Publications by authors named "Oren J Becher"

56 Publications

Radiosensitizing the Vasculature of Primary Brainstem Gliomas Fails to Improve Tumor Response to Radiotherapy.

Int J Radiat Oncol Biol Phys 2021 Oct 4. Epub 2021 Oct 4.

Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710 USA; Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, NC 27710 USA.. Electronic address:

Purpose: Diffuse intrinsic pontine gliomas (DIPGs) arise in the pons and are the leading cause of death from brain tumors in children. DIPGs are routinely treated with radiation therapy, which temporarily improves neurological symptoms but generally fails to achieve local control. As numerous clinical trials have not improved survival from DIPG over standard radiotherapy alone, there is a pressing need to evaluate new therapeutic strategies for this devastating disease. Vascular damage caused by radiation therapy can increase permeability of tumor blood vessels and promote tumor cell death.

Methods And Materials: To investigate the impact of endothelial cell death on tumor response to radiotherapy in DIPG, we employed dual recombinase (Cre + FlpO) technology to generate primary brainstem gliomas which lack ataxia telangiectasia mutated (Atm) in the vasculature.

Results: Here, we show that Atm deficient tumor endothelial cells are sensitized to radiation therapy. Furthermore, radiosensitization of the vasculature in primary gliomas triggered an increase in total tumor cell death. Despite the observed increase in cell killing, in mice with autochthonous DIPGs treated with radiotherapy, deletion of Atm specifically in tumor endothelial cells failed to improve survival.

Conclusions: These results suggest that targeting the tumor cells, rather than endothelial cells, during radiotherapy will be necessary to improve survival of children with DIPG.
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http://dx.doi.org/10.1016/j.ijrobp.2021.09.047DOI Listing
October 2021

Prenatal overexpression of platelet-derived growth factor receptor A results in central nervous system hypomyelination.

Brain Behav 2021 Sep 4:e2332. Epub 2021 Sep 4.

Division of Hematology, Oncology, Neuro-Oncology, and Stem Cell Transplant, Ann & Robert H. Lurie Children's Hospital, Chicago, Illinois, USA.

Background: Platelet-derived growth factor (PDGF) signaling, through the ligand PDGF-A and its receptor PDGFRA, is important for the growth and maintenance of oligodendrocyte progenitor cells (OPCs) in the central nervous system (CNS). PDGFRA signaling is downregulated prior to OPC differentiation into mature myelinating oligodendrocytes. By contrast, PDGFRA is often genetically amplified or mutated in many types of gliomas, including diffuse midline glioma (DMG) where OPCs are considered the most likely cell-of-origin. The cellular and molecular changes that occur in OPCs in response to unregulated PDGFRA expression, however, are not known.

Methods: Here, we created a conditional knock-in (KI) mouse that overexpresses wild type (WT) human PDGFRA (hPDGFRA) in prenatal Olig2-expressing progenitors, and examined in vivo cellular and molecular consequences.

Results: The KI mice exhibited stunted growth, ataxia, and a severe loss of myelination in the brain and spinal cord. When combined with the loss of p53, a tumor suppressor gene whose activity is decreased in DMG, the KI mice failed to develop tumors but still exhibited hypomyelination. RNA-sequencing analysis revealed decreased myelination gene signatures, indicating a defect in oligodendroglial development. Mice overexpressing PDGFRA in prenatal GFAP-expressing progenitors, which give rise to a broader lineage of cells than Olig2-progenitors, also developed myelination defects.

Conclusion: Our results suggest that embryonic overexpression of hPDGFRA in Olig2- or GFAP-progenitors is deleterious to OPC development and leads to CNS hypomyelination.
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http://dx.doi.org/10.1002/brb3.2332DOI Listing
September 2021

Magnetic Resonance Imaging-Guided Focused Ultrasound-Based Delivery of Radiolabeled Copper Nanoclusters to Diffuse Intrinsic Pontine Glioma.

ACS Appl Nano Mater 2020 Nov 29;3(11):11129-11134. Epub 2020 Oct 29.

Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA.

Diffuse intrinsic pontine glioma (DIPG) is an invasive pediatric brainstem malignancy exclusively in children without effective treatment due to the often-intact blood-brain tumor barrier (BBTB), an impediment to the delivery of therapeutics. Herein, we used focused ultrasound (FUS) to transiently open BBTB and delivered radiolabeled nanoclusters (Cu-CuNCs) to tumors for positron emission tomography (PET) imaging and quantification in a mouse DIPG model. First, we optimized FUS acoustic pressure to open the blood-brain barrier (BBB) for effective delivery of Cu-CuNCs to pons in wildtype mice. Then the optimized FUS pressure was used to deliver radiolabeled agents in DIPG mouse. Magnetic resonance imaging (MRI)-guided FUS-induced BBTB opening was demonstrated using a low molecular weight, short-lived Ga-DOTA-ECL1i radiotracer and PET/CT before and after treatment. We then compared the delivery efficiency of Cu-CuNCs to DIPG tumor with and without FUS treatment and demonstrated the FUS-enhanced delivery and time-dependent diffusion of Cu-CuNCs within the tumor.
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http://dx.doi.org/10.1021/acsanm.0c02297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8320805PMC
November 2020

Tumor immune landscape of paediatric high-grade gliomas.

Brain 2021 Apr 15. Epub 2021 Apr 15.

Department of Oncological Sciences, The Tisch Cancer Institute, Mount Sinai Icahn School of Medicine, New York, New York, USA.

