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

    Hoeman, Christine / Shen, Chen / Becher, Oren J

    Frontiers in oncology

    2018  Volume 8, Page(s) 191

    Abstract: 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 ... ...

    Abstract 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.
    Language English
    Publishing date 2018-05-31
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2649216-7
    ISSN 2234-943X
    ISSN 2234-943X
    DOI 10.3389/fonc.2018.00191
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  2. Article ; Online: A novel mouse model of diffuse midline glioma initiated in neonatal oligodendrocyte progenitor cells highlights cell-of-origin dependent effects of H3K27M.

    Tomita, Yusuke / Shimazu, Yosuke / Somasundaram, Agila / Tanaka, Yoshihiro / Takata, Nozomu / Ishi, Yukitomo / Gadd, Samantha / Hashizume, Rintaro / Angione, Angelo / Pinero, Gonzalo / Hambardzumyan, Dolores / Brat, Daniel J / Hoeman, Christine M / Becher, Oren J

    Glia

    2022  Volume 70, Issue 9, Page(s) 1681–1698

    Abstract: Diffuse midline glioma (DMG) is a type of lethal brain tumor that develops mainly in children. The majority of DMG harbor the K27M mutation in histone H3. Oligodendrocyte progenitor cells (OPCs) in the brainstem are candidate cells-of-origin for DMG, yet ...

    Abstract Diffuse midline glioma (DMG) is a type of lethal brain tumor that develops mainly in children. The majority of DMG harbor the K27M mutation in histone H3. Oligodendrocyte progenitor cells (OPCs) in the brainstem are candidate cells-of-origin for DMG, yet there is no genetically engineered mouse model of DMG initiated in OPCs. Here, we used the RCAS/Tv-a avian retroviral system to generate DMG in Olig2-expressing progenitors and Nestin-expressing progenitors in the neonatal mouse brainstem. PDGF-A or PDGF-B overexpression, along with p53 deletion, resulted in gliomas in both models. Exogenous overexpression of H3.3K27M had a significant effect on tumor latency and tumor cell proliferation when compared with H3.3WT in Nestin+ cells but not in Olig2+ cells. Further, the fraction of H3.3K27M-positive cells was significantly lower in DMGs initiated in Olig2+ cells relative to Nestin+ cells, both in PDGF-A and PDGF-B-driven models, suggesting that the requirement for H3.3K27M is reduced when tumorigenesis is initiated in Olig2+ cells. RNA-sequencing analysis revealed that the differentially expressed genes in H3.3K27M tumors were non-overlapping between Olig2;PDGF-B, Olig2;PDGF-A, and Nestin;PDGF-A models. GSEA analysis of PDGFA tumors confirmed that the transcriptomal effects of H3.3K27M are cell-of-origin dependent with H3.3K27M promoting epithelial-to-mesenchymal transition (EMT) and angiogenesis when Olig2 marks the cell-of-origin and inhibiting EMT and angiogenesis when Nestin marks the cell-of-origin. We did observe some overlap with H3.3K27M promoting negative enrichment of TNFA_Signaling_Via_NFKB in both models. Our study suggests that the tumorigenic effects of H3.3K27M are cell-of-origin dependent, with H3.3K27M being more oncogenic in Nestin+ cells than Olig2+ cells.
    MeSH term(s) Animals ; Brain Neoplasms/pathology ; Disease Models, Animal ; Glioma/pathology ; Histones ; Mice ; Mutation/genetics ; Nestin/genetics ; Oligodendrocyte Precursor Cells/pathology
    Chemical Substances Histones ; Nestin
    Language English
    Publishing date 2022-05-07
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 639414-0
    ISSN 1098-1136 ; 0894-1491
    ISSN (online) 1098-1136
    ISSN 0894-1491
    DOI 10.1002/glia.24189
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  3. Article ; Online: Children are not just little adults: recent advances in understanding of diffuse intrinsic pontine glioma biology.

    Schroeder, Kristin M / Hoeman, Christine M / Becher, Oren J

    Pediatric research

    2014  Volume 75, Issue 1-2, Page(s) 205–209

    Abstract: Diffuse intrinsic pontine glioma (DIPG) is a high-grade glioma that originates in the pons and is seen exclusively in children. Despite numerous efforts to improve treatment, DIPG remains incurable with 90% of children dying within 2 y of diagnosis, ... ...

