HGG-53. PROJECT HOPE: “PEDIATRIC AND AYA HIGH-GRADE GLIOMA OMICS PROJECT”- A LONGITUDINAL MOLECULAR LANDSCAPE OF HIGH-GRADE GLIOMAS RESOLVED AT SINGLE-CELL LEVEL

Abstract High-grade gliomas (HGG) are among the most prevalent and fatal cancers in pediatric, adolescent, and young adult (AYA) patients. Especially understudied are older children and young adults, aged 16–39 years. Previously, we profiled primary pediatric HGGs through single-cell transcriptomics and identified the genetic, epigenetic and developmental programs that drive their malignant progression. However, the questions of how these programs compare to those in older HGG patients, what the mechanisms are by which these tumors ultimately evolve to drive recurrence and treatment resistance, and how distinct tumor cell subpopulations bidirectionally communicate with their microenvironment remain to be elucidated. Here, we use single-nucleus RNA sequencing to compare 11 paired, matched high-grade gliomas at diagnosis and recurrence and 15 additional H3K27M primary and recurrent DMG samples in pediatric and AYA patients. In all tumors, we find both undifferentiated and differentiated tumor cells recapitulating distinct glial lineages, as well as diverse microenvironmental cell populations. When longitudinally comparing this tumor architecture within matched pairs, we find substantial differences in transcriptional program expressions. Diagnostic samples include more differentiated, astrocyte-like tumor cells, while cells from recurrent samples more highly express ribosomal and heat-shock protein genes, suggesting tumor progression- and treatment-related shifts. Ongoing sequencing and analysis will allow for unprecedented insight into the evolutionary dynamics of pediatric and AYA high-grade gliomas as well as delineate differences in the biology of DMGs occurring in different age groups. This multi-institutional project was funded by the National Institute of Health.

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EPCO-26. PROJECT HOPE: “PEDIATRIC AND AYA HIGH-GRADE GLIOMA OMICS PROJECT”- A LONGITUDINAL MOLECULAR LANDSCAPE OF HIGH-GRADE GLIOMAS RESOLVED AT SINGLE-CELL LEVEL

Neuro-Oncology ◽

10.1093/neuonc/noaa215.305 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii74-ii75

Author(s):

Li Jiang ◽

Olivia Hack ◽

Husam Babikir ◽

Karin Shamardani ◽

Ilon Liu ◽

...

Keyword(s):

Single Cell ◽

Evolutionary Dynamics ◽

Age Groups ◽

Treatment Resistance ◽

High Grade Glioma ◽

Adolescent And Young Adult ◽

High Grade ◽

Older Children ◽

High Grade Gliomas ◽

Molecular Landscape

Abstract High-grade gliomas (HGG) are among the most prevalent and fatal cancers in pediatric, adolescent, and young adult (AYA) patients. Especially understudied are older children and young adults, aged 16–39 years. Previously, we profiled primary pediatric HGGs through single-cell transcriptomics and identified the genetic, epigenetic and developmental programs that drive their malignant progression. However, the questions of how these programs compare to those in older HGG patients, what the mechanisms are by which these tumors ultimately evolve to drive recurrence and treatment resistance, and how distinct tumor cell subpopulations bidirectionally communicate with their microenvironment remain to be elucidated. In order to investigate these questions, we use single-nucleus RNA sequencing to compare 11 paired, matched high-grade gliomas at diagnosis and recurrence and 15 additional H3K27M primary and recurrent DMG samples in pediatric and AYA patients. In all tumors, we find both undifferentiated and differentiated tumor cells recapitulating distinct glial lineages, as well as diverse microenvironmental cell populations. When longitudinally comparing this tumor architecture within matched pairs, we find substantial differences in transcriptional program expressions. In particular, recurrent samples showed a higher proportion of cells expressing heat- shock proteins (HSPs) and a novel cancer cell program characterized by synaptic formation and neurotransmitter secretory processes, suggesting tumor progression- and treatment-related shifts. Ongoing sequencing and analysis will allow for unprecedented insight into the evolutionary dynamics of pediatric and AYA high-grade gliomas as well as delineate differences in the biology of DMGs occurring in different age groups. This multi-institutional project was funded by the National Institute of Health.