Over the last decade, remarkable progress has been made towards elucidating the origin and genomic landscape of childhood high-grade brain tumors. It has become evident that pediatric high-grade gliomas (pHGGs) differ from adult HGGs with respect to multiple defining aspects including: DNA copy number, gene expression profiles, tumor locations within the central nervous system, and genetic alterations such as somatic histone mutations. Despite these advances, clinical trials for children with glioma have historically been based on ineffective adult regimens that fail to take into consideration the fundamental biological differences between the two. Additionally, although our knowledge of the intrinsic cellular mechanisms driving tumor progression has considerably expanded, little is known concerning the dynamic tumor immune microenvironment (TIME) in pHGGs. In this review, we explore the genetic and epigenetic landscape of pHGGs and how this drives the creation of specific tumor sub-groups with meaningful survival outcomes. Further, we provide a comprehensive analysis of the pHGG TIME and discuss emerging therapeutic efforts aimed at exploiting the immune functions of these tumors.
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http://dx.doi.org/10.1093/brain/awab155DOI Listing
April 2021

Therapeutic targeting of transcriptional elongation in diffuse intrinsic pontine glioma.

Neuro Oncol 2021 08;23(8):1348-1359

Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Background: Diffuse intrinsic pontine glioma (DIPG) is associated with transcriptional dysregulation driven by H3K27 mutation. The super elongation complex (SEC) is required for transcriptional elongation through release of RNA polymerase II (Pol II). Inhibition of transcription elongation by SEC disruption can be an effective therapeutic strategy of H3K27M-mutant DIPG. Here, we tested the effect of pharmacological disruption of the SEC in H3K27M-mutant DIPG to advance understanding of the molecular mechanism and as a new therapeutic strategy for DIPG.

Methods: Short hairpin RNAs (shRNAs) were used to suppress the expression of AF4/FMR2 4 (AFF4), a central SEC component, in H3K27M-mutant DIPG cells. A peptidomimetic lead compound KL-1 was used to disrupt a functional component of SEC. Cell viability assay, colony formation assay, and apoptosis assay were utilized to analyze the effects of KL-1 treatment. RNA- and ChIP-sequencing were used to determine the effects of KL-1 on gene expression and chromatin occupancy. We treated mice bearing H3K27M-mutant DIPG patient-derived xenografts (PDXs) with KL-1. Intracranial tumor growth was monitored by bioluminescence image and therapeutic response was evaluated by animal survival.

Results: Depletion of AFF4 significantly reduced the cell growth of H3K27M-mutant DIPG. KL-1 increased genome-wide Pol II occupancy and suppressed transcription involving multiple cellular processes that promote cell proliferation and differentiation of DIPG. KL-1 treatment suppressed DIPG cell growth, increased apoptosis, and prolonged animal survival with H3K27M-mutant DIPG PDXs.

Conclusions: SEC disruption by KL-1 increased therapeutic benefit in vitro and in vivo, supporting a potential therapeutic activity of KL-1 in H3K27M-mutant DIPG.
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http://dx.doi.org/10.1093/neuonc/noab009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8328031PMC
August 2021

Platelet-derived growth factor beta is a potent inflammatory driver in paediatric high-grade glioma.

Brain 2021 02;144(1):53-69

Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, USA.

Paediatric high-grade gliomas (HGGs) account for the most brain tumour-related deaths in children and have a median survival of 12-15 months. One promising avenue of research is the development of novel therapies targeting the properties of non-neoplastic cell-types within the tumour such as tumour associated macrophages (TAMs). TAMs are immunosuppressive and promote tumour malignancy in adult HGG; however, in paediatric medulloblastoma, TAMs exhibit anti-tumour properties. Much is known about TAMs in adult HGG, yet little is known about them in the paediatric setting. This raises the question of whether paediatric HGGs possess a distinct constituency of TAMs because of their unique genetic landscapes. Using human paediatric HGG tissue samples and murine models of paediatric HGG, we demonstrate diffuse midline gliomas possess a greater inflammatory gene expression profile compared to hemispheric paediatric HGGs. We also show despite possessing sparse T-cell infiltration, human paediatric HGGs possess high infiltration of IBA1+ TAMs. CD31, PDGFRβ, and PDGFB all strongly correlate with IBA1+ TAM infiltration. To investigate the TAM population, we used the RCAS/tv-a system to recapitulate paediatric HGG in newborn immunocompetent mice. Tumours are induced in Nestin-positive brain cells by PDGFA or PDGFB overexpression with Cdkn2a or Tp53 co-mutations. Tumours driven by PDGFB have a significantly lower median survival compared to PDGFA-driven tumours and have increased TAM infiltration. NanoString and quantitative PCR analysis indicates PDGFB-driven tumours have a highly inflammatory microenvironment characterized by high chemokine expression. In vitro bone marrow-derived monocyte and microglial cultures demonstrate bone marrow-derived monocytes are most responsible for the production of inflammatory signals in the tumour microenvironment in response to PDGFB stimulation. Lastly, using knockout mice deficient for individual chemokines, we demonstrate the feasibility of reducing TAM infiltration and prolonging survival in both PDGFA and PDGFB-driven tumours. We identify CCL3 as a potential key chemokine in these processes in both humans and mice. Together, these studies provide evidence for the potent inflammatory effects PDGFB has in paediatric HGGs.
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http://dx.doi.org/10.1093/brain/awaa382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954387PMC
February 2021

Tumor genotype dictates radiosensitization after Atm deletion in primary brainstem glioma models.

J Clin Invest 2021 01;131(1)

Department of Radiation Oncology.

Diffuse intrinsic pontine glioma (DIPG) kills more children than any other type of brain tumor. Despite clinical trials testing many chemotherapeutic agents, palliative radiotherapy remains the standard treatment. Here, we utilized Cre/loxP technology to show that deleting Ataxia telangiectasia mutated (Atm) in primary mouse models of DIPG can enhance tumor radiosensitivity. Genetic deletion of Atm improved survival of mice with p53-deficient but not p53 wild-type gliomas after radiotherapy. Similar to patients with DIPG, mice with p53 wild-type tumors had improved survival after radiotherapy independent of Atm deletion. Primary p53 wild-type tumor cell lines induced proapoptotic genes after radiation and repressed the NRF2 target, NAD(P)H quinone dehydrogenase 1 (Nqo1). Tumors lacking p53 and Ink4a/Arf expressed the highest level of Nqo1 and were most resistant to radiation, but deletion of Atm enhanced the radiation response. These results suggest that tumor genotype may determine whether inhibition of ATM during radiotherapy will be an effective clinical approach to treat DIPGs.
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http://dx.doi.org/10.1172/JCI142158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773366PMC
January 2021

Convection-Enhanced Delivery of Enhancer of Zeste Homolog-2 (EZH2) Inhibitor for the Treatment of Diffuse Intrinsic Pontine Glioma.

