scholarly journals Diffuse intrinsic pontine glioma: current insights and future directions

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Dilakshan Srikanthan ◽  
Michael S. Taccone ◽  
Randy Van Ommeren ◽  
Joji Ishida ◽  
Stacey L. Krumholtz ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Gene Mutations ◽  
Pediatric Brain Tumor ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Pontine Glioma ◽  
Current Standard ◽  
In Vivo Models ◽  
Landscape Models

AbstractDiffuse intrinsic pontine glioma (DIPG) is a lethal pediatric brain tumor and the leading cause of brain tumor–related death in children. As several clinical trials over the past few decades have led to no significant improvements in outcome, the current standard of care remains fractionated focal radiation. Due to the recent increase in stereotactic biopsies, tumor tissue availabilities have enabled our advancement of the genomic and molecular characterization of this lethal cancer. Several groups have identified key histone gene mutations, genetic drivers, and methylation changes in DIPG, providing us with new insights into DIPG tumorigenesis. Subsequently, there has been increased development of in vitro and in vivo models of DIPG which have the capacity to unveil novel therapies and strategies for drug delivery. This review outlines the clinical characteristics, genetic landscape, models, and current treatments and hopes to shed light on novel therapeutic avenues and challenges that remain.

DDRE-07. TARGETING TUMOR HYPOXIA AND MITOCHONDRIAL METABOLISM WITH ANTI-PARASITIC DRUGS AS AN APPROACH TO IMPROVE THE RADIOSENSITIVITY OF DIFFUSE INTRINSIC PONTINE GLIOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi75-vi75
Author(s):  
Faiqa Mudassar ◽  
Cecilia Chang ◽  
Prunella Ing ◽  
Kristina Cook ◽  
Geraldine O'Neill ◽  
...  
Keyword(s):  
Hypoxia Inducible Factor ◽  
Tumor Hypoxia ◽  
Pediatric Brain Tumor ◽  
Diffuse Intrinsic Pontine Glioma ◽  
In Vivo Studies ◽  
Pontine Glioma ◽  
Antiproliferative Effects ◽  
Extracellular Flux

Abstract Diffuse intrinsic pontine glioma (DIPG) is an incurable pediatric brain tumor with a median survival of 12 months. Current management is limited to radiotherapy; however, the tumor recurs secondary to radioresistance. Tumor hypoxia appears to be one of the major contributors to radioresistance of DIPG, as oxygenation is critical to successful radiotherapy treatment. Therefore, strategies to alleviate hypoxia could enhance the effectiveness of radiotherapy and result in improved survival outcomes of patients with DIPG. Recent approaches to target tumor hypoxia are predicated on inhibiting mitochondrial respiration of the tumors to decrease oxygen consumption rate (OCR) and increase oxygenation. Here, we aimed to identify a safe but potent mitochondrial inhibitor that could decrease OCR and hypoxia, and improve the radiosensitivity of DIPG. A subset of anti-parasitic drugs (atovaquone, ivermectin, quinacrine, mefloquine and proguanil) which are known mitochondrial inhibitors were studied against a panel of patient-derived DIPG cell lines. We assessed their antiproliferative effects, OCR inhibition and radiosensitising efficacy using cell proliferation, extracellular flux and colony formation assays. Among the five tested drug candidates, atovaquone was found to be the most potent OCR inhibitor with minimal antiproliferative effects on DIPG cultures. It also decreased hypoxia in 3-dimensional DIPG neurospheres, reduced the expression of hypoxia-inducible factor-1α and improved the radiosensitivity of neurospheres of DIPG. Its anti-mitochondrial role was further confirmed by inhibition of various mitochondrial parameters and increase in reactive oxygen species. Overall, these results provide promising in vitro evidence of atovaquone as a hypoxia modifier and radiosensitiser in DIPG and pave a way for rapid translation to in vivo studies.

TAMI-79. THERAPEUTIC REVERSAL OF PRENATAL PONTINE ID1 SIGNALING IN DIPG

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi215-vi215
Author(s):  
Viveka Nand Yadav ◽  
Micah K Harris ◽  
Dana Messinger ◽  
Chase Thomas ◽  
Jessica R Cummings ◽  
...  
Keyword(s):  
Tumor Model ◽  
Pediatric Brain Tumor ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Normal Brain ◽  
Sequencing Analysis ◽  
In Vivo Models ◽  
Chip Sequencing ◽  
Tumor Expression