    Abstract Diffuse intrinsic pontine glioma (DIPG) is a high-grade glioma that originates in the pons and is seen exclusively in children. Despite numerous efforts to improve treatment, DIPG remains incurable with 90% of children dying within 2 y of diagnosis, making it one of the leading causes of death in children with brain tumors. With the advent of new genomic tools, the genetic landscape of DIPG is slowly being unraveled. The most common genetic alterations include a K27M mutation in H3.3 or H3.1, which are found in up to 78% of DIPGs, whereas p53 mutations are found in up to 77%. Other recently discovered alterations include amplification of components of the receptor tyrosine kinase/Ras/phosphatidylinositol 3-kinase signaling pathway, particularly platelet-derived growth factor receptor A. Recapitulating such alterations, genetically engineered DIPG preclinical models have been developed, and DIPG xenograft models have also been established. Both models have strengths and weaknesses but can help with the prioritization of novel agents for clinical trials for children with DIPG. As we move forward, it is important that we continue to study the complex and unique biology of DIPG and develop improved preclinical models to increase our understanding of DIPG pathogenesis, allowing translation into successful therapies in the not too distant future.
    MeSH term(s) Adult ; Age Factors ; Animals ; Brain Stem Neoplasms/genetics ; Brain Stem Neoplasms/metabolism ; Brain Stem Neoplasms/mortality ; Brain Stem Neoplasms/pathology ; Brain Stem Neoplasms/therapy ; Child ; Clinical Trials as Topic/methods ; Disease Models, Animal ; Genetic Predisposition to Disease ; Glioma/genetics ; Glioma/metabolism ; Glioma/mortality ; Glioma/pathology ; Glioma/therapy ; Humans ; Mutation ; Phenotype ; Signal Transduction ; Translational Medical Research ; Treatment Outcome
    Language English
    Publishing date 2014-01
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
    ZDB-ID 4411-8
    ISSN 1530-0447 ; 0031-3998
    ISSN (online) 1530-0447
    ISSN 0031-3998
    DOI 10.1038/pr.2013.194
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  4. Article ; Online: A New IRF-1-Driven Apoptotic Pathway Triggered by IL-4/IL-13 Kills Neonatal Th1 Cells and Weakens Protection against Viral Infection.

    Miller, Mindy M / Barik, Subhasis / Cattin-Roy, Alexis N / Ukah, Tobechukwu K / Hoeman, Christine M / Zaghouani, Habib

    Journal of immunology (Baltimore, Md. : 1950)

    2019  Volume 202, Issue 11, Page(s) 3173–3186

    Abstract: Early life immune responses are deficient in Th1 lymphocytes that compromise neonatal vaccination. We found that IL-4 and IL-13 engage a developmentally expressed IL-4Rα/IL-13Rα1 heteroreceptor to endow IFN regulatory factor 1 (IRF-1) with apoptotic ... ...

    Abstract Early life immune responses are deficient in Th1 lymphocytes that compromise neonatal vaccination. We found that IL-4 and IL-13 engage a developmentally expressed IL-4Rα/IL-13Rα1 heteroreceptor to endow IFN regulatory factor 1 (IRF-1) with apoptotic functions, which redirect murine neonatal Th1 reactivation to cell death. IL-4/IL-13-induced STAT6 phosphorylation serves to enhance IRF-1 transcription and promotes its egress from the nucleus. In the cytoplasm, IRF-1 can no longer serve as an anti-viral transcription factor but, instead, colocalizes with Bim and instigates the mitochondrial, or intrinsic, death pathway. The new pivotal function of IRF-1 in the death of neonatal Th1 cells stems from the ability of its gene to bind STAT6 for enhanced transcription and the proficiency of its protein to precipitate Bim-driven apoptosis. This cytokine-induced, IRF-1-mediated developmental death network weakens neonatal Th1 responses during early life vaccination and increases susceptibility to viral infection.
    MeSH term(s) Animals ; Animals, Newborn ; Apoptosis ; Bcl-2-Like Protein 11/metabolism ; Disease Resistance ; Humans ; Immunity ; Infant, Newborn ; Interferon Regulatory Factor-1/genetics ; Interferon Regulatory Factor-1/metabolism ; Interleukin-13/metabolism ; Interleukin-13 Receptor alpha1 Subunit/genetics ; Interleukin-4/metabolism ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Knockout ; STAT6 Transcription Factor/metabolism ; Signal Transduction ; Th1 Cells/immunology ; Viral Vaccines/immunology ; Virus Diseases/immunology
    Chemical Substances Bcl-2-Like Protein 11 ; Interferon Regulatory Factor-1 ; Interleukin-13 ; Interleukin-13 Receptor alpha1 Subunit ; STAT6 Transcription Factor ; Viral Vaccines ; Interleukin-4 (207137-56-2)
    Language English
    Publishing date 2019-04-17
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 3056-9
    ISSN 1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
    ISSN (online) 1550-6606
    ISSN 0022-1767 ; 1048-3233 ; 1047-7381
    DOI 10.4049/jimmunol.1800943
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  5. Article ; Online: Overcoming dendritic cell tardiness to triumph over IL-13 receptor: a strategy for the development of effective pediatric vaccines.