Neurosurgery 2020 Jul 16. Epub 2020 Jul 16.

Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Background: Diffuse intrinsic pontine glioma (DIPG) is a fatal childhood brain tumor and the majority of patients die within 2 yr after initial diagnosis. Factors that contribute to the dismal prognosis of these patients include the infiltrative nature and anatomic location in an eloquent area of the brain, which precludes total surgical resection, and the presence of the blood-brain barrier (BBB), which reduces the distribution of systemically administered agents. Convection-enhanced delivery (CED) is a direct infusion technique to deliver therapeutic agents into a target site in the brain and able to deliver a high concentration drug to the infusion site without systemic toxicities.

Objective: To assess the efficacy of enhancer of zeste homolog-2 (EZH2) inhibitor by CED against human DIPG xenograft models.

Methods: The concentration of EZH2 inhibitor (EPZ-6438) in the brainstem tumor was evaluated by liquid chromatography-mass spectrometry (LC/MS). We treated mice-bearing human DIPG xenografts with EPZ-6438 using systemic (intraperitoneal) or CED administration. Intracranial tumor growth was monitored by bioluminescence image, and the therapeutic response was evaluated by animal survival.

Results: LC/MS analysis showed that the concentration of EPZ-6438 in the brainstem tumor was 3.74% of serum concentration after systemic administration. CED of EPZ-6438 suppressed tumor growth and significantly extended animal survival when compared to systemic administration of EPZ-6438 (P = .0475).

Conclusion: Our results indicate that CED of an EZH2 inhibitor is a promising strategy to bypass the BBB and to increase the efficacy of an EZH2 inhibitor for the treatment of DIPG.
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http://dx.doi.org/10.1093/neuros/nyaa301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666886PMC
July 2020

Tumor necrosis factor overcomes immune evasion in p53-mutant medulloblastoma.

Nat Neurosci 2020 07 18;23(7):842-853. Epub 2020 May 18.

Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA.

Many immunotherapies act by enhancing the ability of cytotoxic T cells to kill tumor cells. Killing depends on T cell recognition of antigens presented by class I major histocompatibility complex (MHC-I) proteins on tumor cells. In this study, we showed that medulloblastomas lacking the p53 tumor suppressor do not express surface MHC-I and are therefore resistant to immune rejection. Mechanistically, this is because p53 regulates expression of the peptide transporter Tap1 and the aminopeptidase Erap1, which are required for MHC-I trafficking to the cell surface. In vitro, tumor necrosis factor (TNF) or lymphotoxin-β receptor agonist can rescue expression of Erap1, Tap1 and MHC-I on p53-mutant tumor cells. In vivo, low doses of TNF prolong survival and synergize with immune checkpoint inhibitors to promote tumor rejection. These studies identified p53 as a key regulator of immune evasion and suggest that TNF could be used to enhance sensitivity of tumors to immunotherapy.
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http://dx.doi.org/10.1038/s41593-020-0628-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456619PMC
July 2020

Pharmacologic inhibition of lysine-specific demethylase 1 as a therapeutic and immune-sensitization strategy in pediatric high-grade glioma.

Neuro Oncol 2020 09;22(9):1302-1314

Department of Pediatrics , Research, The MD Anderson Cancer Center, Houston, Texas.

Background: Diffuse midline gliomas (DMG), including brainstem diffuse intrinsic pontine glioma (DIPG), are incurable pediatric high-grade gliomas (pHGG). Mutations in the H3 histone tail (H3.1/3.3-K27M) are a feature of DIPG, rendering them therapeutically sensitive to small-molecule inhibition of chromatin modifiers. Pharmacological inhibition of lysine-specific demethylase 1 (LSD1) is clinically relevant but has not been carefully investigated in pHGG or DIPG.

Methods: Patient-derived DIPG cell lines, orthotopic mouse models, and pHGG datasets were used to evaluate effects of LSD1 inhibitors on cytotoxicity and immune gene expression. Immune cell cytotoxicity was assessed in DIPG cells pretreated with LSD1 inhibitors, and informatics platforms were used to determine immune infiltration of pHGG.

Results: Selective cytotoxicity and an immunogenic gene signature were established in DIPG cell lines using clinically relevant LSD1 inhibitors. Pediatric HGG patient sequencing data demonstrated survival benefit of this LSD1-dependent gene signature. Pretreatment of DIPG with these inhibitors increased lysis by natural killer (NK) cells. Catalytic LSD1 inhibitors induced tumor regression and augmented NK cell infusion in vivo to reduce tumor burden. CIBERSORT analysis of patient data confirmed NK infiltration is beneficial to patient survival, while CD8 T cells are negatively prognostic. Catalytic LSD1 inhibitors are nonperturbing to NK cells, while scaffolding LSD1 inhibitors are toxic to NK cells and do not induce the gene signature in DIPG cells.

Conclusions: LSD1 inhibition using catalytic inhibitors is selectively cytotoxic and promotes an immune gene signature that increases NK cell killing in vitro and in vivo, representing a therapeutic opportunity for pHGG.