Abstract Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive pediatric brain tumor with rare survival beyond two years. This poor prognosis is largely due to the tumor's highly infiltrative and invasive nature. Nearly 80% of DMGs harbor K27M mutation in the genes encoding histone H3.1 (H3F3A) or H3.3 (HISTIH3B), often with concurrent ACVR1 mutation. Inhibitor of DNA-binding (ID) proteins are key transcriptional regulators of genes involved in lineage commitment and are associated with invasiveness and poor clinical outcomes in multiple human cancers. Introduction of H3K27M and ACVR1 mutations increase ID1 expression in cultured astrocytes, but this has not been confirmed in human tumors or targeted therapeutically. We developed an in-utero electroporation (IUE) murine H3K27M-driven tumor model, which demonstrates increased ID1 expression in H3K27M- and ACVR1-mutated tumor cells. Exome and transcriptome sequencing analysis of multi-focal DMG tumors (n=52) and normal brain tissue revealed that increased ID1 expression is associated with H3K27M/ACVR1-mutation and brainstem location, and correlates with poor survival in patients. ChIP-sequencing for H3K27ac and H3K27me3 in multiple DMG tumors (n=5) revealed that the ID1 gene is epigenetically active, which matches the epigenetic state of murine prenatal hindbrain cells. Higher ID1-expressing astrocyte-like DIPG cells share a similar transcriptional program with ID1+/SPARCL1+ positive oligo/astrocyte-precursor (OAPC) cells from the developing human brain and demonstrate upregulation of gene sets involved in regulation of cell migration. Both genetic and pharmacologic [cannabidiol (CBD)] suppression of ID1 result in decreased DIPG cell invasion/migration in vitro and invasion/tumor growth in multiple in vivo models. Mechanistically, CBD reduces proliferation through production of reactive oxygen species. Further, DIPG patients treated off-trial with CBD (n=15) displayed reduced ID1 tumor expression and improved overall survival. In summary, ID1 is upregulated in DIPG through K27M-mediated epigenetic reactivation of a developmental OAPC-like transcriptional state, and ID1-driven invasiveness of DIPG is therapeutically targetable with CBD.

scholarly journals DIPG-10. OPTIMAL HDAC INHIBITION IN DIFFUSE INTRINSIC PONTINE GLIOMA

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii288-iii289
Author(s):  
Nicholas Vitanza ◽  
Matt Biery ◽  
Carrie Myers ◽  
Eric Ferguson ◽  
Giulia Park ◽  
...  
Keyword(s):  
Cell Viability ◽  
Hdac Inhibitors ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Model Systems ◽  
Hdac Inhibition ◽  
Pontine Glioma ◽  
In Vivo Models ◽  
Drug Concentrations

Abstract As the majority of diffuse intrinsic pontine glioma (DIPG) have H3K27M mutations, epigenetic-targeting agents have been studied, though evaluations have been limited by their model systems, untranslatable drug concentrations, and/or evasive mechanisms of action. To develop a more translational model, we used biopsy samples from newly diagnosed DIPG patients to create treatment-naïve in vitro and in vivo models (molecular aberrations in parentheses), including PBT-09FH (H3FA3, PI3KCA), PBT-22FH (H3F3A, TP53), PBT-24FH (PMS2), and PBT-27FH (HIST1H3B, TP53, NTRK2). Models demonstrated radiation-resistance similar to the patient from whom the culture was generated, supporting the models’ relevance (e.g. cell viability after 8 Gy was 36%, 81%, 71%, and 61% in PBT-09FH, -22FH, -24FH, and -27FH, respectively, compared to 7% in the medulloblastoma model MED-411FH). We evaluated cell viability and apoptosis following treatment with a panel of HDAC inhibitors, identifying the low nanomolar IC50 of quisinostat (~50 nM) and romidepsin (~5 nM). While RNA expression changes induced by 100 nM panobinostat and quisinostat included shared overexpression of the top 20/25 genes (e.g. FSTL5, ITIH5) and shared downregulation of the top 22/25 (e.g. GPR37L1, HEPACAM), only 9/25 were downregulated by panobinostat, quisinostat, and romidepsin (e.g. C21orf62, IFIT2), identifying these as potential vulnerabilities or biomarkers of lethal HDAC inhibition. Mass-spectrometry (LC-MS) demonstrated panobinostat as the greatest acetylator of cortactin, potentially related to thrombocytopenia. While PBT-09 flank models demonstrated quisinostat’s on-target acetylation and efficacy, orthotopic xenograft models did not, supporting our model’s intact blood-brain barrier and emphasizing the need for CNS penetrant versions of potentially efficacious agents.

