bims-malgli 2023-08-06 papers

bims-malgli

Biomed News

on Biology of malignant gliomas

Issue of 2023–08–06
seventeen papers selected by
Oltea Sampetrean, Keio University

Decoding key cell sub-populations and molecular alterations in glioblastoma at recurrence by single-cell analysis.
A comprehensive genomic study of 390 H3F3A-mutant pediatric and adult diffuse high-grade gliomas, CNS WHO grade 4.
HDAC1 and HDAC6 are essential for driving growth in IDH1 mutant glioma.
A Closer Look at the Role of Iron in Glioblastoma.
Favorable prognostic impact of phosphatase and tensin homolog alterations in wild-type isocitrate dehydrogenase and telomerase reverse transcriptase promoter glioblastoma.
TRIB1 confers therapeutic resistance in GBM cells by activating the ERK and Akt pathways.
Depth of radiographic response (DpR) and time to tumor regrowth (TTG) predicts overall survival following anti-VEGF therapy in recurrent glioblastoma.
Early clonal extinction in glioblastoma progression revealed by genetic barcoding.
CARs in the brain: can we tackle glioblastoma with engineered NK cells?
SEC61G assists EGFR-amplified glioblastoma to evade immune elimination.
Multiomics analyses reveal DARS1-AS1/YBX1-controlled posttranscriptional circuits promoting glioblastoma tumorigenesis/radioresistance.
IRP1 mediated ferroptosis reverses temozolomide resistance in glioblastoma via affecting LCN2/FPN1 signaling axis depended on NFKB2.
Combining amino acid PET and MRI imaging increases accuracy to define malignant areas in adult glioma.
IDHwt and IDHmut adult-type diffuse gliomas display distinct alterations in ribosome biogenesis and 2'O-methylation of ribosomal RNA.
A Phase I Trial of Panobinostat in Children with Diffuse Intrinsic Pontine Glioma: A Report from the Pediatric Brain Tumor Consortium (PBTC-047).
Morphological and molecular-biological features of glioblastoma progression in tolerant and susceptible to hypoxia Wistar rats.
Genetically modified IL2 bone-marrow-derived myeloid cells reprogram the glioma immunosuppressive tumor microenvironment.

Acta Neuropathol Commun. 2023 Jul 31. 11(1): 125

Decoding key cell sub-populations and molecular alterations in glioblastoma at recurrence by single-cell analysis.

Xin Wang, Qian Sun, Weiwen Wang, Baohui Liu, Ying Gu, Liang Chen.

  Glioblastoma (GBM) is the most frequent malignant brain tumor, the relapse of which is unavoidable following standard treatment. However, the effective treatment for recurrent GBM is lacking, necessitating the understanding of key mechanisms driving tumor recurrence and the identification of new targets for intervention. Here, we integrated single-cell RNA-sequencing data spanning 36 patient-matched primary and recurrent GBM (pGBM and rGBM) specimens, with 6 longitudinal GBM spatial transcriptomics to explore molecular alterations at recurrence, with each cell type characterized in parallel. Genes involved in extracellular matrix (ECM) organization are preferentially enriched in rGBM cells, and MAFK is highlighted as a potential regulator. Notably, we uncover a unique subpopulation of GBM cells that is much less detected in pGBM and highly expresses ECM and mesenchyme related genes, suggesting it may contribute to the molecular transition of rGBM. Further regulatory network analysis reveals that transcription factors, such as NFATC4 and activator protein 1 members, may function as hub regulators. All non-tumor cells alter their specific sets of genes as well and certain subgroups of myeloid cells appear to be physically associated with the mesenchyme-like GBM subpopulation. Altogether, our study provides new insights into the molecular understanding of GBM relapse and candidate targets for rGBM treatment.

Keywords:  Glioblastoma; MAFK; NFATC4; Recurrence; Tumor microenvironment; scRNA-seq

DOI:  https://doi.org/10.1186/s40478-023-01613-x
Acta Neuropathol. 2023 Jul 31.

A comprehensive genomic study of 390 H3F3A-mutant pediatric and adult diffuse high-grade gliomas, CNS WHO grade 4.

Erik A Williams, Priscilla K Brastianos, Hiroaki Wakimoto, Amir Zolal, Mariella G Filbin, Daniel P Cahill, Sandro Santagata, Tareq A Juratli.

