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

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.

scholarly journals A Pilot Study of Vaccine Therapy with Multiple Glioma Oncoantigen/Glioma Angiogenesis-Associated Antigen Peptides for Patients with Recurrent/Progressive High-Grade Glioma

2019 ◽  
Vol 8 (2) ◽  
pp. 263 ◽  
Author(s):  
Ryogo Kikuchi ◽  
Ryo Ueda ◽  
Katsuya Saito ◽  
Shunsuke Shibao ◽  
Hideaki Nagashima ◽  
...  
Keyword(s):  
T Lymphocyte ◽  
High Grade Glioma ◽  
Complete Response ◽  
Recurrent Glioblastoma ◽  
Vaccine Therapy ◽  
High Grade ◽  
Peptide Epitopes ◽  
Dismal Prognosis ◽  
Multiple Glioma ◽  
Lymphocyte Responses

High-grade gliomas (HGGs) carry a dismal prognosis despite current treatments. We previously confirmed the safety and immunogenicity of a vaccine treatment targeting tumor angiogenesis with synthetic peptides, for vascular endothelial growth factor receptor (VEGFR) epitopes in recurrent HGG patients. In this study, we evaluated a novel vaccine therapy targeting not only tumor vasculature but also tumor cells, using multiple glioma oncoantigen (GOA)/glioma angiogenesis-associated antigen (GAAA) peptides in HLA-A2402+ recurrent/progressive HGG patients. The vaccine included peptide epitopes from four GOAs (LY6K, DEPDC1, KIF20A, and FOXM1) and two GAAAs (VEGFR1 and VEGFR2). Ten patients received subcutaneous vaccinations. The primary endpoint was the safety of the treatment. T-lymphocyte responses against GOA/GAAA epitopes and treatment response were evaluated secondarily. The treatment was well tolerated without any severe systemic adverse events. The vaccinations induced immunoreactivity to at least three vaccine-targeted GOA/GAAA in all six evaluable patients. The median overall survival time in all patients was 9.2 months. Five achieved progression-free status lasting at least six months. Two recurrent glioblastoma patients demonstrated stable disease. One patient with anaplastic oligoastrocytoma achieved complete response nine months after the vaccination. Taken together, this regimen was well tolerated and induced robust GOA/GAAA-specific T-lymphocyte responses in recurrent/progressive HGG patients.

scholarly journals H3K27M and TERT Promoter Mutations Are Poor Prognostic Factors in Surgical Cases of Adult Thalamic High-Grade Glioma

2021 ◽  
Author(s):  
Yoshinari Osada ◽  
Ryuta Saito ◽  
Ichiyo Shibahara ◽  
Keisuke Sasaki ◽  
Takuhiro Shoji ◽  
...  
Keyword(s):  
Prognostic Significance ◽  
Progression Free Survival ◽  
High Grade Glioma ◽  
Molecular Characteristics ◽  
High Grade ◽  
Wild Type ◽  
Target Sequencing ◽  
Dismal Prognosis ◽  
Tert Promoter Mutations ◽  
Promoter Mutations

Abstract Background Thalamic high-grade gliomas (HGGs) are rare tumors with a dismal prognosis. H3K27M and telomerase reverse transcriptase promoter (TERTp) mutations reportedly contribute to poor prognoses in HGG cases. We investigated the outcomes of surgically treated adult thalamic HGGs to evaluate the prognostic significance of H3K27M and TERTp mutations. Methods We retrospectively analyzed 25 adult patients with thalamic HGG who underwent maximum surgical resection from January 1997 to March 2020. The histological and molecular characteristics, progression-free survival (PFS), and overall survival (OS) of the patients were compared. For molecular characteristics, target sequencing was used to determine the H3F3A, HIST1H3B, and TERTp mutations. Results H3K27M mutations were detected in 12/25 (48.0%) patients. TERTp mutations were not detected in H3K27M-mutant gliomas but were detected in 8/13 (61.5%) of H3 wild-type gliomas. Although it was not significant, H3K27M-mutant gliomas tended to have a shorter PFS (6.7 vs. 13.1 months; P = 0.2928) and OS (22.8 vs. 24.4 months; P = 0.2875) than H3 wild-type gliomas. Moreover, the prognosis of TERTp-mutant gliomas was as poor as that of H3K27M-mutant gliomas. Contrary, five gliomas harboring both H3 and TERTp wild-type showed a better median PFS (59.2 vs. 6.4 months; P = 0.0456) and OS (71.8 vs. 24.4 months; P = 0.1168) than those harboring H3K27M or TERTp mutations. Conclusions TERTp-mutant gliomas included in the H3 wild-type glioma group limited patient survival as they exhibited an aggressive course similar to H3K27M-mutant gliomas. Comprehensive molecular work-up for the H3 wild-type cases may further confirm this finding.