Key Points: 1. LSD1 inhibition using several clinically relevant compounds is selectively cytotoxic in DIPG and shows in vivo efficacy as a single agent.2. An LSD1-controlled gene signature predicts survival in pHGG patients and is seen in neural tissue from LSD1 inhibitor-treated mice.3. LSD1 inhibition enhances NK cell cytotoxicity against DIPG in vivo and in vitro with correlative genetic biomarkers.
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http://dx.doi.org/10.1093/neuonc/noaa058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523459PMC
September 2020

Epigenetic reprogramming and chromatin accessibility in pediatric diffuse intrinsic pontine gliomas: a neural developmental disease.

Neuro Oncol 2020 02;22(2):195-206

Department of Cell and Developmental Biology and Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, Michigan.

Diffuse intrinsic pontine glioma (DIPG) is a rare but deadly pediatric brainstem tumor. To date, there is no effective therapy for DIPG. Transcriptomic analyses have revealed DIPGs have a distinct profile from other pediatric high-grade gliomas occurring in the cerebral hemispheres. These unique genomic characteristics coupled with the younger median age group suggest that DIPG has a developmental origin. The most frequent mutation in DIPG is a lysine to methionine (K27M) mutation that occurs on H3F3A and HIST1H3B/C, genes encoding histone variants. The K27M mutation disrupts methylation by polycomb repressive complex 2 on histone H3 at lysine 27, leading to global hypomethylation. Histone 3 lysine 27 trimethylation is an important developmental regulator controlling gene expression. This review discusses the developmental and epigenetic mechanisms driving disease progression in DIPG, as well as the profound therapeutic implications of epigenetic programming.
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http://dx.doi.org/10.1093/neuonc/noz218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7032633PMC
February 2020

HDAC inhibitors to the rescue in sonic hedgehog medulloblastoma.

Authors:
Oren J Becher

Neuro Oncol 2019 09;21(9):1091-1092

Division of Hematology, Oncology and Stem Cell Transplant, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.

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http://dx.doi.org/10.1093/neuonc/noz115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594552PMC
September 2019

Radiosensitization by Histone H3 Demethylase Inhibition in Diffuse Intrinsic Pontine Glioma.

Clin Cancer Res 2019 09 21;25(18):5572-5583. Epub 2019 Jun 21.

Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Purpose: Radiotherapy (RT) has long been and remains the only treatment option for diffuse intrinsic pontine glioma (DIPG). However, all patients show evidence of disease progression within months of completing RT. No further clinical benefit has been achieved using alternative radiation strategies. Here, we tested the hypothesis that histone demethylase inhibition by GSK-J4 enhances radiation-induced DNA damage, making it a potential radiosensitizer in the treatment of DIPG. We evaluated the effects of GSK-J4 on genes associated with DNA double-strand break (DSB) repair in DIPG cells by RNA sequence, ATAC sequence, and quantitative real-time PCR. Radiation-induced DNA DSB repair was analyzed by immunocytochemistry of DSB markers γH2AX and 53BP1, DNA-repair assay, and cell-cycle distribution. Clonogenic survival assay was used to determine the effect of GSK-J4 on radiation response of DIPG cells. response to radiation monotherapy and combination therapy of RT and GSK-J4 was evaluated in patient-derived DIPG xenografts.

Results: GSK-J4 significantly reduced the expression of DNA DSB repair genes and DNA accessibility in DIPG cells. GSK-J4 sustained high levels of γH2AX and 53BP1 in irradiated DIPG cells, thereby inhibiting DNA DSB repair through homologous recombination pathway. GSK-J4 reduced clonogenic survival and enhanced radiation effect in DIPG cells. studies revealed increased survival of animals treated with combination therapy of RT and GSK-J4 compared with either monotherapy.

Conclusions: Together, these results highlight GSK-J4 as a potential radiosensitizer and provide a rationale for developing combination therapy with radiation in the treatment of DIPG.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6744979PMC
September 2019

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

Neurosurgery 2020 05;86(5):742-751

Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina.

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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http://dx.doi.org/10.1093/neuros/nyz212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443593PMC
May 2020

Identification of Novel RAS Signaling Therapeutic Vulnerabilities in Diffuse Intrinsic Pontine Gliomas.

Cancer Res 2019 08 14;79(16):4026-4041. Epub 2019 Jun 14.

John G. Rangos Sr. Research Center, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania.

Diffuse intrinsic pontine gliomas (DIPG) are incurable brain tumors with an aggressive onset. Apart from irradiation, there are currently no effective therapies available for patients with DIPG, who have a median survival time of less than one year. Most DIPG cells harbor mutations in genes encoding histone H3 (H3K27M) proteins, resulting in a global reduction of H3K27 trimethylation and activation of oncogenic signaling pathways. Here we show that the H3K27M mutations contribute to RAS pathway signaling, which is augmented by additional RAS activators including PDGFRA. H3K27M mutation led to increased expression of receptor tyrosine kinases (RTK). A RAS pathway functional screen identified ERK5, but not ERK1/2, as a RAS pathway effector important for DIPG growth. Suppression of ERK5 decreased DIPG cell proliferation and induced apoptosis and . In addition, depletion or inhibition of ERK5 significantly increased survival of mice intracranially engrafted with DIPG cells. Mechanistically, ERK5 directly stabilized the proto-oncogene MYC at the protein level. Collectively, our data demonstrate an underappreciated role of H3K27M in RAS activation and reveal novel therapeutic targets for treating DIPG tumors. SIGNIFICANCE: These findings identify the H3K27M mutation as an enhancer of RAS activation in DIPG and ERK5 as a novel, immediately actionable molecular target. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/79/16/4026/F1.large.jpg.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-3521DOI Listing
August 2019

The oncolytic virus Delta-24-RGD elicits an antitumor effect in pediatric glioma and DIPG mouse models.

Nat Commun 2019 05 28;10(1):2235. Epub 2019 May 28.

Health Research Institute of Navarra (IDISNA), Pamplona, Navarra, Spain.