  Malignant brain tumors, known as H3K27-altered diffuse midline glioma (DMG) and H3G34-mutant diffuse hemispheric glioma (DHG), can affect individuals of all ages and are classified as CNS WHO grade 4. We comprehensively characterized 390 H3F3A-mutant diffuse gliomas (201 females, 189 males) arising in pediatric patients (under 20 years old) and adults (20 years and older) evaluated by the CGP program at Foundation Medicine between 2013 and 2020. We assessed information from pathology reports, histopathology review, and clinical data. The cohort included 304 H3K27M-mutant DMG (156 females, 148 males) and 86 H3G34-mutant DHG (45 females, 41 males). Median patient age was 20 years (1-74 years). The frequency of H3K27M-mutant DMG was similar in both pediatric and adult patients in our cohort-48.6% of the patients were over 20 years old, 31.5% over 30, and 18% over 40 at initial diagnosis. FGFR1 hotspot point mutations (N546K and K656E) were exclusively identified in H3K27M-mutant DMG tumors (64/304, 21%; p = 0.0001); these tend to occur in older patients (median age: 32.5 years) and mainly arose in the diencephalon. H3K27M-mutant DMG had higher rates of mutations in NF1 (31.0 vs 8.1%; p = 0.0001) and PIK3CA/PIK3R1 (27.9% vs 15.1%; p = 0.016) compared to H3G34-mutant DHG. However, H3G34-mutant DHG had higher rates of targetable alterations in cell-cycle pathway genes (CDK4 and CDK6 amplification; CDKN2A/B deletion) (27.0 vs 9.0%). Potentially targetable PDGFRA alterations were identified in ~ 20% of both H3G34-mutant DHG and H3K27M-mutant DMG. Overall, in the present study H3K27M-mutant DMG occurred at similar rates in both adult and patient patients. Through our analysis, we were able to identify molecular features characteristic of DMG and DHG. By identifying the recurrent co-mutations including actionable FGFR1 point mutations found in nearly one-third of H3K27M-mutant DMG in young adults, our findings can inform clinical translational studies, patient diagnosis, and clinical trial design.

Keywords:  Astrocytoma; Brain neoplasms; Brain stem neoplasms; CDKN2A; Central nervous system neoplasms; Diffuse intrinsic pontine glioma; FGFR1; Genetics; Genomics; Glioblastoma; Glioma; H3F3A; Infratentorial neoplasms; Molecular pathology; Neuroepithelial neoplasms; Neuropathology; PDGFRA; Supratentorial neoplasms

DOI:  https://doi.org/10.1007/s00401-023-02609-6
Sci Rep. 2023 08 01. 13(1): 12433

HDAC1 and HDAC6 are essential for driving growth in IDH1 mutant glioma.

Matthew C Garrett, Rebecca Albano, Troy Carnwath, Lubayna Elahi, Catherine A Behrmann, Merissa Pemberton, Daniel Woo, Eric O'Brien, Brett VanCauwenbergh, John Perentesis, Sanjit Shah, Matthew Hagan, Ady Kendler, Chuntao Zhao, Aditi Paranjpe, Krishna Roskin, Harley Kornblum, David R Plas, Q Richard Lu.

Low-grade and secondary high-grade gliomas frequently contain mutations in the IDH1 or IDH2 metabolic enzymes that are hypothesized to drive tumorigenesis by inhibiting many of the chromatin-regulating enzymes that regulate DNA structure. Histone deacetylase inhibitors are promising anti-cancer agents and have already been used in clinical trials. However, a clear understanding of their mechanism or gene targets is lacking. In this study, the authors genetically dissect patient-derived IDH1 mutant cultures to determine which HDAC enzymes drive growth in IDH1 mutant gliomas. A panel of patient-derived gliomasphere cell lines (2 IDH1 mutant lines, 3 IDH1 wildtype lines) were subjected to a drug-screen of epigenetic modifying drugs from different epigenetic classes. The effect of LBH (panobinostat) on gene expression and chromatin structure was tested on patient-derived IDH1 mutant lines. The role of each of the highly expressed HDAC enzymes was molecularly dissected using lentiviral RNA interference knock-down vectors and a patient-derived IDH1 mutant in vitro model of glioblastoma (HK252). These results were then confirmed in an in vivo xenotransplant model (BT-142). The IDH1 mutation leads to gene down-regulation, DNA hypermethylation, increased DNA accessibility and H3K27 hypo-acetylation in two distinct IDH1 mutant over-expression models. The drug screen identified histone deacetylase inhibitors (HDACi) and panobinostat (LBH) more specifically as the most selective compounds to inhibit growth in IDH1 mutant glioma lines. Of the eleven annotated HDAC enzymes (HDAC1-11) only six are expressed in IDH1 mutant glioma tissue samples and patient-derived gliomasphere lines (HDAC1-4, HDAC6, and HDAC9). Lentiviral knock-down experiments revealed that HDAC1 and HDAC6 are the most consistently essential for growth both in vitro and in vivo and target very different gene modules. Knock-down of HDAC1 or HDAC6 in vivo led to a more circumscribed less invasive tumor. The gene dysregulation induced by the IDH1 mutation is wide-spread and only partially reversible by direct IDH1 inhibition. This study identifies HDAC1 and HDAC6 as important and drug-targetable enzymes that are necessary for growth and invasiveness in IDH1 mutant gliomas.