scholarly journals EXTH-46. ARTIFICIAL INTELLIGENCE-BASED IDENTIFICATION OF COMBINED VANDETANIB AND EVEROLIMUS IN THE TREATMENT OF ACVR1-MUTANT DIFFUSE INTRINSIC PONTINE GLIOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii97-ii97
Author(s):  
Diana Carvalho ◽  
Peter Richardson ◽  
Nagore Gene Olaciregui ◽  
Reda Stankunaite ◽  
Cinzia Emilia Lavarino ◽  
...  
Keyword(s):  
Artificial Intelligence ◽  
Cell Viability ◽  
Xenograft Model ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Pontine Glioma ◽  
Serine Threonine Kinase ◽  
Orthotopic Xenografts ◽  
Extended Survival

Abstract Somatic mutations in ACVR1, encoding the serine/threonine kinase ALK2 receptor, are found in a quarter of children with the currently incurable brain tumour diffuse intrinsic pontine glioma (DIPG). Treatment of ACVR1-mutant DIPG patient-derived models with multiple inhibitor chemotypes leads to a reduction in cell viability in vitro and extended survival in orthotopic xenografts in vivo, though there are currently no specific ACVR1 inhibitors licensed for DIPG. Using an Artificial Intelligence-based platform to search for approved compounds which could be used to treat ACVR1-mutant DIPG, the combination of vandetanib and everolimus was identified as a possible therapeutic approach. Vandetanib, an approved inhibitor of VEGFR/RET/EGFR, was found to target ACVR1 (Kd=150nM) and reduce DIPG cell viability in vitro, but has been trialed in DIPG patients with limited success, in part due to an inability to cross the blood-brain-barrier. In addition to mTOR, everolimus inhibits both ABCG2 (BCRP) and ABCB1 (P-gp) transporter, and was synergistic in DIPG cells when combined with vandetanib in vitro. This combination is well-tolerated in vivo, and significantly extended survival and reduced tumour burden in an orthotopic ACVR1-mutant patient-derived DIPG xenograft model. Based on these preclinical data, three patients with ACVR1-mutant DIPG were treated with vandetanib and everolimus. These cases may inform on the dosing and the toxicity profile of this combination for future clinical studies. This bench-to-bedside approach represents a rapidly translatable therapeutic strategy in children with ACVR1 mutant DIPG.

scholarly journals MODL-12. DEVELOPMENT OF A NOVEL IMMUNOCOMPETENT MOUSE MODEL FOR DIFFUSE INTRINSIC PONTINE GLIOMA

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii413-iii413
Author(s):  
Maggie Seblani ◽  
Markella Zannikou ◽  
Katarzyna Pituch ◽  
Liliana Ilut ◽  
Oren Becher ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Mouse Model ◽  
Growth Factor Receptor ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Pontine Glioma ◽  
Time Of Application ◽  
Tumor Associated Antigen ◽  
Sarcoma Virus

Abstract Diffuse intrinsic pontine glioma (DIPG) is a devastating brain tumor affecting young children. Immunotherapies hold promise however the lack of immunocompetent models recreating a faithful tumor microenvironment (TME) remains a challenge for development of targeted immunotherapeutics. We propose to generate an immunocompetent DIPG mouse model through induced overexpression of interleukin 13 receptor alpha 2 (IL13Rα2), a tumor-associated antigen overexpressed by glioma cells. A model with an intact TME permits comprehensive preclinical assessment of IL13Rα2-targeted immunotherapeutics. Our novel model uses the retroviral avian leucosis and sarcoma virus (RCAS) for in vivo gene delivery leading to IL13Rα2 expression in proliferating progenitor cells. Transfected cells expressing IL13Rα2 and PDGFB, a ligand for platelet derived growth factor receptor, alongside induced p53 loss via the Cre-Lox system are injected in the fourth ventricle in postnatal pups. We validated the expression of PDGFB and IL13Rα2 transgenes in vitro and in vivo and will characterize the TME through evaluation of the peripheral and tumor immunologic compartments using immunohistochemistry and flow cytometry. We confirmed expression of transgenes via flow cytometry and western blotting. Comparison of survival dynamics in mice inoculated with PDGFB alone with PDGFB+IL13Rα2 demonstrated that co-expression of IL13Rα2 did not significantly affect mice survival compared to the PDGFB model. At time of application, we initiated experiments to characterize the TME. Preliminary data demonstrate establishment of tumors within and adjacent to the brainstem and expression of target transgenes. Preclinical findings in a model recapitulating the TME may provide better insight into outcomes upon translation to clinical application.

