, MMP9 mean protein level was significantly higher in the serum of glioblastoma compared with grade III glioma patients, whereas MUC4 mean protein level was minimally elevated in higher glioma grades (III and IV) compared with control. Our results suggest that MUC4, along with MMP9, might account for glioblastoma progression, representing potential therapeutic targets, and suggesting the 'MUC4/MMP9/EGFR axis' may play a vital role in glioblastoma diagnostics.

DOI: https://doi.org/10.1038/s41598-022-24099-4
Neurooncol Adv. 2022 Nov;4(Suppl 2): ii22-ii32

Noninvasive approaches to detect methylation-based markers to monitor gliomas.

Houtan Noushmehr, Grayson Herrgott, Natalia S Morosini, Ana Valeria Castro.

  In this review, we summarize the current approaches used to detect glioma tissue-derived DNA methylation markers in liquid biopsy specimens with the aim to diagnose, prognosticate and potentially track treatment response and evolution of patients with gliomas.

Keywords:  epigenetics; glioma; liquid biopsy; machine-learning; non-invasive biomarkers

DOI:  https://doi.org/10.1093/noajnl/vdac021
J Clin Invest. 2022 Nov 17. pii: e163592. [Epub ahead of print]

Superenhancer-activation of KLHDC8A drives glioma ciliation and hedgehog signaling.

Derrick Lee, Ryan C Gimple, Xujia Wu, Briana C Prager, Zhixin Qiu, Qiulian Wu, Vikas Daggubati, Aruljothi Mariappan, Jay Gopalakrishnan, Matthew R Sarkisian, David R Raleigh, Jeremy N Rich.

  Glioblastoma ranks among the most aggressive and lethal of all human cancers. Self-renewing, highly tumorigenic glioblastoma stem cells (GSCs) contribute to therapeutic resistance and maintain cellular heterogeneity. Here, we interrogated superenhancer landscapes of primary glioblastoma specimens and patient-derived GSCs, revealing a kelch domain-containing gene (KLHDC8A) with a previously unknown function as an epigenetically-driven oncogene. Targeting KLHDC8A decreased GSC proliferation and self-renewal, induced apoptosis, and impaired in vivo tumor growth. Transcription factor control circuitry analyses revealed that the master transcriptional regulator SOX2 stimulated KLHDC8A expression. Mechanistically, KLHDC8A bound Chaperonin-Containing TCP1 (CCT) to promote assembly of primary cilia to activate Hedgehog signaling. KLHDC8A expression correlated with Aurora B/C Kinase inhibitor activity, which induced primary cilia and Hedgehog signaling. Combinatorial targeting of Aurora B/C Kinase and Hedgehog displayed augmented benefit against GSC proliferation. Collectively, superenhancer-based discovery revealed KLHDC8A as a novel molecular target of cancer stem cells that promotes ciliogenesis to activate the Hedgehog pathway, offering insights into therapeutic vulnerabilities for glioblastoma treatment.

Keywords:  Cancer; Oncology; Stem cells

DOI:  https://doi.org/10.1172/JCI163592
Neurooncol Adv. 2022 Nov;4(Suppl 2): ii15-ii21

Advances in molecular biomarkers and liquid biopsy in gliomas.

Dimitrios Mathios, Jillian Phallen.

  There have been significant strides toward understanding the molecular landscape of brain cancer. These advances have been focused on analyses of the tumor microenvironment and have recently expanded to include liquid biopsies to identify molecular biomarkers noninvasively. Moving from tissue to liquid-based analyses of molecular biomarkers has been challenging and currently, there are no approved noninvasive tests that are clinically useful. However, the emerging field of molecular liquid biopsy assay development in the neuro-oncology space has great potential to revolutionize the detection and monitoring of patients with brain cancer.

Keywords:  circulating biomarker; circulating tumor DNA; glioblastoma; liquid biopsy

DOI:  https://doi.org/10.1093/noajnl/vdac151
Neurooncol Adv. 2022 Jan-Dec;4(1):4(1): vdac166

Single-cell image analysis reveals over-expression of organic anion transporting polypeptides (OATPs) in human glioblastoma tissue.

Elizabeth Cooper, Zoe Woolf, Molly E V Swanson, Jason Correia, Patrick Schweder, Edward Mee, Peter Heppner, Clinton Turner, Richard L M Faull, Emma L Scotter, William A Denny, Peter J Choi, Mike Dragunow, Jiney Jose, Thomas I-H Park.

