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  • 1
    In: Neuro-Oncology, 2018, Vol. 20(suppl2), pp.i142-i142
    Description: Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Even with an intensive therapeutic regimen of surgery, radiation and chemotherapy, one-third of patients still succumb to their disease and survivors suffer devastating side effects from the therapy. Thus, more effective and less toxic therapies are desperately needed. Genomic analyses have identified four major subgroups of MB – WNT, SHH, Group 3 and Group 4 – that differ in terms of mutations, gene expression and patient outcomes. Despite this heterogeneity, all MB patients currently receive similar therapies. To identify novel therapies for each subgroup of MB, we have assembled a panel of patient-derived xenograft (PDX) lines established by orthotopic transplantation of tumor cells obtained from surgery. We used these PDXs to perform high-throughput drug screening, and integrated drug response data with mutational, transcriptional, and epigenetic profiles. These studies revealed significant heterogeneity in drug responses among MB patients, and identified the RNA synthesis inhibitor Actinomycin D as a potent inhibitor of Group 3 MB, the most aggressive form of the disease. Based on these studies, we hope to move away from a one-size-fits-all approach and begin to treat each patient with therapies that are likely to be more effective against their tumor.
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 2
    In: Nature, 2017, Vol.551(7678), p.115
    Description: Mammalian tissues are fuelled by circulating nutrients, including glucose, amino acids, and various intermediary metabolites. Under aerobic conditions, glucose is generally assumed to be burned fully by tissues via the tricarboxylic acid cycle (TCA cycle) to carbon dioxide. Alternatively, glucose can be catabolized anaerobically via glycolysis to lactate, which is itself also a potential nutrient for tissues and tumours. The quantitative relevance of circulating lactate or other metabolic intermediates as fuels remains unclear. Here we systematically examine the fluxes of circulating metabolites in mice, and find that lactate can be a primary source of carbon for the TCA cycle and thus of energy. Intravenous infusions of 13C-labelled nutrients reveal that, on a molar basis, the circulatory turnover flux of lactate is the highest of all metabolites and exceeds that of glucose by 1.1-fold in fed mice and 2.5-fold in fasting mice; lactate is made primarily from glucose but also from other sources. In both fed and fasted mice, 13C-lactate extensively labels TCA cycle intermediates in all tissues. Quantitative analysis reveals that during the fasted state, the contribution of glucose to tissue TCA metabolism is primarily indirect (via circulating lactate) in all tissues except the brain. In genetically engineered lung and pancreatic cancer tumours in fasted mice, the contribution of circulating lactate to TCA cycle intermediates exceeds that of glucose, with glutamine making a larger contribution than lactate in pancreatic cancer. Thus, glycolysis and the TCA cycle are uncoupled at the level of lactate, which is a primary circulating TCA substrate in most tissues and tumours.
    Keywords: Sciences (General) ; Physics;
    ISSN: 0028-0836
    E-ISSN: 1476-4687
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  • 3
    In: Nature, 2014
    Description: Medulloblastoma is a highly malignant paediatric brain tumour currently treated with a combination of surgery, radiation and chemotherapy, posing a considerable burden of toxicity to the developing child. Genomics has illuminated the extensive intertumoral heterogeneity of medulloblastoma, identifying four distinct molecular subgroups. Group 3 and group 4 subgroup medulloblastomas account for most paediatric cases; yet, oncogenic drivers for these subtypes remain largely unidentified. Here we describe a series of prevalent, highly disparate genomic structural variants, restricted to groups 3 and 4, resulting in specific and mutually exclusive activation of the growth factor independent 1 family proto-oncogenes, GFI1 and GFI1B. Somatic structural variants juxtapose GFI1 or GFI1B coding sequences proximal to active enhancer elements, including super-enhancers, instigating oncogenic activity. Our results, supported by evidence from mouse models, identify GFI1 and GFI1B as prominent medulloblastoma oncogenes and implicate 'enhancer hijacking' as an efficient mechanism driving oncogene activation in a childhood cancer.