scholarly journals Preclinical and clinical evaluation of German-sourced ONC201 for the treatment of H3K27M-mutant diffuse intrinsic pontine glioma

2021 ◽  
Vol 3 (1) ◽  
Author(s):  
Ryan J Duchatel ◽  
Abdul Mannan ◽  
Ameha S Woldu ◽  
Tom Hawtrey ◽  
Phoebe A Hindley ◽  
...  
Keyword(s):  
Biological Activity ◽  
High Resolution Mass Spectrometry ◽  
The United States ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Resonance Spectroscopy ◽  
Pontine Glioma ◽  
Drug Bioavailability ◽  
Proliferation And Apoptosis

Abstract Background Diffuse intrinsic pontine glioma (DIPG) is a fatal childhood brainstem tumor for which radiation is the only treatment. Case studies report a clinical response to ONC201 for patients with H3K27M-mutant gliomas. Oncoceutics (ONC201) is only available in the United States and Japan; however, in Germany, DIPG patients can be prescribed and dispensed a locally produced compound—ONC201 German-sourced ONC201 (GsONC201). Pediatric oncologists face the dilemma of supporting the administration of GsONC201 as conjecture surrounds its authenticity. Therefore, we compared GsONC201 to original ONC201 manufactured by Oncoceutics Inc. Methods Authenticity of GsONC201 was determined by high-resolution mass spectrometry and nuclear magnetic resonance spectroscopy. Biological activity was shown via assessment of on-target effects, in vitro growth, proliferation, and apoptosis analysis. Patient-derived xenograft mouse models were used to assess plasma and brain tissue pharmacokinetics, pharmacodynamics, and overall survival (OS). The clinical experience of 28 H3K27M+ mutant DIPG patients who received GsONC201 (2017–2020) was analyzed. Results GsONC201 harbored the authentic structure, however, was formulated as a free base rather than the dihydrochloride salt used in clinical trials. GsONC201 in vitro and in vivo efficacy and drug bioavailability studies showed no difference compared to Oncoceutics ONC201. Patients treated with GsONC201 (n = 28) showed a median OS of 18 months (P = .0007). GsONC201 patients who underwent reirradiation showed a median OS of 22 months compared to 12 months for GsONC201 patients who did not (P = .012). Conclusions This study confirms the biological activity of GsONC201 and documents the OS of patients who received the drug; however, GsONC201 was never used as a monotherapy.

scholarly journals Glial Cells—The Strategic Targets in Amyotrophic Lateral Sclerosis Treatment

2020 ◽  
Vol 9 (1) ◽  
pp. 261 ◽  
Author(s):  
Tereza Filipi ◽  
Zuzana Hermanova ◽  
Jana Tureckova ◽  
Ondrej Vanatko ◽  
Miroslava Anderova
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Current Knowledge ◽  
Gene Mutations ◽  
Cell Types ◽  
In Vivo Models ◽  
Cell Therapies ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease, which is characterized by the degeneration of motor neurons in the motor cortex and the spinal cord and subsequently by muscle atrophy. To date, numerous gene mutations have been linked to both sporadic and familial ALS, but the effort of many experimental groups to develop a suitable therapy has not, as of yet, proven successful. The original focus was on the degenerating motor neurons, when researchers tried to understand the pathological mechanisms that cause their slow death. However, it was soon discovered that ALS is a complicated and diverse pathology, where not only neurons, but also other cell types, play a crucial role via the so-called non-cell autonomous effect, which strongly deteriorates neuronal conditions. Subsequently, variable glia-based in vitro and in vivo models of ALS were established and used for brand-new experimental and clinical approaches. Such a shift towards glia soon bore its fruit in the form of several clinical studies, which more or less successfully tried to ward the unfavourable prognosis of ALS progression off. In this review, we aimed to summarize current knowledge regarding the involvement of each glial cell type in the progression of ALS, currently available treatments, and to provide an overview of diverse clinical trials covering pharmacological approaches, gene, and cell therapies.

scholarly journals ABC Transporter Inhibition Plus Dexamethasone Enhances the Efficacy of Convection Enhanced Delivery in H3.3K27M Mutant Diffuse Intrinsic Pontine Glioma

Neurosurgery ◽  
2019 ◽  
Vol 86 (5) ◽  
pp. 742-751 ◽  
Author(s):  
Vadim Tsvankin ◽  
Rintaro Hashizume ◽  
Hiroaki Katagi ◽  
James E Herndon ◽  
Christopher Lascola ◽  
...  
Keyword(s):  
Abc Transporter ◽  
Kinase Inhibitor ◽  
Mutant Cell ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Pontine Glioma ◽  
Convection Enhanced Delivery ◽  
P Glycoprotein ◽  
Magnetic Resonance Imaging Mri