    Hoeman, Christine / Dhakal, Mermagya / Zaghouani, Habib

    Discovery medicine

    2010  Volume 9, Issue 49, Page(s) 554–559

    Abstract: Neonatal exposure to antigen gives rise to a primary response comprising both T helper 1 (Th1) and T helper 2 (Th2) lymphocytes. However, re-encounter with the same antigen yields an indubitably biased response with minimal Th1 but excessive Th2 cells. ... ...

    Abstract Neonatal exposure to antigen gives rise to a primary response comprising both T helper 1 (Th1) and T helper 2 (Th2) lymphocytes. However, re-encounter with the same antigen yields an indubitably biased response with minimal Th1 but excessive Th2 cells. Since Th1 cells combat microbes while Th2 cells react to allergens, the neonate faces susceptibility to both microbial infections and allergic reactions. The Th1/Th2 imbalance of neonatal immunity stems from a delayed maturation of dendritic cells that yields limited IL-12 cytokine during the neonatal stage. Th1 cells developing under these circumstances up-regulate the IL-13Ralpha1 chain that physically associates with the IL-4Ralpha chain, forming a potentially hazardous heteroreceptor. During re-challenge with antigen, IL-4 from Th2 cells utilizes the heteroreceptor to signal the death of Th1 cells, leading to the Th2 bias of neonatal immunity. Our view to overcome Th1 deficiency is to supplement neonatal immunizations with toll-like receptor ligands that could stimulate maturation of dendritic cells and augment IL-12 production to counter IL-13Ralpha1 up-regulation. This regimen would yield Th1 cells devoid of the heteroreceptor and resistant to IL-4-induced apoptosis. Accordingly, the neonate would have balanced Th1/Th2 immunity and withstand both microbes and allergens. Such approaches could open new avenues for better pediatric vaccines and allergy therapies.
    MeSH term(s) Dendritic Cells/immunology ; Humans ; Infant ; Infant, Newborn ; Receptors, Interleukin-13/immunology ; Vaccines/immunology
    Chemical Substances Receptors, Interleukin-13 ; Vaccines
    Language English
    Publishing date 2010-06
    Publishing country United States
    Document type Journal Article
    ISSN 1944-7930
    ISSN (online) 1944-7930
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  6. Article ; Online: ACVR1 R206H cooperates with H3.1K27M in promoting diffuse intrinsic pontine glioma pathogenesis.

    Hoeman, Christine M / Cordero, Francisco J / Hu, Guo / Misuraca, Katie / Romero, Megan M / Cardona, Herminio J / Nazarian, Javad / Hashizume, Rintaro / McLendon, Roger / Yu, Paul / Procissi, Daniele / Gadd, Samantha / Becher, Oren J

    Nature communications

    2019  Volume 10, Issue 1, Page(s) 1023

    Abstract: 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 ... ...