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

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.

A phase I trial using the proteasome inhibitor bortezomib and concurrent temazolomide and radiotherapy for high grade gliomas

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2061-2061 ◽  
Author(s):  
A. Dicker ◽  
M. Werner-Wasik ◽  
M. Machtay ◽  
G. Mallon ◽  
M. Ramirez ◽  
...  
Keyword(s):  
Phase I ◽  
Proteasome Inhibitor ◽  
Performance Status ◽  
Brain Mri ◽  
Treatment Resistance ◽  
High Grade Glioma ◽  
Proteasome Inhibition ◽  
High Grade ◽  
Open Label ◽  
Dose Levels

2061 Background: Improving the response of patients with high-grade astrocytomas continues to remain a challenge despite advances in chemoradiation. Preclinical studies have demonstrated the importance of the NF-kappaB pathway treatment resistance and enhancement of radiosensitivity by proteasome inhibition. This open-label, phase I study evaluated the safety of 3 dose levels (0.7, 1.0, 1.3 mg/m2/dose) of intravenously administered bortezomib, a reversible proteasome inhibitor with unique properties in combination with chemoradiation. Methods: Eligible patients had a diagnosis of high-grade glioma. Other requirements included performance status 0–1 and adequate hematologic reserve. Previous radiotherapy and/or chemotherapy was allowed. Patients received fraction sizes of XRT that ranged from 1.8–3.5 Gy/day for total doses between 35–66 Gy. During radiotherapy, temozolomide was administered continuously at a daily dose of 75 mg/m2. The starting dose level of bortezomib was 0.7 mg/m2/ days 1, 4, 8, 11 of 21-day cycle for up to 2 cycles. This was followed by 1.0 mg/m2 and 1.3 mg/m2 dose levels. The primary endpoint of the study was dose-limiting toxicity (DLT), defined as any Grade 4–5 toxicity or Grade 3 toxicity(ies) requiring hospitalization and/or XRT interruption. Response was also assessed (1-month post-XRT brain MRI). Results: A total of 27 patients were enrolled. There were no DLTs observed in any dose groups. Grade 1 and 2 toxicities consisted of stomatitis, erythema, and alopecia. Of 24 patients evaluable for response, 1 patient had no evidence of disease, 3 patients had a PR; 9 patients had stable disease and 11 patients had progressive disease. Conclusions: Bortezomib can be combined at full dose with concurrent temozolomide and radiation therapy with minimal adverse effects. Correlative translational endpoints are still pending. The results observed justify further evaluation in a phase II setting. [Table: see text]

scholarly journals MODL-31. RADIATION-DERIVED TREATMENT-RESISTANT PDX AND CELL CULTURE MODELS RECAPITULATE THE CHARACTERISTICS OF MATCHED PRIMARY/RECURRENT PEDIATRIC HIGH-GRADE GLIOMA

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii417-iii417
Author(s):  
Aaron J Knox ◽  
Patrick Flannery ◽  
Anjali Zukosky ◽  
John DeSisto ◽  
Bridget Sanford ◽  
...  
Keyword(s):  
Drug Testing ◽  
Mapk Pathway ◽  
Enrichment Analysis ◽  
High Grade Glioma ◽  
Mek Inhibitor ◽  
Cell Cycle Checkpoint ◽  
High Grade ◽  
Rna Seq ◽  
M Cell ◽  
Pediatric High Grade Glioma

