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

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.

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

Neuro-Oncology ◽

10.1093/neuonc/noaa215.400 ◽

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.

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Diffuse intrinsic pontine glioma: current insights and future directions

Chinese Neurosurgical Journal ◽

10.1186/s41016-020-00218-w ◽

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.

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

Neuro-Oncology ◽

10.1093/neuonc/noaa222.586 ◽

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.

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

Neurosurgery ◽

10.1093/neuros/nyz212 ◽

2019 ◽

Vol 86 (5) ◽

pp. 742-751 ◽

Cited By ~ 3

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.

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09 Could DLX2 regulation of neural progenitor cell fate contribute to differentiation of diffuse intrinsic pontine glioma (DIPG)?

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/cjn.2018.305 ◽

2018 ◽

Vol 45 (S3) ◽

pp. S16-S16

Author(s):

M Nevin ◽

X Song ◽

S Japoni ◽

J Zagozewski ◽

Q Jiang ◽

...

Keyword(s):

Cell Fate ◽

Neural Progenitor Cell ◽

Diffuse Intrinsic Pontine Glioma ◽

Gabaergic Interneuron ◽

Acid Decarboxylase ◽

Pontine Glioma ◽

Double Knockout ◽

Promoter Sequences

Introduction: Diffuse intrinsic pontine glioma (DIPG) is refractory to therapy. The identification of histone H3.1/H3.3 K27M mutations in most DIPG has provided new insights. The DLX homeobox genes are expressed in the developing forebrain. The Dlx1/Dlx2 double knockout (DKO) mouse loses tangential GABAergic interneuron migration to the neocortex. We have identified genes that encode glutamic acid decarboxylase (GAD) enzymes as direct targets of DLX1/DLX2. In DIPG patients with H3.3 K27M mutations there is decreased Dlx2 and increased expression of the myelin transcription factor, Myt1. Methods and Results: We used bioinformatics approaches and chromatin immunoprecipitation (ChIP) assays to identify Olig2, Nkx2.2 and Myt1 promoter sequences as candidate DLX2 targets in vivo. DNA binding specificity was confirmed. The functional consequences of Dlx2 co-expression with reporter constructs of ChIP-isolated promoter fragments of Olig2 and Nkx2.2 demonstrated repression of gene targets in vitro. qPCR showed increased Olig2 and Nkx2.2 expression in the DKO forebrain. Stable transfection of a murine DIPG cell line with Dlx2 resulted in increased Gad1 and Gad2 and decreased Olig2 and Nkx2.2 expression. Of significance, we demonstrated decreased expression of H3.3 K27M and restoration of H3.3 K27 tri-methylation (me3). Conclusions: DLX transcription factors promote GABAergic interneuron and concomitant inhibition of oligodendroglial differentiation in neural progenitors by repression of a suite of genes including Olig2 and Nkx2.2. Restoration of H3 K27me3 expression in DIPG provides a promising lead towards exploration of differentiation as a therapeutic strategy for DIPG.

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EXTH-58. THERAPEUTIC HDAC INHIBITION IN HYPERMUTANT DIFFUSE INTRINSIC PONTINE GLIOMA

Neuro-Oncology ◽

10.1093/neuonc/noab196.697 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi176-vi176

Author(s):

Alyssa Noll ◽

Matt Biery ◽

Carrie Myers ◽

Danyelle Paine ◽

Ye Zheng ◽

...

Keyword(s):

