scholarly journals Defining tumor-associated vascular heterogeneity in pediatric high-grade and diffuse midline gliomas

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Xin Wei ◽  
Michaël H. Meel ◽  
Marjolein Breur ◽  
Marianna Bugiani ◽  
Esther Hulleman ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Neurovascular Unit ◽  
High Grade Glioma ◽  
Model Systems ◽  
High Grade ◽  
Transcriptional Program ◽  
Vascular Phenotype ◽  
Tumor Types ◽  
Tumor Pathogenesis ◽  
Diffuse Midline Glioma

AbstractThe blood–brain barrier (BBB) plays important roles in brain tumor pathogenesis and treatment response, yet our understanding of its function and heterogeneity within or across brain tumor types remains poorly characterized. Here we analyze the neurovascular unit (NVU) of pediatric high-grade glioma (pHGG) and diffuse midline glioma (DMG) using patient derived xenografts and natively forming glioma mouse models. We show tumor-associated vascular differences between these glioma subtypes, and parallels between PDX and mouse model systems, with DMG models maintaining a more normal vascular architecture, BBB function and endothelial transcriptional program relative to pHGG models. Unlike prior work in angiogenic brain tumors, we find that expression of secreted Wnt antagonists do not alter the tumor-associated vascular phenotype in DMG tumor models. Together, these findings highlight vascular heterogeneity between pHGG and DMG and differences in their response to alterations in developmental BBB signals that may participate in driving these pathological differences.

scholarly journals DIPG-80. CLINICAL AND RADIOGRAPHIC RESPONSE TO ONC201 IN A PEDIATRIC PATIENT WITH A THALAMIC H3K27M AND BRAFV600E MUTANT DIFFUSE MIDLINE HIGH GRADE GLIOMA

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii303-iii303
Author(s):  
Elizabeth Duke ◽  
Jonathan Murnick ◽  
Rohinton Tarapore ◽  
Joshua Allen ◽  
Lindsay Kilburn
Keyword(s):  
High Grade Glioma ◽  
Target Lesion ◽  
Subsequent Treatment ◽  
Thalamic Lesion ◽  
High Grade ◽  
Proton Radiation ◽  
Multiple Tumor ◽  
Tumor Types ◽  
The Impact ◽  
Diffuse Midline Glioma

Abstract Recent improved understanding of the molecular markers of high grade glioma has shifted the approach to these aggressive CNS tumors to increasingly use molecularly guided targeted therapies. Treatment of patients with BRAFV600E mutant high grade gliomas with BRAF inhibitors has shown efficacy, however the impact of concomitant H3K27M mutation is unknown. ONC201 targets dopamine receptor D2 (DRD2), which is shown to be broadly overexpressed in the thalamus as well as multiple tumor types; its antagonism has demonstrated anti-tumor efficacy and immunomodulatory properties in preclinical studies. ONC201 has also demonstrated clinical efficacy in patients with H3K27M mutant gliomas. We present the case of a 9-year-old male with a right thalamic H3.3K27M mutant diffuse midline glioma with a concomitant BRAFV600E mutation with an ongoing partial response to ONC201 treatment. The patient was diagnosed in May 2018. He underwent biopsy, followed by standard focal proton radiation therapy (54Gy) and subsequent treatment with dasatinib, bevacizumab and everolimus over the course of five months. After continued radiographic progression on serial imaging, in April 2019 he started ONC201 375mg orally once per week through an expanded access trial. He has tolerated the medication well with grade 1 nausea and fatigue. Over the next nine months, he demonstrated clinical and radiographic improvement with modest increased use of his left side and MRIs showing progressive decrease in size of the thalamic lesion with a 70 % decrease in the target lesion (measuring 53x62mm prior to treatment, decreased to 38x26mm in January 2020).

scholarly journals COT-21 EFFECT OF BEVACIZUMAB FOR PEDIATRIC HIGH GRADE GLIOMA

2019 ◽  
Vol 1 (Supplement_2) ◽  
pp. ii44-ii44
Author(s):  
Yoshihiro Tsukamoto ◽  
Manabu Natsumeda ◽  
Masayasu Okada ◽  
Takeyoshi Eda ◽  
Junichi Yoshimura ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Therapeutic Agent ◽  
High Grade Glioma ◽  
Wound Complication ◽  
Symptomatic Improvement ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Rapid Progression ◽  
High Grade ◽  
Diffuse Midline Glioma ◽  
Pediatric High Grade Glioma