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Image-based personalization of computational models for predicting response of high-grade glioma to chemoradiation

Scientific Reports ◽

10.1038/s41598-021-87887-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

David A. Hormuth ◽

Karine A. Al Feghali ◽

Andrew M. Elliott ◽

Thomas E. Yankeelov ◽

Caroline Chung

Keyword(s):

Mathematical Models ◽

Computational Models ◽

Tumor Response ◽

Treatment Resistance ◽

High Grade Glioma ◽

Information Criteria ◽

Patient Specific ◽

Model Parameters ◽

High Grade ◽

High Grade Gliomas

AbstractHigh-grade gliomas are an aggressive and invasive malignancy which are susceptible to treatment resistance due to heterogeneity in intratumoral properties such as cell proliferation and density and perfusion. Non-invasive imaging approaches can measure these properties, which can then be used to calibrate patient-specific mathematical models of tumor growth and response. We employed multiparametric magnetic resonance imaging (MRI) to identify tumor extent (via contrast-enhanced T1-weighted, and T2-FLAIR) and capture intratumoral heterogeneity in cell density (via diffusion-weighted imaging) to calibrate a family of mathematical models of chemoradiation response in nine patients with unresected or partially resected disease. The calibrated model parameters were used to forecast spatially-mapped individual tumor response at future imaging visits. We then employed the Akaike information criteria to select the most parsimonious member from the family, a novel two-species model describing the enhancing and non-enhancing components of the tumor. Using this model, we achieved low error in predictions of the enhancing volume (median: − 2.5%, interquartile range: 10.0%) and a strong correlation in total cell count (Kendall correlation coefficient 0.79) at 3-months post-treatment. These preliminary results demonstrate the plausibility of using multiparametric MRI data to inform spatially-informative, biologically-based predictive models of tumor response in the setting of clinical high-grade gliomas.

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STEM-05. SINGLE CELL SEQUENCING CHARACTERIZES SPATIAL AND TEMPORAL RELATIONSHIPS OF ENHANCING AND NON-ENHANCING REGIONS IN HIGH-GRADE GLIOMA

Neuro-Oncology ◽

10.1093/neuonc/noaa215.822 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii197-ii197

Author(s):

Kunal Patel ◽

Riki Kawaguchi ◽

Alvaro Alvarado ◽

Deepthi Muthukrishnan ◽

Richard Everson ◽

...

Keyword(s):

Gene Expression ◽

Tumor Cell ◽

Single Cell ◽

Tumor Cells ◽

High Grade Glioma ◽

Cell Types ◽

Magnetic Resonance Images ◽

Stem Cell Markers ◽

High Grade ◽

Single Cell Sequencing

Abstract INTRODUCTION Treatments of high grade glioma focus on the contrast enhancing (CE) portion of the tumor. However, given the invasive nature of glioma, residual tumor cells responsible for recurrence likely exist in the non-enhancing (NE) region. METHODS In 3 patients undergoing surgery for malignant glioma, we used pre-operative magnetic resonance images to prospectively identify biopsy targets in the CE region and locations 0.5-2.0cm beyond the CE edge. We carried out single cell sequencing on image guided biopsy specimens to generate 12,528 RNA profiles. RESULTS In all samples, tumor cells clustered into three predominant groups: tumor cells with astrocyte markers (ASC-like), tumor cells with oligodendrocyte markers (ODC-like), and tumor cells with neither marker. This last group consisted of a small proportion of tumor cells and expressed putative stem cell markers (PROM1, NES, SLC1A3, A2B5, ID1). A trajectory analysis consistently positioned this group as branching off into either ASC-like or ODC-like cells. CE regions had different cellular compositions than NE regions, with higher proportions of tumor, endothelial cells, T-cells, and NK cells. Using location and cell density data, we modeled expected tumor burden, predicting tumor cells up to 1.5cm beyond the CE region of the tumor. There were significant differences in gene expression between CE and NE tumor cells, with increased inflammation and hypoxia in the CE region versus increased proliferative markers in the NE region. Tumor cells in the NE region were characterized by increased proliferation, markers of invasion, and markers of self-renewal. CONCLUSIONS Single cell sequencing illustrates multiple glioma cell types and suggests a hierarchical relationship between tumor cell types. CE and NE regions exhibit different tumor and non-tumor cell populations as well as different gene expression profiles within individual cell types. There remains a significant tumor cell burden in the NE portion of tumor, including actively proliferating cells.

