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

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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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

Neuro-Oncology ◽

10.1093/neuonc/noaa222.333 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii353-iii353

Author(s):

Olivia A Hack ◽

Husam Babikir ◽

Li Jiang ◽

Karin Shamardani ◽

Ilon Liu ◽

...

Keyword(s):

Single Cell ◽

Tumor Cells ◽

Evolutionary Dynamics ◽

Age Groups ◽

Treatment Resistance ◽

High Grade Glioma ◽

Adolescent And Young Adult ◽

High Grade ◽

Older Children ◽

High Grade Gliomas

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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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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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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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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EPID-13. A POPULATION-BASED ANALYSIS OF CNS TUMOR DIAGNOSES, TREATMENT, AND SURVIVAL IN CONGENITAL AND INFANT AGE GROUPS

Neuro-Oncology ◽

10.1093/neuonc/noaa222.199 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii321-iii321

Author(s):

Muriel Hart ◽

Amy Mellies ◽

Alina Beltrami ◽

Ahmed Gilani ◽

Adam Green

Keyword(s):

Age Groups ◽

Young Patients ◽

High Grade Glioma ◽

Population Based ◽

Cns Tumors ◽

Low Grade ◽

Tumor Type ◽

Older Children ◽

Embryonal Tumors ◽

Chi Square

Abstract BACKGROUND Congenital (<3 months) and infant (3 to 11 months) brain tumors are biologically different from tumors in older children, but epidemiology of these tumors has not been studied comprehensively. Insight into epidemiological differences could help tailor treatment recommendations by age and increase overall survival (OS). METHODS Population-based data from the SEER 18 registries was obtained for 14,493 0-19-year-olds diagnosed with CNS tumors between 1990 and 2015. Incidence, treatment, and survival were analyzed using Chi-square and Kaplan-Meier analyses. RESULTS Between the <3 month, 3–5 month, 6–11 month, and 1–19 year age groups, tumor type distribution differed significantly (p<0.001); high-grade glioma (HGG) was most common in the <3-month-olds, while low-grade glioma (LGG) was most common in the other groups. 5-year OS for all tumors was 36.7% (<3 months), 56.0% (<3–5 months), 63.8% (6–11 months), and 74.7% (1–19 years) (log rank p<0.001). OS by tumor type was worst for <3-month-olds with LGG, medulloblastoma, and other embryonal tumors; OS was worst for 3-5-month-olds with ependymoma, <1-year-olds collectively with atypical teratoid-rhabdoid tumor, and 1-19-year-olds with HGG (log rank p<0.02 for all tumor types). <3-month-olds were least likely to receive any treatment for each tumor type and least likely to undergo surgery for all except HGG. <1-year-olds were far less likely than 1-19-year-olds to undergo radiation for embryonal tumors, as expected, but were also less likely to undergo chemotherapy. CONCLUSIONS Congenital/infant CNS tumors differ pathologically, therapeutically, and prognostically from those in older children. Treatment changes could help address poorer outcomes for these young patients.

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Temozolomide radiochemotherapy for high-grade glioma patients with hemodialysis: a case series of 7 patients

Neuro-Oncology Practice ◽

10.1093/nop/npz034 ◽

2019 ◽

Vol 7 (1) ◽

pp. 111-117 ◽

Cited By ~ 1

Author(s):

Jun Muto ◽

Tomoo Matsutani ◽

Ryosuke Matsuda ◽

Masashi Kinoshita ◽

Mitsuteru Oikawa ◽

...