   Background: Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. Whilst the role of the efflux transporters are well established in GBM, the expression and function of uptake transporters, such as the organic anion transporting polypeptide (OATP) family, are not well understood. OATPs possess broad substrate specificity that includes anti-cancer agents; therefore, we sought to investigate the expression of four OATP isoforms in human GBM cell types using patient tumor tissue.
Methods: We used fluorescent immunohistochemical labeling of paraffin-embedded surgically resected tissues and single-cell image analysis methods to explore the expression of the OATP isoforms in different tumor cell types through co-labeling with cell-type specific markers, such as IBA1 (pan-myeloid), GFAP (tumor cell), PDGFRβ (stromal cell), and UEA-1-lectin (endothelial).
Results: We found significant over-expression of all the OATP isoforms (OATP1A2, 2B1, 1C1 and 4A1) in GBM tumor sections when compared to non-neoplastic brain. A single-cell image analysis revealed that OATPs were significantly upregulated throughout the tumor parenchyma, with significantly higher expression found on lectin-positive blood vessels and IBA1-positive myeloid cells in GBM compared to non-tumor brain tissue. Qualitative analysis of the four OATP isoforms demonstrated greater expression of OATP4A1 in peri-necrotic regions of GBM tissue, which correlated with hypoxia-related markers within the Ivy GAP RNAseq dataset.
Conclusion: Here, we demonstrate, for the first time, the protein expression of four OATPs in human GBM tissue, including upregulation within the tumor microenvironment by myeloid cells and tumor vasculature, and isoform-specific upregulation within hypoxic niches.

Keywords:  OATP; glioblastoma; organic anion transporting polypeptides; tumor microenvironment

DOI:  https://doi.org/10.1093/noajnl/vdac166
J Clin Invest. 2022 Nov 15. pii: e164420. [Epub ahead of print]132(22):

STINGing the immune system: lessons learned through a model of G34-mutant pediatric high-grade glioma.

Connor P Hall, James C Cronk, Jeffrey A Rubens.

Pediatric high-grade gliomas (pHGGs) are aggressive diseases with poor outcomes. The diverse molecular heterogeneity in these rare tumors and inadequate tumor models have limited the development of effective therapies. In this issue of the JCI, Haase et al. produced a genetically engineered mouse model of H3.3-G34R-mutant pHGG to help identify vulnerabilities in DNA repair pathways. The authors designed a therapy that combined radiation with DNA damage response inhibitors to induce an adaptive immune response and extend survival. These findings suggest that combinations of small-molecule therapies with immunotherapies could drive a more durable response and improve mortality for patients with pHGG.

DOI: https://doi.org/10.1172/JCI164420
Neurooncol Adv. 2022 Jan-Dec;4(1):4(1): vdac143

Phase I dose escalation and expansion trial of single agent ONC201 in pediatric diffuse midline gliomas following radiotherapy.

Sharon L Gardner, Rohinton S Tarapore, Jeffrey Allen, Susan L McGovern, Wafik Zaky, Yazmin Odia, Doured Daghistani, Zuanel Diaz, Matthew D Hall, Ziad Khatib, Carl Koschmann, Evan Cantor, Ryo Kurokawa, Tobey J MacDonald, Dolly Aguilera, Nicholas A Vitanza, Sabine Mueller, Cassie Kline, Guangrong Lu, Joshua E Allen, Soumen Khatua.

 Background: ONC201, a dopamine receptor D2 (DRD2) antagonist and caseinolytic protease P (ClpP) agonist, has induced durable tumor regressions in adults with recurrent H3 K27M-mutant glioma. We report results from the first phase I pediatric clinical trial of ONC201.
Methods: This open-label, multi-center clinical trial (NCT03416530) of ONC201 for pediatric H3 K27M-mutant diffuse midline glioma (DMG) or diffuse intrinsic pontine glioma (DIPG) employed a dose-escalation and dose-expansion design. The primary endpoint was the recommended phase II dose (RP2D). A standard 3 + 3 dose escalation design was implemented. The target dose was the previously established adult RP2D (625 mg), scaled by body weight. Twenty-two pediatric patients with DMG/DIPG were treated following radiation; prior lines of systemic therapy in addition to radiation were permitted providing sufficient time had elapsed prior to study treatment.
Results: The RP2D of orally administered ONC201 in this pediatric population was determined to be the adult RP2D (625 mg), scaled by body weight; no dose-limiting toxicities (DLT) occurred. The most frequent treatment-emergent Grade 1-2 AEs were headache, nausea, vomiting, dizziness and increase in alanine aminotransferase. Pharmacokinetics were determined following the first dose: T 1/2, 8.4 h; T max, 2.1 h; C max, 2.3 µg/mL; AUC0-tlast, 16.4 hµg/mL. Median duration of treatment was 20.6 weeks (range 5.1-129). Five (22.7%) patients, all of whom initiated ONC201 following radiation and prior to recurrence, were alive at 2 years from diagnosis.
Conclusions: The adult 625 mg weekly RP2D of ONC201 scaled by body weight was well tolerated. Further investigation of ONC201 for DMG/DIPG is warranted.