Abstract INTRODUCTION Bevacizumab (BEV) therapy has been used for pediatric high grade glioma,however the evidence and effectiveness are not understood yet. METHODS We report 7 cases (age 2 to 10 years old) of pediatric high grade glioma treated with BEV. One case is thalamic diffuse midline glioma H3K27 mutant (DMGH3K27M),one case is brain stem DMGH3K27M,one case is cerebellar high grade glioma,and 4 cases are diffuse intrinsic pontine glioma (DIPG) diagnosed clinically without biopsy. 5 cases were treated with BEV when diagnosed as recurrence after chemo-radiotherapy. One case was treated for rapid tumor progression during radiotherapy. One case was started on BEV therapy with radiation and concomitant temozolomide therapy. RESULT The number of times of BEV was 2 to 13 times (median 7 times). The period of BEV was 1 to 9 months (median 4 months). One case which was treated with BEV at rapid progression during radiation showed good response on imaging and improvement of symptoms. 4 of 5 cases who were treated at recurrence clinically showed mild symptomatic improvement. One case treated with BEV and radiotherapy initially was not evaluated. The adverse effects of BEV included wound complication of tracheostomy and rash. CONCLUSION BEV showed good response for rapid progression during radiotherapy,and mild response for recurrence cases. BEV is thought to be an effective therapeutic agent for pediatric HGG at recurrence and rapid tumor progression during radiotherapy.

scholarly journals Pediatric high-grade glioma resources from the Children’s Brain Tumor Tissue Consortium

2019 ◽  
Vol 22 (1) ◽  
pp. 163-165 ◽  
Author(s):  
Heba Ijaz ◽  
Mateusz Koptyra ◽  
Krutika S Gaonkar ◽  
Jo Lynne Rokita ◽  
Valerie P Baubet ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Tumor Tissue ◽  
High Grade Glioma ◽  
High Grade ◽  
Pediatric High Grade Glioma

scholarly journals Drug screening linked to molecular profiling identifies novel dependencies in patient-derived primary cultures of paediatric high grade glioma and DIPG

2020 ◽  
Author(s):  
Diana M Carvalho ◽  
Sara Temelso ◽  
Alan Mackay ◽  
Helen N Pemberton ◽  
Rebecca Rogers ◽  
...  
Keyword(s):  
Drug Screening ◽  
Primary Cultures ◽  
High Grade Glioma ◽  
Rational Approach ◽  
High Grade ◽  
Experimental Conditions ◽  
Original Tumour ◽  
Molecular Comparison ◽  
Diffuse Midline Glioma

ABSTRACTPaediatric high grade glioma and diffuse midline glioma (including DIPG) are comprised of multiple biological and clinical subgroups, the majority of which urgently require novel therapies. Patient-derived in vitro primary cell cultures represent potentially useful tools for mechanistic and preclinical investigation based upon their retention of key features of tumour subgroups under experimental conditions amenable to high-throughput approaches. We present 17 novel primary cultures derived from patients in London, Dublin and Belfast, and together with cultures established or shared from Barcelona, Brisbane, Rome and Stanford, assembled a panel of 52 models under 2D (laminin matrix) and/or 3D (neurospheres) conditions, fully credentialed by phenotypic and molecular comparison to the original tumour sample (methylation BeadArray, panel/exome sequencing, RNAseq). In screening a subset of these against a panel of ~400 approved chemotherapeutics and small molecules, we identified specific dependencies associated with tumour subgroups and/or specific molecular markers. These included MYCN-amplified cells and ATM/DNA-PK inhibitors, and DIPGs with PPM1D activating truncating mutations and inhibitors of MDM2 or PARP1. Specific mutations in PDGFRA were found to confer sensitivity to a range of RTK inhibitors, though not all such mutations conferred sensitivity to targeted agents. Notably, dual PDGFRA/FGFR and downstream pathway MEK inhibitors showed profound effects against both PDGFRA-sensitising mutant and FGFR1-dependent non-brainstem pHGG and DIPG. In total, 85% cells were found to have at least one drug screening hit in short term assays linked to the underlying biology of the patient’s tumour, providing a rational approach for individualised clinical translation.