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IMMU-17. SINGLE-CELL RNA-SEQ REVEALS HIGH-GRADE GLIOMA ASSOCIATED MICROGLIA WITH PROINFLAMMATORY AND STEM-LIKE FEATURES SUPPORT TUMOR PROGRESSION

Neuro-Oncology ◽

10.1093/neuonc/noaa215.447 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii108-ii108

Author(s):

Hailong Liu ◽

Yongqiang Liu ◽

Janusz Franco-Barraza ◽

Xinguang Yu ◽

Shiyu Feng

Keyword(s):

Single Cell ◽

Tumor Cells ◽

Poor Response ◽

High Grade Glioma ◽

High Grade ◽

Rna Seq ◽

Wild Type ◽

Current Therapies ◽

Tgf Β1

Abstract Poor response of human glioblastoma to current therapies are influenced by tumor microenvironment. Although glioblastoma is recognized by large enrichment of microglia, characterization of diverse cell subsets and their functions remain challenging because of high heterogenicity. Here, we analyzed single-cell transcriptomics to comprehensively map the cell populations and determine the roles of microglia in IDH1/2 wild-type (IDH-wt) glioblastoma progression. Besides finding microglia were significantly enriched in IDH-wt glioblastoma compared to IDH1/2 mutant (IDH-mut) gliomas, we identified a unique high-grade glioma microglia (HGAM) subtype characterized by proinflammatory and stem-like features. In particular, HGAM’s pro-tumoral IL1β secretion is mediated via ApoE-induced activation of NLRP1 inflammasome. HGAM phagocytosed OPC-like malignant cells forming the neoplastic microglia, which presented the stem-like potential giving rise to activated microglia. Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation. Additionally, an intricated evaluation of glioma patients revealed that SETD2 mutation/low-expression correlated with adverse prognosis. Further analysis showed that SETD2 -dificient tumor cells presented hypersensitivity to HGAM-derived IL1β via epigenetic dysregulation of PHF6. Also, SETD2 -deficient tumor cells produced TGF-β1 contributing to microglia activation. Finally, targeting the TGF-β1/TβRI signaling impaired HGAM activation and tumor growth. Our studies identify a unique neoplastic microglia subpopulation and establish cellular basis of interactions with tumor cells important for disease progression.

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HGG-36. HIF-2: A NEW DRUG TARGET IN PEDIATRIC HIGH-GRADE GLIOMA WITH PROMISING PRECLINICAL RESULTS

Neuro-Oncology ◽

10.1093/neuonc/noaa222.317 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii350-iii350

Author(s):

Quentin Fuchs ◽

Marina Pierrevelcin ◽

Christophe Papin ◽

Monique Dontenwill ◽

Natacha Entz-Werlé

Keyword(s):

Drug Testing ◽

Treatment Resistance ◽

High Grade Glioma ◽

Clinical Work ◽

Driver Mutations ◽

High Grade ◽

Innovative Strategy ◽

Dismal Prognosis ◽

Cell Arrest ◽

And Migration

Abstract Pediatric high-grade gliomas (pHGGs) have a very dismal prognosis and need new innovative strategy for treatment. Despite the past discovery of histone H3 driver mutations, we are not able for instance to stop this induced epigenetic remodulation. Therefore, proactive translational studies wish to go further discovering new targetable proteins in pHGG. In our past clinical work, we were able to link significantly HIF-2alpha to a worse pHGG outcome and to their treatment resistance. We designed this new work to determine in several patient-derived cell lines (6 PDCLs) with or without H3.3 mutation the variation of HIF-2alpha, its role, its induction in normoxic and hypoxic microenvironment and its transcriptional targets using RNAseq, metabolomics and ChipSeq analyses. Complementary functional analyses were performed using siRNA strategy during cultures and migration assays. Finally, preclinical drug testing involving commercialized and non-commercialized HIF-2alpha specific inhibitors in the same PDCLs were evaluating their antiproliferative and pro-apoptotic effect. Our results confirmed the central role of HIF-2alpha in cell resistance to treatment, in pHGG stemness features and its direct link with metabolism adaptation and histone interaction. After the confirmation of its frequent presence in multiple PDCLs initiated from thalamic pHGGs and DIPG, we were using inhibitors in a single and combinatorial strategy targeting HIF-2alpha plus another hypoxia biomarker (mTor). This preclinical targeting was highly effective to favor cell arrest, apoptosis and to stop cell migration. In conclusion, HIF-2alpha seem to be a major biomarker in pHGGs that might be targeted giving a useful new opportunity for pHGG treatments.