Keyword(s):

Adverse Events ◽

Case Series ◽

High Grade Glioma ◽

Patient Characteristics ◽

The Body ◽

Study Patient ◽

Treatment Schedule ◽

High Grade ◽

Concomitant Radiochemotherapy ◽

High Grade Gliomas

Abstract Background The pharmacokinetics of temozolomide (TMZ) in patients with severe renal impairments (creatinine clearance, <36 mL/min/m2) or in hemodialysis (HD) patients has not been investigated. TMZ and its metabolic products are mainly excreted in urine, as retention of these in the body may result in increased adverse events in HD patients. Methods Seven HD patients with high-grade gliomas from 6 institutions were included in the study. Patient characteristics, treatment schedule, clinical course, pathological/molecular findings, and adverse events were evaluated. Results The histopathological diagnoses were isocitrate dehydrogenase (IDH) wild-type glioblastoma in 4 cases, not other specified (NOS) glioblastoma in 2 cases, and IDH-mutant anaplastic astrocytoma in 1 case. Five of the 7 patients completed radiotherapy (48-60 Gy) with concomitant TMZ (75 mg/m2) followed by adjuvant 5-day TMZ (150 mg/m2) every 28 days. During the entire course of treatment with TMZ, severe (Common Terminology Criteria for Adverse Events [CTCAE] ≥ Grade 3) lymphocytopenia occurred in 57%, neutropenia in 0%, and thrombocytopenia in 14% of the patients. Generally, the frequency and degree of myelosuppression do not increase in HD patients with high-grade gliomas. Two of the 7 (28.5%) patients died of infectious disease despite having no direct correlation to myelosuppression; that is similar to the death rate of 21.9% resulting from infection in HD patients in Japan. Conclusions Decreasing the dose of TMZ might not be required in HD patients with high-grade gliomas during concomitant radiochemotherapy and maintenance therapy. However, careful clinical and hematological observation is required to avoid critical hematotoxicity and infection.

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Elimination of Cancer Stem–Like Side Population in Human Glioblastoma Cells Accompanied With Stemness Gene Suppression by Korean Herbal Recipe MSC500

Integrative Cancer Therapies ◽

10.1177/1534735414549623 ◽

2014 ◽

Vol 13 (6) ◽

pp. 541-554 ◽

Cited By ~ 5

Author(s):

Chih-Jung Yao ◽

Tae-Young Han ◽

Ping-Hsiao Shih ◽

Tsu-Yi Yi ◽

I-Chun Lai ◽

...

Keyword(s):

Glioblastoma Multiforme ◽

Molecular Mechanisms ◽

Side Population ◽

High Grade Glioma ◽

Therapeutic Effects ◽

Mrna Levels ◽

High Grade ◽

Human Glioblastoma ◽

High Grade Gliomas ◽

E Cadherin

Background: High-grade gliomas are the most common and invasive malignant brain tumors in adults, and they are almost universally fatal because of drug resistance and recurrence. In spite of the progress in adjuvant therapy (like temozolomide) and irradiation after surgery, no effective salvage therapy is currently available for relapsed patients. A Korean herbal recipe MSC500 has been reported to have beneficial therapeutic effects in patients with high-grade gliomas who are relapsed or refractory to conventional treatments. But the underlying molecular mechanisms remain unclear. Methods: As Cancer stem cell (CSC) plays a pivotal role in the resistance to conventional cancer therapy, we explored the effects of MSC500 on the CSC-like side population (SP) in GBM8401 human glioblastoma multiforme cells. Results: Compared with the parental cells, the SP cells were more resistant to temozolomide but sensitive to MSC500. The mRNA levels of stemness genes such as Nanog, CD133, and ABCG2 were much higher in the SP cells, and so was E-cadherin, which was reported to correlate with the aggressiveness of glioblastoma multiforme. Treatment with MSC500 decreased the proportion of SP cells and high ALDH activity cells from 1.6% to 0.3% and from 0.9% to 0.1%, respectively, accompanied with suppression of the aforementioned stemness genes and E-cadherin, as well as other CSC markers such as ABCB5, Oct-4, Sox-2, β-catenin, Gli-1, and Notch-1. Conclusion: Our results suggest the potential role of MSC500 as an integrative and complementary therapeutic for advanced or refractory high-grade glioma patients.

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