Keywords: H3 K27M-mutant glioma (DMG); ONC201; diffuse intrinsic pontine glioma (DIPG); diffuse midline glioma

DOI: https://doi.org/10.1093/noajnl/vdac143
Neurooncol Adv. 2022 Nov;4(Suppl 2): ii53-ii60

Decoding vesicle-based precision oncology in gliomas.

Syeda Maheen Batool, Tiffaney Hsia, Sirena K Khanna, Austin S Gamblin, Yulia Rosenfeld, Dong Gil You, Bob S Carter, Leonora Balaj.

  Extracellular vesicles (EVs) represent a valuable tool in liquid biopsy with tremendous clinical potential in diagnosis, prognosis, and therapeutic monitoring of gliomas. Compared to tissue biopsy, EV-based liquid biopsy is a low-cost, minimally invasive method that can provide information on tumor dynamics before, during, and after treatment. Tumor-derived EVs circulating in biofluids carry a complex cargo of molecular biomarkers, including DNA, RNA, and proteins, which can be indicative of tumor growth and progression. Here, we briefly review current commercial and noncommercial methods for the isolation, quantification, and biochemical characterization of plasma EVs from patients with glioma, touching on whole EV analysis, mutation detection techniques, and genomic and proteomic profiling. We review notable advantages and disadvantages of plasma EV isolation and analytical methods, and we conclude with a discussion on clinical translational opportunities and key challenges associated with the future implementation of EV-based liquid biopsy for glioma treatment.

Keywords:  extracellular vesicles; glioma; liquid biopsy; plasma

DOI:  https://doi.org/10.1093/noajnl/vdac035
Nat Biomed Eng. 2022 Nov 14.

Transmembrane water-efflux rate measured by magnetic resonance imaging as a biomarker of the expression of aquaporin-4 in gliomas.

Yinhang Jia, Shangchen Xu, Guangxu Han, Bao Wang, Zejun Wang, Chuanjin Lan, Peng Zhao, Meng Gao, Yi Zhang, Wenhong Jiang, Biying Qiu, Rui Liu, Yi-Cheng Hsu, Yi Sun, Chong Liu, Yingchao Liu, Ruiliang Bai.

The water-selective channel protein aquaporin-4 (AQP4) contributes to the migration and proliferation of gliomas, and to their resistance to therapy. Here we show, in glioma cell cultures, in subcutaneous and orthotopic gliomas in rats, and in glioma tumours in patients, that transmembrane water-efflux rate is a sensitive biomarker of AQP4 expression and can be measured via conventional dynamic-contrast-enhanced magnetic resonance imaging. Water-efflux rates correlated with stages of glioma proliferation as well as with changes in the heterogeneity of intra-tumoural and inter-tumoural AQP4 in rodent and human gliomas following treatment with temozolomide and with the AQP4 inhibitor TGN020. Regions with low water-efflux rates contained higher fractions of stem-like slow-cycling cells and therapy-resistant cells, suggesting that maps of water-efflux rates could be used to identify gliomas that are resistant to therapies.

DOI: https://doi.org/10.1038/s41551-022-00960-9
Neurooncol Adv. 2022 Jan-Dec;4(1):4(1): vdac161

Leveraging the CSF proteome toward minimally-invasive diagnostics surveillance of brain malignancies.

Nicholas Mikolajewicz, Shahbaz Khan, Mara Trifoi, Anna Skakdoub, Vladmir Ignatchenko, Sheila Mansouri, Jeffrey Zuccatto, Brad E Zacharia, Michael Glantz, Gelareh Zadeh, Jason Moffat, Thomas Kislinger, Alireza Mansouri.