Pediatric high-grade glioma (pHGG) and diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors in desperate need of a curative treatment. Oncolytic virotherapy is emerging as a solid therapeutic approach. Delta-24-RGD is a replication competent adenovirus engineered to replicate in tumor cells with an aberrant RB pathway. This virus has proven to be safe and effective in adult gliomas. Here we report that the administration of Delta-24-RGD is safe in mice and results in a significant increase in survival in immunodeficient and immunocompetent models of pHGG and DIPGs. Our results show that the Delta-24-RGD antiglioma effect is mediated by the oncolytic effect and the immune response elicited against the tumor. Altogether, our data highlight the potential of this virus as treatment for patients with these tumors. Of clinical significance, these data have led to the start of a phase I/II clinical trial at our institution for newly diagnosed DIPG (NCT03178032).
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http://dx.doi.org/10.1038/s41467-019-10043-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6538754PMC
May 2019

Combined targeting of PI3K and MEK effector pathways via CED for DIPG therapy.

Neurooncol Adv 2019 May-Dec;1(1):vdz004. Epub 2019 May 28.

Department of Neurosurgery, Weill Cornell Medicine, New York, New York.

Background: Midline gliomas like diffuse intrinsic pontine glioma (DIPG) carry poor prognosis and lack effective treatment options. Studies have implicated amplifications in the phosphatidylinositol 3-kinase (PI3K) signaling pathway in tumorigenesis; compensatory activation of parallel pathways (eg, mitogen-activated protein kinase [MEK]) may underlie the resistance to PI3K inhibition observed in the clinic.

Methods: Three patient-derived cell lines (SU-DIPG-IV, SU-DIPG-XIII, and SF8628) and a mouse-derived brainstem glioma cell line were treated with PI3K (ZSTK474) and MEK (trametinib) inhibitors, alone or in combination. Synergy was analyzed using Chou-Talalay combination index (CI). These agents were also used alone or in combination in a subcutaneous SU-DIPG-XIII tumor model and in an intracranial genetic mouse model of DIPG, given via convection-enhanced delivery (CED).

Results: We found that these agents abrogate cell proliferation in a dose-dependent manner. Combination treatments were found to be synergistic (CI < 1) across cell lines tested. They also showed significant tumor suppression when given systemically against a subcutaneous DIPG model (alone or in combination) or when given via direct intracranial injection (CED) in a intracranial DIPG mouse model (combination only, median survival 47 vs 35 days post-induction, = .038). No significant short- or long-term neurotoxicity of ZSTK474 and trametinib delivered via CED was observed.

Conclusions: Our data indicate that ZSTK474 and trametinib combinatorial treatment inhibits malignant growth of DIPG cells in vitro and in vivo, prolonging survival. These results suggest a promising new combinatorial approach using CED for DIPG therapy, which warrants further investigation.
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http://dx.doi.org/10.1093/noajnl/vdz004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212917PMC
May 2019

CDK4/6 and diffuse intrinsic pontine glioma - Evaluate at diagnosis?

Authors:
Oren J Becher

EBioMedicine 2019 06 13;44:16-17. Epub 2019 May 13.

Division of Hematology, Oncology and Stem Cell Transplant, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA; Malnati Brain Tumor Center and Lurie Cancer Center, Northwestern University, Chicago, IL, USA; Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, IL, USA. Electronic address:

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http://dx.doi.org/10.1016/j.ebiom.2019.05.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6604365PMC
June 2019

Delta-24-RGD combined with radiotherapy exerts a potent antitumor effect in diffuse intrinsic pontine glioma and pediatric high grade glioma models.

Acta Neuropathol Commun 2019 04 29;7(1):64. Epub 2019 Apr 29.

The Health Research Institute of Navarra (IDISNA), Pamplona, Navarra, Spain.

Pediatric high grade gliomas (pHGG), including diffuse intrinsic pontine gliomas (DIPGs), are aggressive tumors with a dismal outcome. Radiotherapy (RT) is part of the standard of care of these tumors; however, radiotherapy only leads to a transient clinical improvement. Delta-24-RGD is a genetically engineered tumor-selective adenovirus that has shown safety and clinical efficacy in adults with recurrent gliomas. In this work, we evaluated the feasibility, safety and therapeutic efficacy of Delta-24-RGD in combination with radiotherapy in pHGGs and DIPGs models. Our results showed that the combination of Delta-24-RGD with radiotherapy was feasible and resulted in a synergistic anti-glioma effect in vitro and in vivo in pHGG and DIPG models. Interestingly, Delta-24-RGD treatment led to the downregulation of relevant DNA damage repair proteins, further sensitizing tumors cells to the effect of radiotherapy. Additionally, Delta-24-RGD/radiotherapy treatment significantly increased the trafficking of immune cells (CD3, CD4+ and CD8+) to the tumor niche compared with single treatments. In summary, administration of the Delta-24-RGD/radiotherapy combination to pHGG and DIPG models is safe and significantly increases the overall survival of mice bearing these tumors. Our data offer a rationale for the combination Delta-24-RGD/radiotherapy as a therapeutic option for children with these tumors. SIGNIFICANCE: Delta-24-RGD/radiotherapy administration is safe and significantly increases the survival of treated mice. These positive data underscore the urge to translate this approach to the clinical treatment of children with pHGG and DIPGs.
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http://dx.doi.org/10.1186/s40478-019-0714-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6487528PMC
April 2019

ACVR1 R206H cooperates with H3.1K27M in promoting diffuse intrinsic pontine glioma pathogenesis.

Nat Commun 2019 03 4;10(1):1023. Epub 2019 Mar 4.

Department of Pediatrics, Northwestern University, Chicago, IL, 60611, USA.