DOI: https://doi.org/10.1038/s41598-023-33889-3
Neuro Oncol. 2023 Aug 04. pii: noad136. [Epub ahead of print]

A Closer Look at the Role of Iron in Glioblastoma.

Ganesh Shenoy, James R Connor.

  Glioblastoma is among the deadliest malignancies facing modern oncology. While our understanding of certain aspects of glioblastoma biology has significantly increased over the last decade, other aspects, such as the role of bioactive metals in glioblastoma progression, have remain understudied. Iron is the most abundant transition metal found within the earth's crust and plays an intricate role in human physiology owing to its ability to participate in oxidation-reduction reactions. The importance of iron homeostasis in human physiology is apparent when examining the clinical consequences of iron deficiency or iron overload. Despite this, the role of iron in glioblastoma progression has not been well described. Here we review and synthesize the existing literature examining iron's role in glioblastoma progression and patient outcomes, as well as provide a survey of iron's effects on the major cell types found within the glioblastoma microenvironment at the molecular and cellular level. Iron represents an accessible target given the availability of already approved iron supplements and chelators. Improving our understanding of iron's role in glioblastoma biology may pave the way for iron modulating approaches to improve patient outcomes.

Keywords:  anemia; chelator; glioblastoma; iron; iron supplement

DOI:  https://doi.org/10.1093/neuonc/noad136
Neurooncol Adv. 2023 Jan-Dec;5(1):5(1): vdad078

Favorable prognostic impact of phosphatase and tensin homolog alterations in wild-type isocitrate dehydrogenase and telomerase reverse transcriptase promoter glioblastoma.

Nayuta Higa, Toshiaki Akahane, Seiya Yokoyama, Ryutaro Makino, Hajime Yonezawa, Hiroyuki Uchida, Tomoko Takajo, Mari Kirishima, Taiji Hamada, Naoki Noguchi, Ryosuke Otsuji, Daisuke Kuga, Shohei Nagasaka, Hitoshi Yamahata, Junkoh Yamamoto, Koji Yoshimoto, Akihide Tanimoto, Ryosuke Hanaya.

   Background: Telomerase reverse transcriptase promoter (TERTp) mutations are a biological marker of glioblastoma; however, the prognostic significance of TERTp mutational status is controversial. We evaluated this impact by retrospectively analyzing the outcomes of patients with isocitrate dehydrogenase (IDH)- and TERTp-wild-type glioblastomas.
Methods: Using custom next-generation sequencing, we analyzed 208 glioblastoma samples harboring wild-type IDH.
Results: TERTp mutations were detected in 143 samples (68.8%). The remaining 65 (31.2%) were TERTp-wild-type. Among the TERTp-wild-type glioblastoma samples, we observed a significant difference in median progression-free survival (18.6 and 11.4 months, respectively) and overall survival (not reached and 15.7 months, respectively) in patients with and without phosphatase and tensin homolog (PTEN) loss and/or mutation. Patients with TERTp-wild-type glioblastomas with PTEN loss and/or mutation were younger and had higher Karnofsky Performance Status scores than those without PTEN loss and/or mutation. We divided the patients with TERTp-wild-type into 3 clusters using unsupervised hierarchical clustering: Good (PTEN and TP53 alterations; lack of CDKN2A/B homozygous deletion and platelet-derived growth factor receptor alpha (PDGFRA) alterations), intermediate (PTEN alterations, CDKN2A/B homozygous deletion, lack of PDGFRA, and TP53 alterations), and poor (PDGFRA and TP53 alterations, CDKN2A/B homozygous deletion, and lack of PTEN alterations) outcomes. Kaplan-Meier survival analysis indicated that these clusters significantly correlated with the overall survival of TERTp-wild-type glioblastoma patients.
Conclusions: Here, we report that PTEN loss and/or mutation is the most useful marker for predicting favorable outcomes in patients with IDH- and TERTp-wild-type glioblastomas. The combination of 4 genes, PTEN, TP53, CDKN2A/B, and PDGFRA, is important for the molecular classification and individual prognosis of patients with IDH- and TERTp-wild-type glioblastomas.

Keywords:  PTEN; TERTp; TERTp-wild-type glioblastoma; prognostic markers

DOI:  https://doi.org/10.1093/noajnl/vdad078
Sci Rep. 2023 08 01. 13(1): 12424

TRIB1 confers therapeutic resistance in GBM cells by activating the ERK and Akt pathways.