    Abstract 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.
    MeSH term(s) Activin Receptors, Type I/genetics ; Activin Receptors, Type I/metabolism ; Animals ; Astrocytoma/drug therapy ; Astrocytoma/genetics ; Astrocytoma/metabolism ; Astrocytoma/pathology ; Brain Stem Neoplasms/drug therapy ; Brain Stem Neoplasms/genetics ; Brain Stem Neoplasms/metabolism ; Brain Stem Neoplasms/pathology ; Carrier Proteins/pharmacology ; Cell Line, Tumor/drug effects ; Cell Proliferation ; Disease Models, Animal ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic/genetics ; Genome, Human/genetics ; Glioma/drug therapy ; Glioma/genetics ; Glioma/metabolism ; Glioma/pathology ; Histones/genetics ; Histones/metabolism ; Humans ; Mice ; Mutation ; Platelet-Derived Growth Factor/metabolism ; Pyrazoles/pharmacology ; Pyrimidines/pharmacology ; Quinolines/pharmacology ; STAT3 Transcription Factor/metabolism ; Signal Transduction
    Chemical Substances Carrier Proteins ; Histones ; LDN-212854 ; Platelet-Derived Growth Factor ; Pyrazoles ; Pyrimidines ; Quinolines ; STAT3 Transcription Factor ; STAT3 protein, human ; platelet-derived growth factor A ; noggin protein (148294-77-3) ; ACVR1 protein, human (EC 2.7.11.30) ; Activin Receptors, Type I (EC 2.7.11.30)
    Language English
    Publishing date 2019-03-04
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-019-08823-9
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  7. Article ; Online: Neonatal immunity: faulty T-helpers and the shortcomings of dendritic cells.

    Zaghouani, Habib / Hoeman, Christine M / Adkins, Becky

    Trends in immunology

    2009  Volume 30, Issue 12, Page(s) 585–591

    Abstract: Immunity in the newborn is characterized by minimal T helper (Th)1 function but an excess of Th2 activity. Since Th1 lymphocytes are important to counter microbes and Th2 cells favor allergies, the newborn faces susceptibility to microbial infections and ...

    Abstract Immunity in the newborn is characterized by minimal T helper (Th)1 function but an excess of Th2 activity. Since Th1 lymphocytes are important to counter microbes and Th2 cells favor allergies, the newborn faces susceptibility to microbial infections and allergic reactions. Delayed maturation of certain dendritic cells leads to limited interleukin (IL)-12 production during the neonatal period. The Th2 cytokine locus of neonatal CD4(+) T cells is poised epigenetically for rapid and robust production of IL-4 and IL-13. Together, these circumstances lead to efficient differentiation of Th2 cells and the expression of an IL-4Ralpha/IL-13Ralpha1 heteroreceptor on Th1 cells. Upon re-challenge, Th2 cells rapidly produce IL-4 which utilizes the heteroreceptor to drive apoptosis of Th1 cells, thus yielding the Th2 bias of neonatal immunity.
    MeSH term(s) Animals ; Animals, Newborn ; Cell Differentiation ; Cytokines/genetics ; Cytokines/metabolism ; Dendritic Cells/immunology ; Epigenesis, Genetic/immunology ; Gene Expression Regulation, Developmental/immunology ; Humans ; Immunity ; Infant, Newborn ; Th1 Cells/immunology ; Th2 Cells/immunology
    Chemical Substances Cytokines
    Language English
    Publishing date 2009-10-19
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 2036831-8
    ISSN 1471-4981 ; 1471-4906
    ISSN (online) 1471-4981
    ISSN 1471-4906
    DOI 10.1016/j.it.2009.09.002
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  8. Article ; Online: Developmental expression of IL-12Rβ2 on murine naive neonatal T cells counters the upregulation of IL-13Rα1 on primary Th1 cells and balances immunity in the newborn.

    Hoeman, Christine M / Dhakal, Mermagya / Zaghouani, Adam A / Cascio, Jason A / Wan, Xiaoxiao / Khairallah, Marie-Therese / Chen, Weirong / Zaghouani, Habib

    Journal of immunology (Baltimore, Md. : 1950)

    2013  Volume 190, Issue 12, Page(s) 6155–6163

    Abstract: Upon exposure to Ag on the day of birth, neonatal mice mount balanced primary Th1 and Th2 responses, with the former displaying upregulated IL-13Rα1 expression. This chain associates with IL-4Rα to form a heteroreceptor (IL-4Rα/IL-13Rα1) that marks the ... ...