Abstract BACKGROUND Pediatric high-grade glioma (pHGG) is the most common cause of childhood cancer death. Recurrence after therapy is a major challenge, since recurrent pHGG proliferates aggressively and resists therapy. We developed and validated preclinical models of matched primary and recurrent tumors, providing a method to study recurrence and potential therapies. METHODS We irradiated H3K27M thalamic pHGG cells (BT245) (8 Gy/week,2Gy fractions x3 weeks) and propagated the surviving cells (BT245R). We developed a murine recurrence model by orthotopically implanting BT245 cells, irradiating the resultant tumors (4 Gy/day x2d) and propagating irradiated (BT245RM) or control (BT245CM) tumor cells at endpoint. We performed phenotypic analyses, RNA-Seq, and drug testing. RESULTS BT245R cells were more stemlike than BT245, with an 8-fold greater rate of neurosphere formation (p<0.03). Geneset enrichment analysis showed similar molecular changes in BT245RM cells and primary/recurrent H3K27M pHGG patient sample pair, including relaxation of the G2/M cell cycle checkpoint (Hallmark_G2M_Checkpoint: BT245RM NES=-5.95, FDR=0.0; patient NES=-5.86, FDR=0.0), downregulation of MYC targets (Hallmark_MYC_Targets_V1: BT245RM NES=-7.43, FDR=0.0; patient NES=-5.86, FDR=0.0), and decreased differentiation (Go_Regulation_of_Stem_Cell_Differentiation: BT245RM NES=-3.35, FDR=0.0; patient NES=-3.15, FDR=0.0). Enrichment of the protein_kinase_C_signaling in BT245RM (NES=2.18,FDR=0.03) suggested response to MAPK pathway inhibition. BT245R cells were twice as sensitive as BT245 cells to the MEK inhibitor trametinib (p<0.05). CONCLUSIONS Our neurosphere and murine orthotopic patient-derived xenograft models recapitulate gene expression changes of matched primary/recurrent pHGG. RNA-Seq analysis validated the model against patient samples and identified trametinib as potentially effective in recurrent pHGG.

scholarly journals DIPG-75. PRECISION MEDICINE FOR PAEDIATRIC HIGH-GRADE DIFFUSE MIDLINE GLIOMAS - RESULTS FROM THE ZERO CHILDHOOD CANCER COMPREHENSIVE PRECISION MEDICINE PROGRAM

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii302-iii302
Author(s):  
Dong-Anh Khuong-Quang ◽  
Sumanth Nagabushan ◽  
Neevika Manoharan ◽  
Greg Arndt ◽  
Paulette Barahona ◽  
...  
Keyword(s):  
Childhood Cancer ◽  
Precision Medicine ◽  
Drug Testing ◽  
Kinase Inhibitors ◽  
Mtor Inhibitors ◽  
High Grade Glioma ◽  
Molecular Profiling ◽  
Response To Treatment ◽  
High Grade

Abstract The Australian Zero Childhood Cancer (ZERO) program aims to assess the feasibility of a comprehensive precision medicine approach to improve outcomes for patients with an expected survival <30%. ZERO combines molecular profiling (whole genome sequencing, whole transcriptome sequencing, DNA methylation profiling) with in vitro high-throughput drug screening (HTS) and patient-derived xenograft drug efficacy testing. We report on the cohort of patients with midline high-grade glioma (HGG), including H3-K27M DMG, enrolled on the pilot study (TARGET) and on the ongoing ZERO clinical trial (PRISM). We identified 48 patients with midline HGG. Fresh or cryopreserved samples were submitted in 37 cases and cell culture was attempted in 30/37 cases with 45% success rate. The most commonly mutated genes/pathways identified by molecular profiling include H3-K27M mutations, DNA repair pathway, and PI3K/mTOR pathway. Two targetable fusions (NTRK and FGFR1) were reported. Five patients with germline alterations were identified. Thirty-five (72%) patients received a therapeutic recommendation from the ZERO molecular tumour board and the main recommended therapies were mTOR inhibitors, PARP inhibitors or tyrosine kinase inhibitors. HTS added evidence for the recommended therapy (n=3) or identified novel potential therapy (n=1). Out of the 35 patients, 16 received a recommended drug. Response to treatment was complete response for five months (n=1), partial response for nine months (n=1), stable disease (n=4), and progressive disease (n=10). These results highlight the feasibility of the ZERO platform and the value of fresh biopsy, necessary for pre-clinical drug testing. Targetable alterations were identified leading to clinical benefit in six patients.