Karnika Singh, Chunhua Han, Jessica L Fleming, Aline P Becker, Joseph McElroy, Tiantian Cui, Benjamin Johnson, Ashok Kumar, Ebin Sebastian, Christian A Showalter, Morgan S Schrock, Matthew K Summers, Valesio Becker, Zhen-Yue Tong, Xiaomei Meng, Heather R Manring, Monica Venere, Erica H Bell, Pierre A Robe, A L Grosu, S Jaharul Haque, Arnab Chakravarti.

GBM (Glioblastoma) is the most lethal CNS (Central nervous system) tumor in adults, which inevitably develops resistance to standard treatments leading to recurrence and mortality. TRIB1 is a serine/threonine pseudokinase which functions as a scaffold platform that initiates degradation of its substrates like C/EBPα through the ubiquitin proteasome system and also activates MEK and Akt signaling. We found that increased TRIB1 gene expression associated with worse overall survival of GBM patients across multiple cohorts. Importantly, overexpression of TRIB1 decreased RT/TMZ (radiation therapy/temozolomide)-induced apoptosis in patient derived GBM cell lines in vitro. TRIB1 directly bound to MEK and Akt and increased ERK and Akt phosphorylation/activation. We also found that TRIB1 protein expression was maximal during G2/M transition of cell cycle in GBM cells. Furthermore, TRIB1 bound directly to HDAC1 and p53. Importantly, mice bearing TRIB1 overexpressing tumors had worse overall survival. Collectively, these data suggest that TRIB1 induces resistance of GBM cells to RT/TMZ treatments by activating the cell proliferation and survival pathways thus providing an opportunity for developing new targeted therapeutics.

DOI: https://doi.org/10.1038/s41598-023-32983-w
Clin Cancer Res. 2023 Aug 04. pii: CCR-23-1235. [Epub ahead of print]

Depth of radiographic response (DpR) and time to tumor regrowth (TTG) predicts overall survival following anti-VEGF therapy in recurrent glioblastoma.

Benjamin M Ellingson, Akifumi Hagiwara, Connor J Morris, Nicholas S Cho, Sonoko Oshima, Francesco Sanvito, Talia C Oughourlian, Donatello Telesca, Catalina Raymond, Lauren E Abrey, Josep Garcia, Dana T Aftab, Colin Hessel, Tamar Rachmilewitz Minei, Dror Harats, David A Nathanson, Patrick Y Wen, Timothy F Cloughesy.

PURPOSE: Anti-angiogenic therapies are known to cause high radiographic response rates due to reduction in vascular permeability resulting in a lower degree of contrast extravasation. In the current study, we investigate the prognostic ability for model-derived parameters describing enhancing tumor volumetric dynamics to predict survival in recurrent glioblastoma treated with anti-angiogenic therapy.
EXPERIMENTAL DESIGN: N=276 patients in two phase II trials were used as training data, including bevacizumab +/- irinotecan (NCT00345163) and cabozantinib (NCT00704288), and N=74 patients in the bevacizumab arm of a phase III trial (NCT02511405) were used for validation. Enhancing volumes were estimated using T1 subtraction maps, and a biexponential model was used to estimate regrowth (g) and regression (d) rates, time to tumor regrowth (TTG), and the depth of response (DpR). Response characteristics were compared to diffusion MR phenotypes previously shown to predict survival.
RESULTS: Optimized thresholds occurred at g=0.07months-1 (phase II:HR=0.2579,P=5x10-20; phase III:HR=0.2197, P=5x10-5); d=0.11months-1 (HR=0.3365, P<0.0001; HR=0.3675,P=0.0113); TTG=3.8 months (HR=0.2702,P=6x10-17;HR=0.2061,P=2x10-5); and DpR=11.3% (HR=0.6326,P=0.0028;HR=0.4785, P=0.0206). Multivariable Cox regression controlling for age and baseline tumor volume confirmed these factors as significant predictors of survival. Patients with a favorable pre-treatment diffusion MRI phenotype had a significantly longer TTG and slower regrowth.
CONCLUSIONS: Recurrent glioblastoma patients with a large, durable radiographic response to anti-angiogenic agents have significantly longer survival. This information is useful for interpreting activity of anti-angiogenic agents in recurrent glioblastoma.

DOI: https://doi.org/10.1158/1078-0432.CCR-23-1235
Cancer Cell. 2023 Jul 20. pii: S1535-6108(23)00241-6. [Epub ahead of print]

Early clonal extinction in glioblastoma progression revealed by genetic barcoding.