Abstract BACKGROUND An impermeable blood–brain barrier and drug efflux via ATP-binding cassette (ABC) transporters such as p-glycoprotein may contribute to underwhelming efficacy of peripherally delivered agents to treat diffuse intrinsic pontine glioma (DIPG). OBJECTIVE To explore the pharmacological augmentation of convection-enhanced delivery (CED) infusate for DIPG. METHODS The efficacy of CED dasatinib, a tyrosine kinase inhibitor, in a transgenic H3.3K27M mutant murine model was assessed. mRNA expression of ABCB1 (p-glycoprotein) was analyzed in 14 tumor types in 274 children. In Vitro viability studies of dasatinib, the p-glycoprotein inhibitor, tariquidar, and dexamethasone were performed in 2 H3.3K27M mutant cell lines. Magnetic resonance imaging (MRI) was used to evaluate CED infusate (gadolinium/dasatinib) distribution in animals pretreated with tariquidar and dexamethasone. Histological assessment of apoptosis was performed. RESULTS Continuous delivery CED dasatinib improved median overall survival (OS) of animals harboring DIPG in comparison to vehicle (39.5 and 28.5 d, respectively; P = .0139). Mean ABCB1 expression was highest in K27M gliomas. In Vitro, the addition of tariquidar and dexamethasone further enhanced the efficacy of dasatinib (P < .001). In Vivo, MRI demonstrated no difference in infusion dispersion between animals pretreated with dexamethasone plus tariquidar prior to CED dasatinib compared to the CED dasatinib. However, tumor apoptosis was the highest in the pretreatment group (P < .001). Correspondingly, median OS was longer in the pretreatment group (49 d) than the dasatinib alone group (39 d) and no treatment controls (31.5 d, P = .0305). CONCLUSION ABC transporter inhibition plus dexamethasone enhances the efficacy of CED dasatinib, resulting in enhanced tumor cellular apoptosis and improved survival in H3.3K27M mutant DIPG.

scholarly journals PDTM-25. STUDY OF ONC201 IN PRE-CLINICAL MODELS OF DIPG

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi192-vi192
Author(s):  
Ajay Sharma ◽  
Yanlai Lai ◽  
Bridget Kennis ◽  
Sreepradha Sridharan ◽  
Tara Dobson ◽  
...  
Keyword(s):  
Intraperitoneal Administration ◽  
Pediatric Brain Tumor ◽  
Standard Of Care ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Tumor Burden ◽  
Phosphorylated Akt ◽  
Ic50 Values ◽  
Different Response

Abstract Diffuse Intrinsic Pontine Glioma (DIPG) is an incurable pediatric brain tumor that occur in the pons and brainstem and have a peak onset of age between 6–9 years of age. Radiation is currently used as standard of care. Chemotherapy has shown no improvements in survival. Here, we report our study of ONC201, a first-in-class anticancer small molecule developed by Oncoceutics, Inc., against DIPG cells in vitro and in mouse orthotopic models. ONC201 was discovered in a screen as a p53-independent inducer of the pro-apoptotic cytokine TRAIL. It is known to directly and selectively inhibit dopamine receptor D2 (DRD2), a member of the G protein-coupled receptor (GPCR) family. MTT assays to determine the sensitivity of DIPG cells to ONC201 revealed a slight but not significantly different response to the drug based on their expression of wild type (WT) histone H3 or histone H3K27M mutant protein, with IC50 values in the range of 3-8mM. Decrease in cell growth was associated with a decrease in AKT and ERK phosphorylation and an increase in TRAIL expression. In vivo, intraperitoneal administration of ONC201 to mice bearing pontine DIPG tumors, once every week for 6 weeks, caused a significant reduction in tumor burden relative to untreated controls as measured by bioluminescence assays. However, stoppage of treatment resulted in tumor regrowth within 6 weeks, suggesting the existence of a population that were not eliminated by the current schedule of ONC210. Single cell proteomic analyses-based comparison of untreated and ONC201-treated DIPG cells showed an expected global reduction in pro-survival signals such as phosphorylated AKT and ERK. Molecules with potential to predict susceptibility of cells to ONC201 were also revealed, and are being confirmed by transcriptome analyses. Results of a chemical screen to target ONC201-refractory tumor cells will be discussed.

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