    Abstract Upon exposure to Ag on the day of birth, neonatal mice mount balanced primary Th1 and Th2 responses, with the former displaying upregulated IL-13Rα1 expression. This chain associates with IL-4Rα to form a heteroreceptor (IL-4Rα/IL-13Rα1) that marks the Th1 cells for death by IL-4 produced by Th2 cells during rechallenge with Ag, hence the Th2 bias of murine neonatal immunity. The upregulation of IL-13Rα1 on neonatal Th1 cells was due to the paucity of IL-12 in the neonatal environment. In this study, we show that by day 8 after birth, naive splenic T cells are no longer susceptible to IL-13Rα1 upregulation even when exposed to Ag within the neonatal environment. Furthermore, during the 8-d lapse, the naive splenic T cells spontaneously and progressively upregulate the IL-12Rβ2 chain, perhaps due to colonization by commensals, which induce production of IL-12 by cells of the innate immune system such as dendritic cells. In fact, mature T cells from the thymus, a sterile environment not accessible to microbes, did not upregulate IL-12Rβ2 and were unable to counter IL-13Rα1 upregulation. Finally, the 8-d naive T cells were able to differentiate into Th1 cells even independently of IL-12 but required the cytokine to counter upregulation of IL-13Rα1. Thus, in neonatal mice, IL-12, which accumulates in the environment progressively, uses IL-12Rβ2 to counter IL-13Rα1 expression in addition to promoting Th1 differentiation.
    MeSH term(s) Adoptive Transfer ; Animals ; Animals, Newborn ; Apoptosis/immunology ; Cell Differentiation/immunology ; Cytokines/biosynthesis ; Enzyme-Linked Immunosorbent Assay ; Flow Cytometry ; Interleukin-13 Receptor alpha1 Subunit/immunology ; Interleukin-13 Receptor alpha1 Subunit/metabolism ; Mice ; Mice, Inbred BALB C ; Mice, Transgenic ; Real-Time Polymerase Chain Reaction ; Receptors, Interleukin-12/biosynthesis ; Receptors, Interleukin-12/immunology ; Reverse Transcriptase Polymerase Chain Reaction ; T-Lymphocytes/cytology ; T-Lymphocytes/immunology ; Th1 Cells/cytology ; Th1 Cells/immunology ; Up-Regulation
    Chemical Substances Cytokines ; Interleukin-13 Receptor alpha1 Subunit ; Receptors, Interleukin-12
    Language English
    Publishing date 2013-05-06
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 3056-9
    ISSN 1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
    ISSN (online) 1550-6606
    ISSN 0022-1767 ; 1048-3233 ; 1047-7381
    DOI 10.4049/jimmunol.1202207
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  9. Article ; Online: Antigen-free adjuvant assists late effector CD4 T cells to transit to memory in lymphopenic hosts.

    Guloglu, F Betul / Ellis, Jason S / Wan, Xiaoxiao / Dhakal, Mermagya / Hoeman, Christine M / Cascio, Jason A / Zaghouani, Habib

    Journal of immunology (Baltimore, Md. : 1950)

    2013  Volume 191, Issue 3, Page(s) 1126–1135

    Abstract: The events controlling the transition of T cells from effector to memory remain largely undefined. Many models have been put forth to account for the origin of memory precursors, but for CD4 T cells initial studies reported that memory T cells derive ... ...