Davide Ceresa, Francesco Alessandrini, Sara Lucchini, Daniela Marubbi, Francesca Piaggio, Jorge Miguel Mena Vera, Isabella Ceccherini, Daniele Reverberi, Irene Appolloni, Paolo Malatesta.

  Glioblastoma progression in its early stages remains poorly understood. Here, we transfer PDGFB and genetic barcodes in mouse brain to initiate gliomagenesis and enable direct tracing of glioblastoma evolution from its earliest possible stage. Unexpectedly, we observe a high incidence of clonal extinction events and progressive divergence in clonal sizes, even after the acquisition of malignant phenotype. Computational modeling suggests these dynamics result from clonal-based cell-cell competition. Through bulk and single-cell transcriptome analyses, coupled with lineage tracing, we reveal that Myc transcriptional targets have the strongest correlation with clonal size imbalances. Moreover, we show that the downregulation of Myc expression is sufficient to drive competitive dynamics in intracranially transplanted gliomas. Our findings provide insights into glioblastoma evolution that are inaccessible using conventional retrospective approaches, highlighting the potential of combining clonal tracing and transcriptomic analyses in this field.

Keywords:  Cancer dynamics computational model; Glioblastoma evolution; Lineage tracing coupled to scRNA-seq; Myc-driven cell-cell competition; PDGFB mouse glioma model; Tumor clonal dynamics

DOI:  https://doi.org/10.1016/j.ccell.2023.07.001
Neuro Oncol. 2023 Jul 31. pii: noad131. [Epub ahead of print]

CARs in the brain: can we tackle glioblastoma with engineered NK cells?

Patrick Roth.

DOI: https://doi.org/10.1093/neuonc/noad131
Proc Natl Acad Sci U S A. 2023 Aug 08. 120(32): e2303400120

SEC61G assists EGFR-amplified glioblastoma to evade immune elimination.

Kunlin Zeng, Yu Zeng, Hongchao Zhan, Ziling Zhan, Li Wang, Yuxin Xie, Yanqing Tang, Cuiying Li, Yanwen Chen, Shangbiao Li, Ming Liu, Xiaoxia Chen, Li Liang, Fan Deng, Ye Song, Aidong Zhou.

  Amplification of chromosome 7p11 (7p11) is the most common alteration in primary glioblastoma (GBM), resulting in gains of epidermal growth factor receptor (EGFR) copy number in 50 to 60% of GBM tumors. However, treatment strategies targeting EGFR have thus far failed in clinical trials, and the underlying mechanism remains largely unclear. We here demonstrate that EGFR amplification at the 7p11 locus frequently encompasses its neighboring genes and identifies SEC61G as a critical regulator facilitating GBM immune evasion and tumor growth. We found that SEC61G is always coamplified with EGFR and is highly expressed in GBM. As an essential subunit of the SEC61 translocon complex, SEC61G promotes translocation of newly translated immune checkpoint ligands (ICLs, including PD-L1, PVR, and PD-L2) into the endoplasmic reticulum and promotes their glycosylation, stabilization, and membrane presentation. Depletion of SEC61G promotes the infiltration and cytolytic activity of CD8+ T cells and thus inhibits GBM occurrence. Further, SEC61G inhibition augments the therapeutic efficiency of EGFR tyrosine kinase inhibitors in mice. Our study demonstrates a critical role of SEC61G in GBM immune evasion, which provides a compelling rationale for combination therapy of EGFR-amplified GBMs.

Keywords:  EGFR; PD-L1; SEC61G; glioblastoma; immune evasion

DOI:  https://doi.org/10.1073/pnas.2303400120
Sci Adv. 2023 Aug 04. 9(31): eadf3984

Multiomics analyses reveal DARS1-AS1/YBX1-controlled posttranscriptional circuits promoting glioblastoma tumorigenesis/radioresistance.

Caishang Zheng, Yanjun Wei, Qiang Zhang, Ming Sun, Yunfei Wang, Jiakai Hou, Peng Zhang, Xiangdong Lv, Dan Su, Yujie Jiang, Joy Gumin, Nidhi Sahni, Baoli Hu, Wenyi Wang, Xi Chen, Daniel J McGrail, Chaolin Zhang, Suyun Huang, Han Xu, Junjie Chen, Frederick F Lang, Jian Hu, Yiwen Chen.