   Background: Diagnosis and prognostication of intra-axial brain tumors hinges on invasive brain sampling, which carries risk of morbidity. Minimally-invasive sampling of proximal fluids, also known as liquid biopsy, can mitigate this risk. Our objective was to identify diagnostic and prognostic cerebrospinal fluid (CSF) proteomic signatures in glioblastoma (GBM), brain metastases (BM), and primary central nervous system lymphoma (CNSL).
Methods: CSF samples were retrospectively retrieved from the Penn State Neuroscience Biorepository and profiled using shotgun proteomics. Proteomic signatures were identified using machine learning classifiers and survival analyses.
Results: Using 30 µL CSF volumes, we recovered 755 unique proteins across 73 samples. Proteomic-based classifiers identified malignancy with area under the receiver operating characteristic (AUROC) of 0.94 and distinguished between tumor entities with AUROC ≥0.95. More clinically relevant triplex classifiers, comprised of just three proteins, distinguished between tumor entities with AUROC of 0.75-0.89. Novel biomarkers were identified, including GAP43, TFF3 and CACNA2D2, and characterized using single cell RNA sequencing. Survival analyses validated previously implicated prognostic signatures, including blood-brain barrier disruption.
Conclusions: Reliable classification of intra-axial malignancies using low CSF volumes is feasible, allowing for longitudinal tumor surveillance.

Keywords:  biomarkers; brain metastasis; cerebrospinal fluid; disease surveillance; glioblastoma

DOI:  https://doi.org/10.1093/noajnl/vdac161
Cancer Cell. 2022 Nov 09. pii: S1535-6108(22)00520-7. [Epub ahead of print]

Revealing de novo pyrimidine synthesis as a key vulnerability in brain tumors.

Tanya Schild, Kayvan R Keshari.

Brain tumors are notoriously difficult to treat. Three recent Cancer Cell articles aim to uncover novel druggable targets in IDH mutant gliomas, diffuse midline gliomas, and medulloblastomas, respectively, and show that these brain tumor types shift their metabolism to become reliant on de novo pyrimidine synthesis.

DOI: https://doi.org/10.1016/j.ccell.2022.10.023
Oncogene. 2022 Nov 17.

Hypoxia-induced circADAMTS6 in a TDP43-dependent manner accelerates glioblastoma progression via ANXA2/ NF-κB pathway.

Shulin Zhao, Boyan Li, Rongrong Zhao, Ziwen Pan, Shouji Zhang, Wei Qiu, Qindong Guo, Yanhua Qi, Zijie Gao, Yang Fan, Hao Xu, Ming Li, Jian Zhang, Huizhi Wang, Jianye Xu, Shaobo Wang, Qingtong Wang, Jiawei Qiu, Lin Deng, Xing Guo, Ping Zhang, Hao Xue, Gang Li.

Circular RNAs (circRNAs) play important roles in the malignant progression of tumours. Herein, we identified an unreported circRNA (hsa-circ-0072688, also named circADAMTS6) that is specifically upregulated in the hypoxic microenvironment of glioblastoma and closely correlated with poor prognosis of gliblastoma patients. We found that circADAMTS6 promotes the malignant progression of glioblastoma by promoting cell proliferation and inhibiting apoptosis. Mechanistically, the hypoxic tumour microenvironment upregulates circADAMTS6 expression through transcription factor activator protein 1 (AP-1) and RNA-binding protein TAR DNA-binding protein 43 (TDP43). Moreover, circADAMTS6 accelerates glioblastoma progression by recruiting and stabilising annexin A2 (ANXA2) in a proteasomes-dependent manner. Furthermore, we found T-5224 (AP-1 inhibitor) treatment induces downregulation of circADAMTS6 and then inhibits tumour growth. In conclusion, our findings highlight the important role of the circADAMTS6/ANXA2 axis based on hypoxic microenvironment in glioblastoma progression, as well as its regulation in NF-κB pathway. Targeting circADAMTS6 is thus expected to become a novel therapeutic strategy for glioblastoma.

DOI: https://doi.org/10.1038/s41388-022-02542-0
JAMA Oncol. 2022 Nov 17.