    Abstract The events controlling the transition of T cells from effector to memory remain largely undefined. Many models have been put forth to account for the origin of memory precursors, but for CD4 T cells initial studies reported that memory T cells derive from IFN-γ-nonproducing effectors, whereas others suggested that memory emanates from highly activated IFN-γ-producing effectors. In this study, using cell proliferation, expression of activation markers, and production of IFN-γ as a measure of activation, we defined two types of effector CD4 T cells and investigated memory generation. The moderately activated early effectors readily transit to memory, whereas the highly activated late effectors, regardless of their IFN-γ production, develop minimal memory. Boosting with Ag-free adjuvant, however, rescues late effectors from cell death and sustains both survival and IFN-γ cytokine responses in lymphopenic hosts. The adjuvant-mediated memory transition of late effectors involves the function of TLRs, most notably TLR9. These findings uncover the mechanism by which late effector CD4 T cells are driven to transit to memory and suggest that timely boosts with adjuvant may enhance vaccine efficacy.
    MeSH term(s) Adjuvants, Immunologic/administration & dosage ; Animals ; CD4-Positive T-Lymphocytes/immunology ; CD4-Positive T-Lymphocytes/metabolism ; Immunologic Memory/immunology ; Interferon-gamma ; Lymphocyte Activation/immunology ; Lymphopenia/immunology ; Mice ; Mice, Inbred BALB C ; Mice, Transgenic ; Toll-Like Receptor 9/immunology ; Toll-Like Receptor 9/metabolism
    Chemical Substances Adjuvants, Immunologic ; Tlr9 protein, mouse ; Toll-Like Receptor 9 ; Interferon-gamma (82115-62-6)
    Language English
    Publishing date 2013-07-01
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 3056-9
    ISSN 1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
    ISSN (online) 1550-6606
    ISSN 0022-1767 ; 1048-3233 ; 1047-7381
    DOI 10.4049/jimmunol.1202262
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  10. Article ; Online: A high-throughput in vitro drug screen in a genetically engineered mouse model of diffuse intrinsic pontine glioma identifies BMS-754807 as a promising therapeutic agent.

    Halvorson, Kyle G / Barton, Kelly L / Schroeder, Kristin / Misuraca, Katherine L / Hoeman, Christine / Chung, Alex / Crabtree, Donna M / Cordero, Francisco J / Singh, Raj / Spasojevic, Ivan / Berlow, Noah / Pal, Ranadip / Becher, Oren J

    PloS one

    2015  Volume 10, Issue 3, Page(s) e0118926

    Abstract: Diffuse intrinsic pontine gliomas (DIPGs) represent a particularly lethal type of pediatric brain cancer with no effective therapeutic options. Our laboratory has previously reported the development of genetically engineered DIPG mouse models using the ... ...

    Abstract Diffuse intrinsic pontine gliomas (DIPGs) represent a particularly lethal type of pediatric brain cancer with no effective therapeutic options. Our laboratory has previously reported the development of genetically engineered DIPG mouse models using the RCAS/tv-a system, including a model driven by PDGF-B, H3.3K27M, and p53 loss. These models can serve as a platform in which to test novel therapeutics prior to the initiation of human clinical trials. In this study, an in vitro high-throughput drug screen as part of the DIPG preclinical consortium using cell-lines derived from our DIPG models identified BMS-754807 as a drug of interest in DIPG. BMS-754807 is a potent and reversible small molecule multi-kinase inhibitor with many targets including IGF-1R, IR, MET, TRKA, TRKB, AURKA, AURKB. In vitro evaluation showed significant cytotoxic effects with an IC50 of 0.13 μM, significant inhibition of proliferation at a concentration of 1.5 μM, as well as inhibition of AKT activation. Interestingly, IGF-1R signaling was absent in serum-free cultures from the PDGF-B; H3.3K27M; p53 deficient model suggesting that the antitumor activity of BMS-754807 in this model is independent of IGF-1R. In vivo, systemic administration of BMS-754807 to DIPG-bearing mice did not prolong survival. Pharmacokinetic analysis demonstrated that tumor tissue drug concentrations of BMS-754807 were well below the identified IC50, suggesting that inadequate drug delivery may limit in vivo efficacy. In summary, an unbiased in vitro drug screen identified BMS-754807 as a potential therapeutic agent in DIPG, but BMS-754807 treatment in vivo by systemic delivery did not significantly prolong survival of DIPG-bearing mice.
    MeSH term(s) Animals ; Antineoplastic Agents/therapeutic use ; Brain Stem Neoplasms/drug therapy ; Brain Stem Neoplasms/pathology ; Disease Models, Animal ; Glioma/drug therapy ; Glioma/pathology ; High-Throughput Screening Assays ; Mice ; Mice, Inbred C57BL ; Pyrazoles/therapeutic use ; Survival Rate ; Triazines/therapeutic use
    Chemical Substances Antineoplastic Agents ; BMS 754807 ; Pyrazoles ; Triazines
    Language English
    Publishing date 2015
    Publishing country United States
    Document type Journal Article
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0118926
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