Tumor Regression ◽

Hdac Inhibitors ◽

Cancer Cell Line ◽

Residual Tumor ◽

Diffuse Intrinsic Pontine Glioma ◽

Cross Resistance ◽

Pontine Glioma ◽

Dismal Prognosis

Abstract Diffuse intrinsic pontine glioma (DIPG) continues to carry a dismal prognosis despite a growing understanding of its epigenetic regulation. While generally reclassified as diffuse midline glioma, H3 K27M-mutant (DMG), a subgroup of DIPGs do not harbor the classic histone mutation, with a further subset exhibiting a hypermutant phenotype. To evaluate whether hypermutant DIPG shares transcriptional vulnerabilities with H3K27M-mutant DMG, we screened a biopsy-derived treatment-naive PMS2 mutant DIPG model (PBT-24FH) for sensitivity to a panel of HDAC inhibitors (HDACi). In vitro evaluation of cell viability revealed the low nanomolar IC50 of quisinostat (50nM) and romidepsin (2nM). Dose-dependent increases in H3 acetylation and c-PARP were confirmed by western blot. Despite romidepsin’s superior potency in vitro, quisinostat demonstrated greater efficacy in an in vivo PBT-24FH flank study. 42 days following drug initiation, quisinostat-treated mice displayed dramatic tumor regression (mean volume= 33mm3, n= 7) compared to mice treated with romidepsin (mean volume= 669mm3, n= 7)(p= 0.005), or vehicle (mean volume= 990mm3, n= 6)(p< 0.001). Immunohistochemistry of quisinostat-treated tumors revealed few residual tumor cells displaying a low proliferative index. To evaluate cross-resistance, romidepsin-treated mice (mean volume= 1158mm3, n= 2) were switched to quisinostat treatment and displayed swift tumor regression (mean volume after 25 days of quisinostat= 419mm3), emphasizing quisinostat’s in vivo cytotoxic effect against both large tumors and tumors previously treated by another HDACi. To evaluate quisinostat’s effect on other hypermutant tumors, we tested HCT-116, a colon cancer cell line bearing a biallelic MLH1 deletion and observed similar cytotoxicity. We also aim to repeat these studies utilizing additional pediatric hypermutant high grade glioma models. Transcriptomic and proteomic investigations are underway to identify the mechanism of action underlying quisinostat-induced cytotoxicity. Ultimately, we are the first to demonstrate in vivo efficacy of the HDACi quisinostat against hypermutant DIPG, supporting further investigation and clinical advancement.

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Design considerations of an IL13Rα2 antibody–drug conjugate for diffuse intrinsic pontine glioma

Acta Neuropathologica Communications ◽

10.1186/s40478-021-01184-9 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Xiaolei Lian ◽

Dina Kats ◽

Samuel Rasmussen ◽

Leah R. Martin ◽

Anju Karki ◽

...

Keyword(s):

Therapeutic Target ◽

The United States ◽

Diffuse Intrinsic Pontine Glioma ◽

Normal Brain ◽

Cell Models ◽

Pontine Glioma ◽

Antibody Drug Conjugate ◽

Drug Conjugate ◽

Antibody Drug

AbstractDiffuse intrinsic pontine glioma (DIPG), a rare pediatric brain tumor, afflicts approximately 350 new patients each year in the United States. DIPG is noted for its lethality, as fewer than 1% of patients survive to five years. Multiple clinical trials involving chemotherapy, radiotherapy, and/or targeted therapy have all failed to improve clinical outcomes. Recently, high-throughput sequencing of a cohort of DIPG samples identified potential therapeutic targets, including interleukin 13 receptor subunit alpha 2 (IL13Rα2) which was expressed in multiple tumor samples and comparably absent in normal brain tissue, identifying IL13Rα2 as a potential therapeutic target in DIPG. In this work, we investigated the role of IL13Rα2 signaling in progression and invasion of DIPG and viability of IL13Rα2 as a therapeutic target through the use of immunoconjugate agents. We discovered that IL13Rα2 stimulation via canonical ligands demonstrates minimal impact on both the cellular proliferation and cellular invasion of DIPG cells, suggesting IL13Rα2 signaling is non-essential for DIPG progression in vitro. However, exposure to an anti-IL13Rα2 antibody–drug conjugate demonstrated potent pharmacological response in DIPG cell models both in vitro and ex ovo in a manner strongly associated with IL13Rα2 expression, supporting the potential use of targeting IL13Rα2 as a DIPG therapy. However, the tested ADC was effective in most but not all cell models, thus selection of the optimal payload will be essential for clinical translation of an anti-IL13Rα2 ADC for DIPG.