Association of Autologous Tumor Lysate-Loaded Dendritic Cell Vaccination With Extension of Survival Among Patients With Newly Diagnosed and Recurrent Glioblastoma: A Phase 3 Prospective Externally Controlled Cohort Trial.

Linda M Liau, Keyoumars Ashkan, Steven Brem, Jian L Campian, John E Trusheim, Fabio M Iwamoto, David D Tran, George Ansstas, Charles S Cobbs, Jason A Heth, Michael E Salacz, Stacy D'Andre, Robert D Aiken, Yaron A Moshel, Joo Y Nam, Clement P Pillainayagam, Stephanie A Wagner, Kevin A Walter, Rekha Chaudary, Samuel A Goldlust, Ian Y Lee, Daniela A Bota, Heinrich Elinzano, Jai Grewal, Kevin Lillehei, Tom Mikkelsen, Tobias Walbert, Steven Abram, Andrew J Brenner, Matthew G Ewend, Simon Khagi, Darren S Lovick, Jana Portnow, Lyndon Kim, William G Loudon, Nina L Martinez, Reid C Thompson, David E Avigan, Karen L Fink, Francois J Geoffroy, Pierre Giglio, Oleg Gligich, Dietmar Krex, Scott M Lindhorst, Jose Lutzky, Hans-Jörg Meisel, Minou Nadji-Ohl, Lhagva Sanchin, Andrew Sloan, Lynne P Taylor, Julian K Wu, Erin M Dunbar, Arnold B Etame, Santosh Kesari, David Mathieu, David E Piccioni, David S Baskin, Michel Lacroix, Sven-Axel May, Pamela Z New, Timothy J Pluard, Steven A Toms, Victor Tse, Scott Peak, John L Villano, James D Battiste, Paul J Mulholland, Michael L Pearlman, Kevin Petrecca, Michael Schulder, Robert M Prins, Alton L Boynton, Marnix L Bosch.

Importance: Glioblastoma is the most lethal primary brain cancer. Clinical outcomes for glioblastoma remain poor, and new treatments are needed.
Objective: To investigate whether adding autologous tumor lysate-loaded dendritic cell vaccine (DCVax-L) to standard of care (SOC) extends survival among patients with glioblastoma.
Design, Setting, and Participants: This phase 3, prospective, externally controlled nonrandomized trial compared overall survival (OS) in patients with newly diagnosed glioblastoma (nGBM) and recurrent glioblastoma (rGBM) treated with DCVax-L plus SOC vs contemporaneous matched external control patients treated with SOC. This international, multicenter trial was conducted at 94 sites in 4 countries from August 2007 to November 2015. Data analysis was conducted from October 2020 to September 2021.
Interventions: The active treatment was DCVax-L plus SOC temozolomide. The nGBM external control patients received SOC temozolomide and placebo; the rGBM external controls received approved rGBM therapies.
Main Outcomes and Measures: The primary and secondary end points compared overall survival (OS) in nGBM and rGBM, respectively, with contemporaneous matched external control populations from the control groups of other formal randomized clinical trials.
Results: A total of 331 patients were enrolled in the trial, with 232 randomized to the DCVax-L group and 99 to the placebo group. Median OS (mOS) for the 232 patients with nGBM receiving DCVax-L was 19.3 (95% CI, 17.5-21.3) months from randomization (22.4 months from surgery) vs 16.5 (95% CI, 16.0-17.5) months from randomization in control patients (HR = 0.80; 98% CI, 0.00-0.94; P = .002). Survival at 48 months from randomization was 15.7% vs 9.9%, and at 60 months, it was 13.0% vs 5.7%. For 64 patients with rGBM receiving DCVax-L, mOS was 13.2 (95% CI, 9.7-16.8) months from relapse vs 7.8 (95% CI, 7.2-8.2) months among control patients (HR, 0.58; 98% CI, 0.00-0.76; P < .001). Survival at 24 and 30 months after recurrence was 20.7% vs 9.6% and 11.1% vs 5.1%, respectively. Survival was improved in patients with nGBM with methylated MGMT receiving DCVax-L compared with external control patients (HR, 0.74; 98% CI, 0.55-1.00; P = .03).
Conclusions and Relevance: In this study, adding DCVax-L to SOC resulted in clinically meaningful and statistically significant extension of survival for patients with both nGBM and rGBM compared with contemporaneous, matched external controls who received SOC alone.
Trial Registration: ClinicalTrials.gov Identifier: NCT00045968.