scholarly journals Development of barcode and proteome profiling of glioblastoma

2014 ◽  
Vol 60 (3) ◽  
pp. 308-321 ◽  
Author(s):  
S.N. Naryzhny ◽  
N.L. Ronzhina ◽  
M.A. Mainskova ◽  
N.V. Belyakova ◽  
R.A. Pantina ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Brain Tumor ◽  
Cell Lines ◽  
High Grade Glioma ◽  
Initial Step ◽  
High Grade ◽  
Glioblastoma Cell ◽  
Cancer Death ◽  
Annexin 1 ◽  
Glioblastoma Cell Lines

High grade glioma (glioblastoma) is the most common brain tumor. Its malignancy makes it the fourth biggest cause of cancer death. In our experiments we used several glioblastoma cell lines generated in our laboratory to obtain proteomics information specific for this disease. This study starts our developing the complete 2DE map of glioblastoma proteins. 2DE separation with following imaging, immunochemistry, spot picking, and mass-spectrometry allowed us detecting and identifying more than 100 proteins. Several of them have prominent differences in their level between norm and cancer. Among them are alpha-enolase (ENOA_HUMAN), pyruvate kinase isozymes M1/M2 (KPYM_HUMAN), cofilin 1 (COF1_HUMAN), translationally-controlled tumor protein TCTP_HUMAN, annexin 1 (ANXA1_HUMAN), PCNA (PCNA_HUMAN), p53 (TP53_HUMAN) and others. Most interesting results were obtained with protein p53. In all glioblastoma cell lines, its level was dramatically up regulated and enriched by multiple additional isoforms. This distribution is well correlated with presence of these proteins inside of cells themselves. At this initial step we suggest the panel of specific brain tumor markers (signature) to help creating noninvasive techniques to diagnose disease. These preliminary data point to these proteins as promising markers of glioblastoma.

scholarly journals A New Mouse Model of Diffuse Midline Glioma to Test Targeted Immunotherapies

2021 ◽  
Author(s):  
Maggie D Seblani ◽  
Markella Zannikou ◽  
Joseph Duffy ◽  
Rebecca N Levine ◽  
Qianli Liu ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Cell Lines ◽  
Median Survival ◽  
Delivery System ◽  
De Novo ◽  
High Grade Glioma ◽  
Cre Recombinase ◽  
High Grade ◽  
Diffuse Midline Glioma ◽  
De Novo Tumors

BACKGROUND: Diffuse midline gliomas remain incurable, with consistently poor outcomes in children despite radiotherapy. Immunotherapeutic approaches hold promise, with the integration of the host's immune system fundamental to their design. Here, we describe a new, genetically engineered immunocompetent model that incorporates interleukin 13 receptor alpha 2 (IL13Rα2), a tumor-associated antigen, which is suitable for further evaluation of the antitumor activity of IL13Rα2-targeted immunotherapeutics in preclinical studies. METHODS: The RCAS-Tv-a delivery system was used to induce gliomagenesis through overexpression of PDGFB and p53 deletion with and without human IL13Rα2 in Nestin-Tva; p53fl/fl mice. Neonatal pups were infected with Cre recombinase and PDGFB+IL13Rα2 or Cre recombinase and PDGFB in forth ventricle or right cortex of the brain to model diffuse midline glioma and pediatric high-grade glioma, respectively. Immunoblotting and flow cytometry was used to confirm target expression. Kaplan-Meier survival curves were established to compare tumor latency in both models. Tumor tissue was analyzed through immunohistochemistry and H&E staining. Cell lines generated from tumor-bearing mice were used for in vitro studies and orthotopic injections. RESULTS: The protein expression of PDGFB and IL13Rα2 was confirmed by flow cytometry and western blot. In both groups, de novo tumors developed without significant difference in median survival between PDGFB and p53 loss (n=25, 40 days) and PDGB, IL13Rα2, and p53 loss (n=33, 38 days, p=0.62). Tumors demonstrated characteristics of high-grade glioma such as infiltration, palisading necrosis, microvascular proliferation, high Ki-67 index, heterogeneous IL13Rα2 expression, and CD11b+ macrophages, along with a low proportion of CD3+ T cells. Orthotopic tumors developed from cell lines retained histopathological characteristics of de novo tumors. Mice orthotopically implanted with cells in the 4th ventricle or right cortex showed a median survival of 42 days and 41 (p=0.56) days, respectively. CONCLUSION: Generation of de novo tumors using the RCAS-Tv-a delivery system was successful, with tumors possessing histopathologic features common to pediatric diffuse gliomas. The development of these models opens the opportunity for preclinical assessment of IL13Rα2-directed immunotherapies with the potential for clinical translation.