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MODL-29. EVALUATING TUMOR-IMMUNE INTERACTIONS IN MOUSE MODELS OF DIFFUSE INTRINSIC PONTINE GLIOMA

Neuro-Oncology ◽

10.1093/neuonc/noaa222.602 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii417-iii417

Author(s):

Robin Furnish ◽

Heather Bear ◽

Xin Wei ◽

Timothy Phoenix

Keyword(s):

Mouse Models ◽

Diffuse Intrinsic Pontine Glioma ◽

In Vivo Studies ◽

In Vitro Assays ◽

Preclinical Studies ◽

Check Point ◽

Pontine Glioma ◽

Therapeutic Benefits

Abstract BACKGROUND While adult gliomas show some level of immune cell infiltration, diffuse intrinsic pontine glioma (DIPG) is characterized as having an “immune cold” state. We have developed new immunocompetent mouse models of DIPG. These models faithfully recapitulate the pathological hallmarks of DIPG and provides a unique platform to investigate immune modulatory therapies and potential therapeutic benefits of check point inhibitor combination therapies. METHODS To evaluate the effects of CDK4/6 inhibition (CDK4/6i) on cell proliferation and immune interactions we performed a series of in vitro and in vivo studies using DIPG mouse models. In vitro assays included dose response curves, transcriptional profiling, and MHC1 expression. In vivo preclinical studies treated mouse models with CDK4/6i with or without immune check-point inhibitors (ICI). We also examined other candidate immune modulatory therapies in vitro. RESULTS CDK4/6i (Abemeciclib) reduced proliferation of DIPG cells derived from mouse models, and displayed a modest increase in immune activation by MHC1 expression and transcriptome. Pilot in vivo preclinical studies did not show any significant changes in DIPG proliferation or immune changes with CDK4/6i treatment, ICI treatment, or the combination of CDK4/6i + ICI. In vitro testing of other immune-modulatory drugs identified additional candidates that can be tested in vivo. CONCLUSION CDK4/6i displayed in vitro action, but lacked efficacy in DIPG mouse models in vivo. Further use of spontaneous DIPG mouse models will provide a rapid preclinical platform to evaluate in vivo tumor-immune interactions, drug efficacy, and mechanisms of resistance.

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H3K27me3-mediated silencing of Wilms Tumor 1 supports the proliferation of brain tumor cells harboring the H3.3K27M mutation

10.1101/114082 ◽

2017 ◽

Author(s):

Dong Fang ◽

Haiyun Gan ◽

Liang Cheng ◽

Jeong-Heon Lee ◽

Hui Zhou ◽

...

Keyword(s):

Wilms Tumor ◽

Suppressor Gene ◽

Diffuse Intrinsic Pontine Glioma ◽

Pontine Glioma ◽

Mutant Proteins ◽

Brain Tumor Cells ◽

Wilms Tumor 1 ◽

Global Reduction

AbstractThe lysine 27 to methionine mutation of histone H3.3 (H3.3K27M) is detected in over 75% of diffuse intrinsic pontine glioma (DIPG). The H3.3K27M mutant proteins inhibit H3K27 methyltransferase complex PRC2, resulting in a global reduction of tri-methylation of H3K27 (H3K27me3). Paradoxically, high levels of H3K27me3 were also detected at hundreds of genomic loci. However, it is not known how and why H3K27me3 is redistributed in DIPG cells. Here we show that lower levels of H3.3K27M mutant proteins at some genomic loci contribute to the retention of H3K27me3 peaks. But more importantly, Jarid2, a PRC2-associated protein, strongly correlates the presence of H3K27me3 and relieves the H3.3K27M-mediated inhibition in vivo and in vitro. Furthermore, we show that H3K27me3-mediated silencing of tumor suppressor gene Wilms Tumor 1 (WT1) supports the proliferation of DIPG cells and reaction of WT1 inhibits DIPG proliferation. Together, these studies reveal mechanisms whereby H3K27me3 is retained in the environment of global loss of this mark, and how persistence of this mark contributes to DIPG tumorigenesis.

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

Neuro-Oncology ◽

10.1093/neuonc/noab196.291 ◽

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.

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