DOI: https://doi.org/10.1001/jamaoncol.2022.5370
Neurooncol Adv. 2022 Nov;4(Suppl 2): ii45-ii52

Circulating tumor cells and extracellular vesicles as liquid biopsy markers in neuro-oncology: prospects and limitations.

Manfred Westphal, Klaus Pantel, Franz L Ricklefs, Cecile Maire, Sabine Riethdorf, Malte Mohme, Harriet Wikman, Katrin Lamszus.

  For many tumor entities, tumor biology and response to therapy are reflected by components that can be detected and captured in the blood stream. The so called "liquid biopsy" has been stratified over time into the analysis of circulating tumor cells (CTC), extracellular vesicles (EVs), and free circulating components such as cell-free nucleic acids or proteins. In neuro-oncology, two distinct areas need to be distinguished, intrinsic brain tumors and tumors metastatic to the brain. For intrinsic brain tumors, specifically glioblastoma, CTCs although present in low abundance, contain highly relevant, yet likely incomplete biological information for the whole tumor. For brain metastases, CTCs can have clinical relevance for patients especially with oligometastatic disease and brain metastasis in cancers like breast and lung cancer. EVs shed from the tumor cells and the tumor environment provide complementary information. Sensitive technologies have become available that are able to detect both, CTCs and EVs in the peripheral blood of patients with intrinsic and metastatic brain tumors despite the blood brain barrier. In reference to glioblastoma EVs, being shed by tumor cells and microenvironment and being more diffusible than CTCs may yield a more complete reflection of the whole tumor compared to low-abundance CTCs representing only a fraction of the multiclonal tumor heterogeneity. We here review the emerging aspects of CTCs and EVs as liquid biopsy biomarkers in neuro-oncology.

Keywords:  brain metastasis; glioblastoma

DOI:  https://doi.org/10.1093/noajnl/vdac015
Neurooncol Pract. 2022 Dec;9(6): 552-558

Neuro-oncology at the American Society for Clinical Oncology 2022 Annual Meeting.

Rimas V Lukas, Steven J Chmura, Ian F Parney, Aaron Mammoser, Sonali M Smith, Jing Li.

  In the following brief report, we highlight the advances in the neuro-oncology space from the ASCO 2022 Annual Meeting. We put into context the phase 2 and 3 trials and how these may alter the standard of care going forward. In addition, we highlight some other earlier work that will lead to future and potentially practice-changing trials.

Keywords:  brain metastases; glioblastoma; glioma; leptomeningeal metastases; meeting report; neuro-oncology

DOI:  https://doi.org/10.1093/nop/npac071
Nat Cancer. 2022 Nov 17.

An armed oncolytic virus for GBM Destruction.

Judit Sanchez Gil, Samuel D Rabkin.

DOI: https://doi.org/10.1038/s43018-022-00457-z
Neurooncol Adv. 2022 Nov;4(Suppl 2): ii33-ii40

Tapping into the genome: the role of CSF ctDNA liquid biopsy in glioma.

Joshua S Friedman, Charli Ann J Hertz, Matthias A Karajannis, Alexandra M Miller.

  Liquid biopsy has emerged as a novel noninvasive tool in cancer diagnostics. While significant strides have been made in other malignancies using liquid biopsy for diagnosis, disease monitoring, and treatment selection, development of these assays has been more challenging for brain tumors. Recently, research in primary and metastatic brain tumors has begun to harness the potential utility of liquid biopsy-particularly using circulating tumor DNA (ctDNA). Initial studies to identify ctDNA in plasma of brain tumor patients have shown feasibility, but the yield of ctDNA is far below that for other malignancies. Attention has therefore turned to the cerebrospinal fluid (CSF) as a more robust source of ctDNA. This review discusses the unique considerations in liquid biopsy for glioma and places them in the context of the work to date. We address the utility of CSF liquid biopsy for diagnosis, longitudinal monitoring, tracking tumor evolution, clinical trial eligibility, and prognostication. We discuss the differences in assay requirements for each clinical application to best optimize factors such as efficacy, cost, and speed. Ultimately, CSF liquid biopsy has the potential to transform how we manage primary brain tumor patients.

Keywords:  cerebrospinal fluid (CSF); circulating tumor DNA (ctDNA); glioma; liquid biopsy; primary brain tumors

DOI:  https://doi.org/10.1093/noajnl/vdac034