Diffuse intrinsic pontine glioma (DIPG) is an incurable pediatric brain tumor, with approximately 25% of DIPGs harboring activating ACVR1 mutations that commonly co-associate with H3.1K27M mutations. Here we show that in vitro expression of ACVR1 R206H with and without H3.1K27M upregulates mesenchymal markers and activates Stat3 signaling. In vivo expression of ACVR1 R206H or G328V with H3.1K27M and p53 deletion induces glioma-like lesions but is not sufficient for full gliomagenesis. However, in combination with PDGFA signaling, ACVR1 R206H and H3.1K27M significantly decrease survival and increase tumor incidence. Treatment of ACVR1 R206H mutant DIPGs with exogenous Noggin or the ACVR1 inhibitor LDN212854 significantly prolongs survival, with human ACVR1 mutant DIPG cell lines also being sensitive to LDN212854 treatment. Together, our results demonstrate that ACVR1 R206H and H3.1K27M promote tumor initiation, accelerate gliomagenesis, promote a mesenchymal profile partly due to Stat3 activation, and identify LDN212854 as a promising compound to treat DIPG.
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http://dx.doi.org/10.1038/s41467-019-08823-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6399349PMC
March 2019

CDK4/6 and PDGFRA Signaling as Therapeutic Targets in Diffuse Intrinsic Pontine Glioma.

Front Oncol 2018 31;8:191. Epub 2018 May 31.

Department of Pediatrics, Northwestern University, Chicago, IL, United States.

Diffuse intrinsic pontine gliomas (DIPGs) are incurable childhood brain tumors, whereby the standard of care is focal radiation, a treatment that provides temporary relief for most patients. Surprisingly, decades of clinical trials have failed to identify additional therapies that can prolong survival in this disease. In this conference manuscript, we discuss how genetic engineered mouse modeling techniques with the use of a retroviral gene delivery system can help dissect the complex pathophysiology of this disease. With this approach, autochthonous murine DIPG models can be readily induced to (1) help interrogate the function of novel genetic alterations in tumorigenesis, (2) identify candidate cells of origin for this disease, (3) address how region-specific differences in the central nervous system influence the process of gliomagenesis, and (4) evaluate novel therapeutics in an immunocompetent model.
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http://dx.doi.org/10.3389/fonc.2018.00191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5990603PMC
May 2018

A phase I study of single-agent perifosine for recurrent or refractory pediatric CNS and solid tumors.

PLoS One 2017 5;12(6):e0178593. Epub 2017 Jun 5.

Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.

The PI3K/Akt/mTOR signaling pathway is aberrantly activated in various pediatric tumors. We conducted a phase I study of the Akt inhibitor perifosine in patients with recurrent/refractory pediatric CNS and solid tumors. This was a standard 3+3 open-label dose-escalation study to assess pharmacokinetics, describe toxicities, and identify the MTD for single-agent perifosine. Five dose levels were investigated, ranging from 25 to 125 mg/m2/day for 28 days per cycle. Twenty-three patients (median age 10 years, range 4-18 years) with CNS tumors (DIPG [n = 3], high-grade glioma [n = 5], medulloblastoma [n = 2], ependymoma [n = 3]), neuroblastoma (n = 8), Wilms tumor (n = 1), and Ewing sarcoma (n = 1) were treated. Only one DLT occurred (grade 4 hyperuricemia at dose level 4). The most common grade 3 or 4 toxicity at least possibly related to perifosine was neutropenia (8.7%), with the remaining grade 3 or 4 toxicities (fatigue, hyperglycemia, fever, hyperuricemia, and catheter-related infection) occurring in one patient each. Pharmacokinetics was dose-saturable at doses above 50 mg/m2/day with significant inter-patient variability, consistent with findings reported in adult studies. One patient with DIPG (dose level 5) and 4 of 5 patients with high-grade glioma (dose levels 2 and 3) experienced stable disease for two months. Five subjects with neuroblastoma (dose levels 1 through 4) achieved stable disease which was prolonged (≥11 months) in three. No objective responses were noted. In conclusion, the use of perifosine was safe and feasible in patients with recurrent/refractory pediatric CNS and solid tumors. An MTD was not defined by the 5 dose levels investigated. Our RP2D is 50 mg/m2/day.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0178593PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5459446PMC
September 2017

Histone H3.3K27M Represses to Accelerate Gliomagenesis in a Murine Model of DIPG.

Mol Cancer Res 2017 09 18;15(9):1243-1254. Epub 2017 May 18.

Division of Hematology-Oncology, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina.

Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive pediatric brainstem tumor genetically distinguished from adult GBM by the high prevalence of the K27M mutation in the histone H3 variant H3.3 (). This mutation reprograms the H3K27me3 epigenetic landscape of DIPG by inhibiting the H3K27-specific histone methyltransferase EZH2. This globally reduces H3K27me2/3, critical repressive marks responsible for cell fate decisions, and also causes focal gain of H3K27me3 throughout the epigenome. To date, the tumor-driving effects of H3.3K27M remain largely unknown. Here, it is demonstrated that H3.3K27M cooperates with PDGF-B enhancing gliomagenesis and reducing survival of p53 wild-type (WT) and knockout murine models of DIPG. H3.3K27M expression drives increased proliferation of tumor-derived murine neurospheres, suggesting that cell-cycle deregulation contributes to increased malignancy in mutant tumors. RNA sequencing on tumor tissue from H3.3K27M-expressing mice indicated global upregulation of PRC2 target genes, and a subset of newly repressed genes enriched in regulators of development and cell proliferation. Strikingly, H3.3K27M induced targeted repression of the p16/ink4a () locus, a critical regulator of the G-G to S-phase transition. Increased levels of H3K27me3 were observed at the p16 promoter; however, pharmacologic reduction of methylation at this promoter did not rescue p16 expression. Although DNA methylation is also present at this promoter, it is not K27M dependent. Intriguingly, inhibition of DNA methylation restores p16 levels and is cytotoxic against murine tumor cells. Importantly, these data reveal that H3.3K27M-mediated p16 repression is an important mechanism underlying the proliferation of H3.3K27M tumor cells, as knockout eliminates the survival difference between H3.3K27M and H3.3WT tumor-bearing mice. This study shows that H3.3K27M mutation and PDGF signaling act in concert to accelerate gliomagenesis in a genetic mouse model and identifies repression of p16 tumor suppressor as a target of H3.3K27M, highlighting the G-S cell-cycle transition as a promising therapeutic avenue. .
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http://dx.doi.org/10.1158/1541-7786.MCR-16-0389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5581686PMC
September 2017

Pre-Clinical Study of Panobinostat in Xenograft and Genetically Engineered Murine Diffuse Intrinsic Pontine Glioma Models.