scholarly journals PENGARUH HIPERKOAGULASI TERHADAP MORTALITAS ASTROSITOMA PADA PEMANTAUAN 12 BULAN

2020 ◽  
Vol 37 (1) ◽  
Author(s):  
Among Wibowo ◽  
Tiara Aninditha ◽  
Henry Riyanto Sofyan ◽  
Rini Andriani
Keyword(s):  
Brain Tumor ◽  
Prothrombin Time ◽  
Partial Thromboplastin Time ◽  
High Grade Glioma ◽  
Activated Partial Thromboplastin Time ◽  
Hypercoagulable State ◽  
Cancer Center ◽  
High Grade ◽  
D Dimer

EFFECT OF HYPERCOAGULABILITY TO ASTROCYTOMA MORTALITY WITHIN 12-MONTHS OF FOLLOW UPABSTRACTIntroduction: Astrocytoma is the most common primary brain tumor. Hypercoagulable state is one of brain tumor complications which can cause vein thromboembolism (VTE). Vein thromboembolism incidence is increased in astrocytoma patients. Hypercoagulable state in astrocytoma could lower patient’s survival.Aim: To investigate the effect of hypercoagulable state on mortality within 12 months of follow up in astrocytoma patients.Methods: This study design was retrospective cohort. This research data was taken from medical records in Cipto Mangunkusumo General Hospital and Dharmais Cancer Center Hospital on December 2017-February 2018. The subjects were adult astrocytoma patients who had histopathology and hemostasis examination. The variables investigated in this study were gender, age, prothrombin time (PT), activated partial thromboplastin time (aPTT), and D-dimer. Data processed descriptively and analytically using SPSS ver. 20 for Windows.Results: There were 49 subjects in this research. Around 30 (61.2%) subjects were men and 20 (40.8%) subjects aged >50 years old. High grade glioma was found in 39 (79.6%) subjects and hypercoagulable state was found in 34 (69.4%) subjects. There were 20 subjects deceased in 12-month follow-up. Subjects with hypercoagulable state had relative risk (RR) of 3.97 more susceptible to die in 12-month follow-up compared to control (p=0.009).Discussion: Hypercoagulation was a mortality risk factor in 12-month follow-up in patients with astrocytoma.Keywords: Astrocytoma, hypercoagulation, mortality within 12-months of follow upABSTRAKPendahuluan: Astrositoma merupakan tumor otak primer yang paling sering ditemukan. Salah satu komplikasi dari tumor otak adalah keadaan hiperkoagulasi. Keadaan hiperkoagulasi dapat menyebabkan tromboemboli vena. Insiden tromboemboli vena meningkat pada astrositoma. Keadaan hiperkoagulasi pada astrositoma dapat menurunkan kesintasan atau meningkatkan mortalitas pada pasien astrositoma.Tujuan: Mengetahui pengaruh hiperkoagulasi pada mortalitas pasien astrositoma dalam 12 bulan pemantauan.Metode: Penelitian kohort retrospektif terhadap pasien tumor otak jenis astrositoma yang dirawat oleh Divisi Neuroonkologi di RSUPN Dr. Cipto Mangunkusumo (RSCM) dan RS Pusat Kanker Dharmais (RSKD) pada bulan Desember 2017 hingga Februari 2018. Sumber data adalah data sekunder berupa rekam medis pasien dewasa yang telah memiliki hasil pemeriksaan histopatologis dan hemostasis. Variabel yang diambil dalam penelitian ini adalah jenis kelamin, usia, prothrombin time (PT), activated partial thromboplastin time (aPTT), dan D-dimer. Data diolah secara deskriptif dan analitik bivariat menggunakan SPSS ver. 20 for Windows.Hasil: Terdapat 49 subjek dalam penelitian ini yang mayoritas (61,2%) laki-laki, berusia <50 tahun (59,2%), dan memiliki jenis high grade gliomas (75,8%). Sebagian besar subjek mengalami hiperkoagulasi (69,4%) dan dalam kondisi hidup (59,2%) pada 12 bulan pascaperawatan. Subjek dengan hiperkoagulasi memiliki risiko relatif (RR) 3,97 kali lebih rentan mengalami kematian setelah 12 bulan dibandingkan kontrol (p=0,009).Diskusi: Hiperkoagulasi merupakan salah satu faktor risiko kematian dalam 12 bulan pada pasien astrositoma.Kata kunci: Astrositoma, hiperkoagulasi, mortalitas 12 bulan

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