The glioblastoma (GBM) stem cell-like cells (GSCs) are critical for tumorigenesis/therapeutic resistance of GBM. Mounting evidence supports tumor-promoting function of long noncoding RNAs (lncRNAs), but their role in GSCs remains poorly understood. By combining CRISPRi screen with orthogonal multiomics approaches, we identified a lncRNA DARS1-AS1-controlled posttranscriptional circuitry that promoted the malignant properties of GBM cells/GSCs. Depleting DARS1-AS1 inhibited the proliferation of GBM cells/GSCs and self-renewal of GSCs, prolonging survival in orthotopic GBM models. DARS1-AS1 depletion also impaired the homologous recombination (HR)-mediated double-strand break (DSB) repair and enhanced the radiosensitivity of GBM cells/GSCs. Mechanistically, DARS1-AS1 interacted with YBX1 to promote target mRNA binding and stabilization, forming a mixed transcriptional/posttranscriptional feed-forward loop to up-regulate expression of the key regulators of G1-S transition, including E2F1 and CCND1. DARS1-AS1/YBX1 also stabilized the mRNA of FOXM1, a master transcription factor regulating GSC self-renewal and DSB repair. Our findings suggest DARS1-AS1/YBX1 axis as a potential therapeutic target for sensitizing GBM to radiation/HR deficiency-targeted therapy.

DOI: https://doi.org/10.1126/sciadv.adf3984
iScience. 2023 Aug 18. 26(8): 107377

IRP1 mediated ferroptosis reverses temozolomide resistance in glioblastoma via affecting LCN2/FPN1 signaling axis depended on NFKB2.

Yufei Lan, Tao Yang, Qu Yue, Zhao Wang, Xiangyang Zhong, Xin Luo, Boming Zuo, Manqing Zhang, Tianci Zeng, Boyang Liu, Hongbo Guo.

  The prognosis of glioblastoma (GBM) patients is poor, and temozolomide (TMZ) resistance has become an important obstacle to its treatment effect. A growing number of researches have revealed the special characteristics of iron metabolism in GBM chemosensitivity. Iron regulatory protein 1 (IRP1) is an important protein for maintaining intracellular iron homeostasis. IRP1 has been indicated to have additional vital roles beyond its conventional metabolic activity, but the underlying mechanisms and biological consequences remain elusive. Here, we unprecedentedly demonstrated that amplifying IRP1 signals can reverse TMZ resistance and suppress tumor growth in vivo via inhibiting NFKB2 in the noncanonical NF-κB signaling pathway. In addition, we identified that NFKB2 affected TMZ sensitivity of GBM by modulating the expression of LCN2 and FPN1. Taken together, this study established a role for the IRP1/NFKB2 pathway in regulating LCN2/FPN1 signaling axis among the progression of TMZ resistance, suggesting a potential innovative GBM therapeutic strategy.

Keywords:  Biological sciences; Molecular biology; Oncology

DOI:  https://doi.org/10.1016/j.isci.2023.107377
Nat Commun. 2023 07 29. 14(1): 4572

Combining amino acid PET and MRI imaging increases accuracy to define malignant areas in adult glioma.

Maciej Harat, Józefina Rakowska, Marek Harat, Tadeusz Szylberg, Jacek Furtak, Izabela Miechowicz, Bogdan Małkowski.

Accurate determination of the extent and grade of adult-type diffuse gliomas is critical to patient management. In clinical practice, contrast-enhancing areas of diffuse gliomas in magnetic resonance imaging (MRI) sequences are usually used to target biopsy, surgery, and radiation therapy, but there can be discrepancies between these areas and the actual tumor extent. Here we show that adding 18F-fluoro-ethyl-tyrosine positron emission tomography (FET-PET) to MRI sequences accurately locates the most malignant areas of contrast-enhancing gliomas, potentially impacting subsequent management and outcomes. We present a prospective analysis of over 300 serial biopsy specimens from 23 patients with contrast-enhancing adult-type diffuse gliomas using a hybrid PET-MRI scanner to compare T2-weighted and contrast-enhancing MRI images with FET-PET. In all cases, we observe and confirm high FET uptake in early PET acquisitions (5-15 min after 18F-FET administration) outside areas of contrast enhancement on MRI, indicative of high-grade glioma. In 30% cases, inclusion of FET-positive sites changes the biopsy result to a higher tumor grade.

DOI: https://doi.org/10.1038/s41467-023-39731-8
Neuro Oncol. 2023 Aug 02. pii: noad140. [Epub ahead of print]

IDHwt and IDHmut adult-type diffuse gliomas display distinct alterations in ribosome biogenesis and 2'O-methylation of ribosomal RNA.

Hermes Paraqindes, Nour-El-Houda Mourksi, Samantha Ballesta, Jordan Hedjam, Fleur Bourdelais, Tanguy Fenouil, Thiébaud Picart, Frédéric Catez, Théo Combe, Anthony Ferrari, Janice Kielbassa, Emilie Thomas, Laurie Tonon, Alain Viari, Valéry Attignon, Marjorie Carrere, Jessie Perrossier, Stéphane Giraud, Christophe Vanbelle, Mathieu Gabut, Danny Bergeron, Michelle S Scott, Luis Castro Vega, Nathalie Magne, Emmanuelle Huillard, Marc Sanson, David Meyronet, Jean-Jacques Diaz, François Ducray, Virginie Marcel, Sébastien Durand.