scholarly journals RARE-19. PEDIATRIC HIGH GRADE GLIOMA WITH DNA REPAIR PATHWAY ABERRATIONS, CLINICAL CHARACTERISTICS AND OUTCOME

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii446-iii446
Author(s):  
Muhammad Baig ◽  
David McCall ◽  
Tyler Moss ◽  
David Sandberg ◽  
Gregory Fuller ◽  
...  
Keyword(s):  
Family History ◽  
Lynch Syndrome ◽  
Mismatch Repair ◽  
Median Time ◽  
Treatment Resistance ◽  
High Grade Glioma ◽  
Low Grade ◽  
High Grade ◽  
Loss Of Function ◽  
Mmr Genes

Abstract DNA mismatch repair machinery is an integral part of the human genome and its defect has been involved in tumorigenesis and treatment resistance. Heterozygous monoallelic germline loss of function in MLH-1, MSH-2, MSH-6 or PMS-2 is involved in Lynch syndrome, whereas biallelic mutations cause constitutional mismatch repair deficiency (CMMRD) which is associated with hematologic malignancies and glioblastoma. We report here the clinical characterization and molecular analyses of 7 patients who presented with gliomas and MMR machinery aberrations. Two patients had a clinical diagnosis of NF-1 with dermatologic stigmata, of whom one patient has CMMRD and the other has Lynch syndrome. Two patients had a known family history of Lynch syndrome upon their diagnosis of glioma. Three patients with high-grade glioma and negative family history, 2 had germline mutations in MMR genes, and one had numerous mutations including MMR genes with microsatellite instability. Patients were initially treated with chemotherapy and radiation for high-grade gliomas (HGG); 5/7 had progression. Median time to progression was 12 months (range: 5–52), and median time from progression to death was 7 months (range: 2–25). One patient had low-grade glioma initially but progressed to HGG and is currently on therapy. Another patient treated with temozolomide and radiation is currently receiving maintenance therapy without any disease recurrence. Although the literature data on brain tumors with MMR deficiency is limited, these consistently show that MMRD-associated gliomas are treatment-resistant and have a dismal outcome. Collaborative efforts are needed to better understand this subgroup of pediatric HGG and to define optimal treatment strategy.

scholarly journals 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

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.

scholarly journals Comparative proteogenomic characterization of glioblastoma

CNS Oncology ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. CNS37 ◽  
Author(s):  
Samia Asif ◽  
Rawish Fatima ◽  
Rebecca Krc ◽  
Joseph Bennett ◽  
Shahzad Raza
Keyword(s):  
Survival Data ◽  
Hot Spot ◽  
High Grade Glioma ◽  
Egfr Mutations ◽  
Driver Mutations ◽  
Driver Gene ◽  
Major Pathway ◽  
Genomic Expression ◽  
Dismal Prognosis ◽  
Egfr Expression

Aim: Glioblastoma multiforme (GBM) carries a dismal prognosis. Integrated proteogenomic analysis was performed to understand GBM pathophysiology. Patients & methods: 17 patient samples were analyzed for driver mutations, oncogenes, major pathway alterations and molecular changes at gene and protein level. Clinical, treatment and survival data were collected. Results: Significantly mutated genes included TP53, EGFR, PIK3R1, PTEN, NF1, RET and STAG2. EGFR mutations noted included EGFRvIII-expression, EGFR- L816Q missense mutation-exon 21 and EGFR fusion (FGFR3-TACC3). TP53 mutations were noticed in COSMIC hot-spot driver gene and accompany IDH1 and ATRX mutations suggesting low- to high-grade glioma transformation. Proteomics showed higher (53%) EGFR expression than genomic expression (23%). MGMT methylation was present in two-thirds of cases. Conclusion: This study identifies a distinct biological process that may characterize each GBM differently. Proteogenomic data identify potential therapeutic targets of GBM.

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