PLoS One 2017 4;12(1):e0169485. Epub 2017 Jan 4.

Department of Pediatrics, Duke University Medical Center, Durham, NC, United States of America.

Background: Diffuse intrinsic pontine glioma (DIPG), or high-grade brainstem glioma (BSG), is one of the major causes of brain tumor-related deaths in children. Its prognosis has remained poor despite numerous efforts to improve survival. Panobinostat, a histone deacetylase inhibitor, is a targeted agent that has recently shown pre-clinical efficacy and entered a phase I clinical trial for the treatment of children with recurrent or progressive DIPG.

Methods: A collaborative pre-clinical study was conducted using both a genetic BSG mouse model driven by PDGF-B signaling, p53 loss, and ectopic H3.3-K27M or H3.3-WT expression and an H3.3-K27M orthotopic DIPG xenograft model to confirm and extend previously published findings regarding the efficacy of panobinostat in vitro and in vivo.

Results: In vitro, panobinostat potently inhibited cell proliferation, viability, and clonogenicity and induced apoptosis of human and murine DIPG cells. In vivo analyses of tissue after short-term systemic administration of panobinostat to genetically engineered tumor-bearing mice indicated that the drug reached brainstem tumor tissue to a greater extent than normal brain tissue, reduced proliferation of tumor cells and increased levels of H3 acetylation, demonstrating target inhibition. Extended consecutive daily treatment of both genetic and orthotopic xenograft models with 10 or 20 mg/kg panobinostat consistently led to significant toxicity. Reduced, well-tolerated doses of panobinostat, however, did not prolong overall survival compared to vehicle-treated mice.

Conclusion: Our collaborative pre-clinical study confirms that panobinostat is an effective targeted agent against DIPG human and murine tumor cells in vitro and in short-term in vivo efficacy studies in mice but does not significantly impact survival of mice bearing H3.3-K27M-mutant tumors. We suggest this may be due to toxicity associated with systemic administration of panobinostat that necessitated dose de-escalation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0169485PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5215670PMC
August 2017

A phase I study of perifosine with temsirolimus for recurrent pediatric solid tumors.

Pediatr Blood Cancer 2017 Jul 30;64(7). Epub 2016 Dec 30.

Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.

Background: The PI3K/AKT/mTOR pathway is aberrantly activated in many pediatric solid tumors including gliomas and medulloblastomas. Preclinical data in a pediatric glioma model demonstrated that the combination of perifosine (AKT inhibitor) and temsirolimus (mTOR inhibitor) is more potent at inhibiting the axis than either agent alone. We conducted this study to assess pharmacokinetics and identify the maximum tolerated dose for the combination.

Procedure: We performed a standard 3+3 phase I, open-label, dose-escalation study in patients with recurrent/refractory pediatric solid tumors. Four dose levels of perifosine (25-75 mg/m /day) and temsirolimus (25-75 mg/m IV weekly) were investigated.

Results: Twenty-three patients (median age 8.5 years) with brain tumors (diffuse intrinsic pontine glioma [DIPG] n = 8, high-grade glioma n = 6, medulloblastoma n = 2, ependymoma n = 1), neuroblastoma (n = 4), or rhabdomyosarcoma (n = 2) were treated. The combination was generally well tolerated and no dose-limiting toxicity was encountered. The most common grade 3 or 4 toxicities (at least possibly related) were thrombocytopenia (38.1%), neutropenia (23.8%), lymphopenia (23.8%), and hypercholesterolemia (19.0%). Pharmacokinetic findings for temsirolimus were similar to those observed in the temsirolimus single-agent phase II pediatric study and pharmacokinetic findings for perifosine were similar to those in adults. Stable disease was seen in 9 of 11 subjects with DIPG or high-grade glioma; no partial or complete responses were achieved.

Conclusions: The combination of these AKT and mTOR inhibitors was safe and feasible in patients with recurrent/refractory pediatric solid tumors.
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http://dx.doi.org/10.1002/pbc.26409DOI Listing
July 2017

Vamorolone, a dissociative steroidal compound, reduces pro-inflammatory cytokine expression in glioma cells and increases activity and survival in a murine model of cortical tumor.

Oncotarget 2017 Feb;8(6):9366-9374

Research Center for Genetic Medicine, Children's National Health System, Washington, DC, USA.

Corticosteroids, such as dexamethasone, are routinely used as palliative care in neuro-oncology for their anti-inflammatory benefits, however many patients experience dose limiting side effects caused by glucocorticoid response element (GRE)-mediated transcription. The purpose of this study was to use a murine model to investigate a new steroid alternative, vamorolone, which promises to reduce side effects through dissociating GRE-mediated transcription and NF-κB -mediated anti-inflammatory actions. To compare vamorolone to dexamethasone in reducing pro-inflammatory signals in vitro, murine glioma cells were treated with dexamethasone, vamorolone or vehicle control. Changes in mRNA expression were assessed using the nanostring inflammatory platform. Furthermore, drug efficacy, post-treatment behavioral activity and side effects were assessed by treating two cohorts of brain tumor bearing mice with dexamethasone, vamorolone, or vehicle control. Our investigation showed that treatment with vamorolone resulted in a reduction of pro-inflammatory signals in tumor cells in vitro similar to treatment with dexamethasone. Treatment with vamorolone resulted in a better safety profile in comparison to dexamethasone treatment. Vamorolone- treated mice showed similar or better activity and survival when compared to dexamethasone-treated mice. Our data indicate vamorolone is a potential steroid-sparing alternative for treating patients with brain tumors.
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http://dx.doi.org/10.18632/oncotarget.14070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5354737PMC
February 2017

A phase I/Ib trial targeting the Pi3k/Akt pathway using perifosine: Long-term progression-free survival of patients with resistant neuroblastoma.