   BACKGROUND: High-grade adult-type diffuse gliomas (HGGs) constitute a heterogeneous group of aggressive tumors that are mostly incurable. Recent advances highlighting the contribution of ribosomes to cancer development have offered new clinical perspectives. Here, we uncovered that IDHwt and IDHmut HGGs display distinct alterations of ribosome biology, in terms of rRNA epitranscriptomics and ribosome biogenesis, which could constitute novel hallmarks that can be exploited for the management of these pathologies.
METHODS: We analyzed (i) the ribosomal RNA 2'O-ribose methylation (rRNA 2'Ome) using RiboMethSeq and in-house developed bioinformatics tools (h t t p s : //github.com/RibosomeCRCL/ribomethseq-nfandrRMSAnalyzer) on three independent cohorts compiling 71 HGGs (IDHwt n=30, IDHmut n=41) and 9 non-neoplastic samples, (ii) the expression of ribosome biogenesis factors using medium throughput RT-qPCR as a readout of ribosome biogenesis, and (iii) the sensitivity of 5 HGG cell lines to RNA Pol I inhibitors (CX5461, BMH21).
RESULTS: Unsupervised analysis demonstrated that HGGs could be distinguished based on their rRNA 2'Ome epitranscriptomic profile, with IDHwt glioblastomas displaying the most significant alterations of rRNA 2'Ome at specific sites. In contrast, IDHmut HGGs are largely characterized by an overexpression of ribosome biogenesis factors compared to non-neoplastic tissues or IDHwt glioblastomas. Finally, IDHmut HGG-derived spheroids display higher cytotoxicity to CX5461 than IDHwt glioblastoma, while all HGG spheroids display a similar cytotoxicity to BMH-21.
CONCLUSION: In HGGs, IDH mutational status is associated with specific alterations of the ribosome biology and with distinct sensitivities to RNA Pol I inhibitors.

Keywords:  IDH mutational status; epitranscriptomics; glioma; ribosome; ribosome biogenesis factors

DOI:  https://doi.org/10.1093/neuonc/noad140
Neuro Oncol. 2023 Aug 01. pii: noad141. [Epub ahead of print]

A Phase I Trial of Panobinostat in Children with Diffuse Intrinsic Pontine Glioma: A Report from the Pediatric Brain Tumor Consortium (PBTC-047).

Michelle Monje, Tabitha Cooney, John Glod, Jie Huang, Cody J Peer, Damien Faury, Patricia Baxter, Kim Kramer, Alicia Lenzen, Nathan J Robison, Lindsay Kilburn, Anna Vinitsky, William D Figg, Nada Jabado, Maryam Fouladi, Jason Fangusaro, Arzu Onar-Thomas, Ira J Dunkel, Katherine E Warren.

   STUDY OBJECTIVES: Diffuse intrinsic pontine glioma (DIPG) is a lethal childhood cancer with median survival of less than 1 year. Panobinostat is an oral multi-histone deacetylase inhibitor with preclinical activity in DIPG models. Study objectives were to determine safety, tolerability, maximum tolerated dose (MTD), toxicity profile and pharmacokinetics of panobinostat in children with DIPG.
PATIENTS AND METHODS: In stratum 1, panobinostat was administered three days per week for three weeks on, one week off to children with progressive DIPG, with dose escalation following a two-stage continual reassessment method. After this MTD was determined, the study was amended to evaluate the MTD in children with non-progressive DIPG/Diffuse midline glioma (DMG) (stratum 2) on an alternate schedule, three days a week every other week in an effort to escalate the dose.
RESULTS: For stratum 1, 19 subjects enrolled with 17/19 evaluable for dose-finding. The MTD was 10 mg/m 2/dose. Dose-limiting toxicities included thrombocytopenia and neutropenia. Posterior reversible encephalopathy syndrome was reported in one patient. For stratum 2, 34 eligible subjects enrolled with 29/34 evaluable for dose-finding. The MTD on this schedule was 22 mg/m 2/dose. DLTs included thrombocytopenia, neutropenia, neutropenia with grade 4 thrombocytopenia, prolonged intolerable nausea, and increased ALT.
CONCLUSIONS: The MTD of panobinostat is 10 mg/m 2/dose administered 3 times per week for 3 weeks on/1 week off in children with progressive DIPG/DMG and 22 mg/m 2/dose administered 3 times per week for 1 week on/1 week off when administered in a similar population pre-progression. The most common toxicity for both schedules was myelosuppression.