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Against the Resilience of High-Grade Gliomas: The Immunotherapeutic Approach (Part I)

Brain Sciences ◽

10.3390/brainsci11030386 ◽

2021 ◽

Vol 11 (3) ◽

pp. 386

Author(s):

Alice Giotta Lucifero ◽

Sabino Luzzi

Keyword(s):

Monoclonal Antibodies ◽

Natural Killer ◽

Immune Escape ◽

Meta Analysis ◽

Treatment Options ◽

High Grade Glioma ◽

High Grade ◽

Future Challenges ◽

Genetic Landscape ◽

High Grade Gliomas

The resilience of high-grade gliomas (HGGs) against conventional chemotherapies is due to their heterogeneous genetic landscape, adaptive phenotypic changes, and immune escape mechanisms. Innovative immunotherapies have been developed to counteract the immunosuppressive capability of gliomas. Nevertheless, further research is needed to assess the efficacy of the immuno-based approach. The aim of this study is to review the newest immunotherapeutic approaches for glioma, focusing on the drug types, mechanisms of action, clinical pieces of evidence, and future challenges. A PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis)-based literature search was performed on PubMed/Medline and ClinicalTrials.gov databases using the keywords “active/adoptive immunotherapy,” “monoclonal antibodies,” “vaccine,” and “engineered T cell.”, combined with “malignant brain tumor”, “high-grade glioma.” Only articles written in English published in the last 10 years were selected, filtered based on best relevance. Active immunotherapies include systemic temozolomide, monoclonal antibodies, and vaccines. In several preclinical and clinical trials, adoptive immunotherapies, including T, natural killer, and natural killer T engineered cells, have been shown to be potential treatment options for relapsing gliomas. Systemic temozolomide is considered the backbone for newly diagnosed HGGs. Bevacizumab and rindopepimut are promising second-line treatments. Adoptive immunotherapies have been proven for relapsing tumors, but further evidence is needed.

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Convection Enhanced Delivery in the Setting of High-Grade Gliomas

Pharmaceutics ◽

10.3390/pharmaceutics13040561 ◽

2021 ◽

Vol 13 (4) ◽

pp. 561

Author(s):

Chibueze D. Nwagwu ◽

Amanda V. Immidisetti ◽

Michael Y. Jiang ◽

Oluwasegun Adeagbo ◽

David C. Adamson ◽

...

Keyword(s):

Rapid Development ◽

Systemic Exposure ◽

Therapeutic Index ◽

High Grade Glioma ◽

High Grade ◽

Clinical Experiences ◽

Convection Enhanced Delivery ◽

Drug Concentrations ◽

Infiltrative Growth Pattern ◽

High Grade Gliomas

Development of effective treatments for high-grade glioma (HGG) is hampered by (1) the blood–brain barrier (BBB), (2) an infiltrative growth pattern, (3) rapid development of therapeutic resistance, and, in many cases, (4) dose-limiting toxicity due to systemic exposure. Convection-enhanced delivery (CED) has the potential to significantly limit systemic toxicity and increase therapeutic index by directly delivering homogenous drug concentrations to the site of disease. In this review, we present clinical experiences and preclinical developments of CED in the setting of high-grade gliomas.

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Sonodynamic Therapy for the Treatment of Intracranial Gliomas

Journal of Clinical Medicine ◽

10.3390/jcm10051101 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1101

Author(s):

Antonio D’Ammando ◽

Luca Raspagliesi ◽

Matteo Gionso ◽

Andrea Franzini ◽

Edoardo Porto ◽

...

Keyword(s):

Tumor Cells ◽

Therapeutic Option ◽

Malignant Gliomas ◽

Progression Free Survival ◽

High Grade ◽

Sonodynamic Therapy ◽

Treatment Protocols ◽

Ultrasound Waves ◽

High Grade Gliomas ◽

Preclinical And Clinical Studies

High-grade gliomas are the most common and aggressive malignant primary brain tumors. Current therapeutic schemes include a combination of surgical resection, radiotherapy and chemotherapy; even if major advances have been achieved in Progression Free Survival and Overall Survival for patients harboring high-grade gliomas, prognosis still remains poor; hence, new therapeutic options for malignant gliomas are currently researched. Sonodynamic Therapy (SDT) has proven to be a promising treatment combining the effects of low-intensity ultrasound waves with various sound-sensitive compounds, whose activation leads to increased immunogenicity of tumor cells, increased apoptotic rates and decreased angiogenetic potential. In addition, this therapeutic technique only exerts its cytotoxic effects on tumor cells, while both ultrasound waves and sensitizing compound are non-toxic per se. This review summarizes the present knowledge regarding mechanisms of action of SDT and currently available sonosensitizers and focuses on the preclinical and clinical studies that have investigated its efficacy on malignant gliomas. To date, preclinical studies implying various sonosensitizers and different treatment protocols all seem to confirm the anti-tumoral properties of SDT, while first clinical trials will soon start recruiting patients. Accordingly, it is crucial to conduct further investigations regarding the clinical applications of SDT as a therapeutic option in the management of intracranial gliomas.