Int J Cancer 2017 Jan 30;140(2):480-484. Epub 2016 Sep 30.

Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY.

AKT plays a pivotal role in driving the malignant phenotype of many cancers, including high-risk neuroblastoma (HR-NB). AKT signaling, however, is active in normal tissues, raising concern about excessive toxicity from its suppression. The oral AKT inhibitor perifosine showed tolerable toxicity in adults and in our phase I trial in children with solid tumors (clinicaltrials.gov NCT00776867). We now report on the HR-NB experience. HR-NB patients received perifosine 50-75 mg m  day after a loading dose of 100-200 mg m on day 1, and continued on study until progressive disease. The 27 HR-NB patients included three treated for primary refractory disease and 24 with disease resistant to salvage therapy after 1-5 (median 2) relapses; only one had MYCN-amplified HR-NB. Pharmacokinetic studies showed μM concentrations consistent with cytotoxic levels in preclinical models. Nine patients (all MYCN-non-amplified) remained progression-free through 43+ to 74+ (median 54+) months from study entry, including the sole patient to show a complete response and eight patients who had persistence of abnormal I-metaiodobenzylguanidine skeletal uptake but never developed progressive disease. Toxicity was negligible in all 27 patients, even with the prolonged treatment (11-62 months, median 38) in the nine long-term progression-free survivors. The clinical findings (i) confirm the safety of therapeutic serum levels of an AKT inhibitor in children; (ii) support perifosine for MYCN-non-amplified HR-NB as monotherapy after completion of standard treatment or combined with other agents (based on preclinical studies) to maximize antitumor effects; and (iii) highlight the welcome possibility that refractory or relapsed MYCN-non-amplified HR-NB is potentially curable.
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http://dx.doi.org/10.1002/ijc.30440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5118186PMC
January 2017

Pediatric high-grade glioma: biologically and clinically in need of new thinking.

Neuro Oncol 2017 02;19(2):153-161

Departments of Pediatrics, Neurology, and Neurological Surgery, University of California San Francisco, San Francisco, California, USA.

High-grade gliomas in children are different from those that arise in adults. Recent collaborative molecular analyses of these rare cancers have revealed previously unappreciated connections among chromatin regulation, developmental signaling, and tumorigenesis. As we begin to unravel the unique developmental origins and distinct biological drivers of this heterogeneous group of tumors, clinical trials need to keep pace. It is important to avoid therapeutic strategies developed purely using data obtained from studies on adult glioblastoma. This approach has resulted in repetitive trials and ineffective treatments being applied to these children, with limited improvement in clinical outcome. The authors of this perspective, comprising biology and clinical expertise in the disease, recently convened to discuss the most effective ways to translate the emerging molecular insights into patient benefit. This article reviews our current understanding of pediatric high-grade glioma and suggests approaches for innovative clinical management.
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http://dx.doi.org/10.1093/neuonc/now101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5464243PMC
February 2017

Pediatric Neuro-Oncology: Time to Go Molecular.

Authors:
Oren J Becher

Oncology (Williston Park) 2016 May;30(5):424-5

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May 2016

ABCG2 and ABCB1 Limit the Efficacy of Dasatinib in a PDGF-B-Driven Brainstem Glioma Model.

Mol Cancer Ther 2016 05 16;15(5):819-29. Epub 2016 Feb 16.

Department of Pediatrics, Duke University, Durham, North Carolina. Department of Pathology, Duke University, Durham, North Carolina. Preston Robert Tisch Brain Tumor Center, Durham, North Carolina.

Dasatinib is a multikinase inhibitor in clinical trials for glioma, and thus far has failed to demonstrate significant efficacy. We investigated whether the ABC efflux transporters ABCG2 and ABCB1 expressed in the blood-brain barrier (BBB), are limiting the efficacy of dasatinib in the treatment of glioma using genetic and pharmacologic approaches. We utilized a genetic brainstem glioma mouse model driven by platelet-derived growth factor-B and p53 loss using abcg2/abcb1 wild-type (ABC WT) or abcg2/abcb1 knockout mice (ABC KO). First, we observed that brainstem glioma tumor latency is significantly prolonged in ABC KO versus ABC WT mice (median survival of 47 vs. 34 days). Dasatinib treatment nearly doubles the survival of brainstem glioma-bearing ABC KO mice (44 vs. 80 days). Elacridar, an ABCG2 and ABCB1 inhibitor, significantly increases the efficacy of dasatinib in brainstem glioma-bearing ABC WT mice (42 vs. 59 days). Pharmacokinetic analysis demonstrates that dasatinib delivery into the normal brain, but not into the tumor core, is significantly increased in ABC KO mice compared with ABC WT mice. Surprisingly, elacridar did not significantly increase dasatinib delivery into the normal brain or the tumor core of ABC WT mice. Next, we demonstrate that the tight junctions of the BBB of this model are compromised as assessed by tissue permeability to Texas Red dextran. Finally, elacridar increases the cytotoxicity of dasatinib independent of ABCG2 and ABCB1 expression in vitro In conclusion, elacridar improves the efficacy of dasatinib in a brainstem glioma model without significantly increasing its delivery to the tumor core. Mol Cancer Ther; 15(5); 819-29. ©2016 AACR.
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http://dx.doi.org/10.1158/1535-7163.MCT-15-0093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4873451PMC
May 2016
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