Keywords:  DIPG; HDAC inhibitors; brainstem glioma; epigenetics; midline glioma

DOI:  https://doi.org/10.1093/neuonc/noad141
Sci Rep. 2023 Aug 04. 13(1): 12694

Morphological and molecular-biological features of glioblastoma progression in tolerant and susceptible to hypoxia Wistar rats.

D Sh Dzhalilova, N A Zolotova, V A Mkhitarov, A M Kosyreva, I S Tsvetkov, A S Khalansky, A I Alekseeva, T H Fatkhudinov, O V Makarova.

Hypoxia is a major pathogenetic factor in many cancers. Individual resistance to suboptimal oxygen availability is subject to broad variation and its possible role in tumorigenesis remains underexplored. This study aimed at specific characterization of glioblastoma progression in male tolerant and susceptible to hypoxia Wistar rats. Hypoxia resistance was assessed by gasping time measurement in an 11,500 m altitude-equivalent hypobaric decompression chamber. Based on the outcome, the animals were assigned to three groups termed 'tolerant to hypoxia' (n = 13), 'normal', and 'susceptible to hypoxia' (n = 24). The 'normal' group was excluded from subsequent experiments. One month later, the animals underwent inoculation with rat glioblastoma 101.8 followed by monitoring of survival, body weight dynamics and neurological symptoms. The animals were sacrificed on post-inoculation days 11 (subgroup 1) and 15 (subgroup 2). Relative vessels number, necrosis areas and Ki-67 index were assessed microscopically; tumor volumes were determined by 3D reconstruction from histological images; serum levels of HIF-1α, IL-1β, and TNFα were determined by ELISA. None of the tolerant to hypoxia animals died of the disease during observation period, cf. 85% survival on day 11 and 55% survival on day 15 in the susceptible group. On day 11, proliferative activity of the tumors in the tolerant animals was higher compared with the susceptible group. On day 15, proliferative activity, necrosis area and volume of the tumors in the tolerant to hypoxia animals were higher compared with the susceptible group. ELISA revealed no dynamics in TNFα levels, elevated levels of IL-1β in the susceptible animals on day 15 in comparison with day 11 and tolerant ones. Moreover, there were elevated levels of HIF-1α in the tolerant animals on day 15 in comparison with day 11. Thus, the proliferative activity of glioblastoma cells and the content of HIF-1α were higher in tolerant to hypoxia rats, but the mortality associated with the tumor process and IL-1β level in them were lower than in susceptible animals. Specific features of glioblastoma 101.8 progression in tolerant and susceptible to hypoxia rats, including survival, tumor growth rates and IL-1β level, can become the basis of new personalized approaches for cancer diseases treatment in accordance to individual hypoxia resistance.

DOI: https://doi.org/10.1038/s41598-023-39914-9
Cell Rep. 2023 Jul 28. pii: S2211-1247(23)00902-6. [Epub ahead of print]42(8): 112891

Genetically modified IL2 bone-marrow-derived myeloid cells reprogram the glioma immunosuppressive tumor microenvironment.

Alessandro Canella, Matthew Nazzaro, Sakthi Rajendran, Claire Schmitt, Abigail Haffey, Giovanni Nigita, Diana Thomas, Justin M Lyberger, Gregory K Behbehani, Nduka M Amankulor, Elaine R Mardis, Timothy P Cripe, Prajwal Rajappa.

  Gliomas are one of the leading causes of cancer-related death in the adolescent and young adult (AYA) population. Two-thirds of AYA glioma patients are affected by low-grade gliomas (LGGs), but there are no specific treatments. Malignant progression is supported by the immunosuppressive stromal component of the tumor microenvironment (TME) exacerbated by M2 macrophages and a paucity of cytotoxic T cells. A single intravenous dose of engineered bone-marrow-derived myeloid cells that release interleukin-2 (GEMys-IL2) was used to treat mice with LGGs. Our results demonstrate that GEMys-IL2 crossed the blood-brain barrier, infiltrated the TME, and reprogrammed the immune cell composition and transcriptome. Moreover, GEMys-IL2 extended survival in an LGG immunocompetent mouse model. Here, we report the efficacy of an in vivo approach that demonstrates the potential for a cell-mediated innate immunotherapy designed to enhance the recruitment of activated effector T and natural killer cells within the glioma TME.

Keywords:  CP: Cancer; CP: Immunology; GEMys; IL2; LGG; RCAS/t-va; TME; genetically engineered myeloid cells; immunotherapy; interleukin-2; myeloid cells; reprogramming TME

DOI:  https://doi.org/10.1016/j.celrep.2023.112891