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Impact of mass effect, tumor location, age, and surgery on the cognitive outcome of patients with high-grade gliomas: a longitudinal study

Neuro-Oncology Practice ◽

10.1093/nop/npw030 ◽

2017 ◽

Vol 4 (4) ◽

pp. 229-240 ◽

Cited By ~ 5

Author(s):

Monica Dallabona ◽

Silvio Sarubbo ◽

Stefano Merler ◽

Francesco Corsini ◽

Giuseppe Pulcrano ◽

...

Keyword(s):

Tumor Volume ◽

High Grade Glioma ◽

Joint Effect ◽

Cognitive Outcome ◽

Tumor Localization ◽

High Grade ◽

Patient Age ◽

Patient Âgé ◽

High Grade Gliomas

Abstract Background High-grade gliomas are the most frequently occurring brain tumors and carry unfavorable prognosis. Literature is controversial regarding the effects of surgery on cognitive functions. Methods We analyzed a homogenous population of 30 patients with high-grade glioma who underwent complete resection. Patients underwent extensive neuropsychological analysis before surgery, 7 days after surgery, and approximately 40 days after surgery, before adjuvant treatments. Thirty-four neuropsychological tests were administered in the language, memory, attention, executive functions, and praxis domains. Results The preoperative percentage of patients with impairment in the considered tests ranged from 0% to 53.3% (mean 20.9%). Despite a general worsening at early follow-up, a significant recovery was observed at late follow-up. Preoperative performances in language and verbal memory tasks depended on the joint effect of tumor volume, volume of surrounding edema, and tumor localization, with major deficits in patients with left lateralized tumor, especially insular and temporal. Preoperative performances in attention and constructive abilities tasks depended on the joint effect of tumor volume, volume of surrounding edema, and patient age, with major deficits in patients ≥ 65 years old. Recovery at late follow-up depended on the volume of resected tumor, edema resorption, and patient age. Conclusions Longitudinal neuropsychological performance of patients affected by high-grade glioma depends, among other factors, on the complex interplay of tumor volume, volume of surrounding edema, tumor localization, and patient age. Reported results support the definition of criteria for surgical indication based on the above factors. They may be used to propose more customized surgical, oncological, and rehabilitative strategies.

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Single-Cell Transcriptomic Analysis Revealed a Critical Role of SPP1/CD44-Mediated Crosstalk Between Macrophages and Cancer Cells in Glioma

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.779319 ◽

2021 ◽

Vol 9 ◽

Author(s):

Cong He ◽

Luoyan Sheng ◽

Deshen Pan ◽

Shuai Jiang ◽

Li Ding ◽

...

Keyword(s):

Single Cell ◽

Tumor Heterogeneity ◽

Molecular Mechanisms ◽

Critical Role ◽

Cell Communication ◽

High Grade Glioma ◽

Sequencing Analysis ◽

High Grade ◽

Cellular Components

High-grade glioma is one of the most lethal human cancers characterized by extensive tumor heterogeneity. In order to identify cellular and molecular mechanisms that drive tumor heterogeneity of this lethal disease, we performed single-cell RNA sequencing analysis of one high-grade glioma. Accordingly, we analyzed the individual cellular components in the ecosystem of this tumor. We found that tumor-associated macrophages are predominant in the immune microenvironment. Furthermore, we identified five distinct subpopulations of tumor cells, including one cycling, two OPC/NPC-like and two MES-like cell subpopulations. Moreover, we revealed the evolutionary transition from the cycling to OPC/NPC-like and MES-like cells by trajectory analysis. Importantly, we found that SPP1/CD44 interaction plays a critical role in macrophage-mediated activation of MES-like cells by exploring the cell-cell communication among all cellular components in the tumor ecosystem. Finally, we showed that high expression levels of both SPP1 and CD44 correlate with an increased infiltration of macrophages and poor prognosis of glioma patients. Taken together, this study provided a single-cell atlas of one high-grade glioma and revealed a critical role of macrophage-mediated SPP1/CD44 signaling in glioma progression, indicating that the SPP1/CD44 axis is a potential target for glioma treatment.

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