    Keywords: Medulloblastoma – Research ; Medulloblastoma – Health Aspects ; DNA Sequencing – Analysis ; Growth Factor Receptors – Analysis;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 4
    Language: English
    In: Cancer research, 15 October 2013, Vol.73(20), pp.6310-22
    Description: Medulloblastoma is the most common malignant brain tumor in children. Although aggressive surgery, radiation, and chemotherapy have improved outcomes, survivors suffer severe long-term side effects, and many patients still succumb to their disease. For patients whose tumors are driven by mutations in the sonic hedgehog (SHH) pathway, SHH antagonists offer some hope. However, many SHH-associated medulloblastomas do not respond to these drugs, and those that do may develop resistance. Therefore, more effective treatment strategies are needed for both SHH and non-SHH-associated medulloblastoma. One such strategy involves targeting the cells that are critical for maintaining tumor growth, known as tumor-propagating cells (TPC). We previously identified a population of TPCs in tumors from patched mutant mice, a model for SHH-dependent medulloblastoma. These cells express the surface antigen CD15/SSEA-1 and have elevated levels of genes associated with the G2-M phases of the cell cycle. Here, we show that CD15(+) cells progress more rapidly through the cell cycle than CD15(-) cells and contain an increased proportion of cells in G2-M, suggesting that they might be vulnerable to inhibitors of this phase. Indeed, exposure of tumor cells to inhibitors of Aurora kinase (Aurk) and Polo-like kinases (Plk), key regulators of G2-M, induces cell-cycle arrest, apoptosis, and enhanced sensitivity to conventional chemotherapy. Moreover, treatment of tumor-bearing mice with these agents significantly inhibits tumor progression. Importantly, cells from human patient-derived medulloblastoma xenografts are also sensitive to Aurk and Plk inhibitors. Our findings suggest that targeting G2-M regulators may represent a novel approach for treatment of human medulloblastoma.
    Keywords: Aurora Kinase A -- Antagonists & Inhibitors ; Brain Neoplasms -- Genetics ; Cell Cycle Proteins -- Antagonists & Inhibitors ; Hedgehog Proteins -- Genetics ; Medulloblastoma -- Drug Therapy ; Protein Kinase Inhibitors -- Pharmacology ; Protein-Serine-Threonine Kinases -- Antagonists & Inhibitors ; Proto-Oncogene Proteins -- Antagonists & Inhibitors
    ISSN: 00085472
    E-ISSN: 1538-7445
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  • 5
    In: altamiracut, 12/31/2015, Vol.2(7), pp.30-35
    ISSN: altamiracut
    E-ISSN: 20078854
    Source: CrossRef
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  • 6
    Language: English
    In: Cancer Cell, 14 March 2016, Vol.29(3), pp.311-323
    Description: Medulloblastoma (MB) is a highly malignant pediatric brain tumor. Despite aggressive therapy, many patients succumb to the disease, and survivors experience severe side effects from treatment. -driven MB has a particularly poor prognosis and would greatly benefit from more effective therapies. We used an animal model of -driven MB to screen for drugs that decrease viability of tumor cells. Among the most effective compounds were histone deacetylase inhibitors (HDACIs). HDACIs potently inhibit survival of -driven MB cells in vitro, in part by inducing expression of the tumor suppressor gene. HDACIs also synergize with phosphatidylinositol 3-kinase inhibitors to inhibit tumor growth in vivo. These studies identify an effective combination therapy for the most aggressive form of MB. -driven medulloblastoma (MB) has a poor prognosis. Pei et al. report that HDAC inhibitors potently inhibit -driven MB cell growth in vitro, in part by inducing the expression of FOXO1, and synergize with PI3K inhibitors to inhibit tumor growth in vivo.
    Keywords: Medicine
    ISSN: 1535-6108
    E-ISSN: 1878-3686
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  • 7
    In: Neuro-Oncology, 2014, Vol. 16(suppl3), pp.iii29-iii29
    Description: BACKGROUND: Medulloblastoma (MB) is a highly malignant pediatric brain tumor. Despite aggressive therapy, many patients succumb to the disease, and survivors experience severe side effects from treatment. MBs with high levels of the MYC oncogene have a particularly poor prognosis, and would benefit from novel therapies. METHODS: To identify such therapies, we used an animal model of MYC-driven MB for high-throughput drug screening (HTS). RESULTS: Among the most effective compounds identified by HTS were histone deacetylase inhibitors (HDACI). In vitro, HDACI potently inhibited growth of murine and human MYC-driven MB cells, with minimal toxicity to normal cells. In vivo, HDACI significantly slowed growth of MYC-driven tumors, and synergized with PI3-Kinase inhibitors to cause tumor regression. CONCLUSIONS: These studies highlight the value of HTS for identification of effective therapies, and point to HDACI and PI3K inhibitors as promising agents for treatment of aggressive MB. SECONDARY CATEGORY: Preclinical Experimental Therapeutics.
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 8
    Language: English
    In: Cell, 18 April 2019, Vol.177(3), pp.572-586.e22
    Description: Drug resistance and relapse remain key challenges in pancreatic cancer. Here, we have used RNA sequencing (RNA-seq), chromatin immunoprecipitation (ChIP)-seq, and genome-wide CRISPR analysis to map the molecular dependencies of pancreatic cancer stem cells, highly therapy-resistant cells that preferentially drive tumorigenesis and progression. This integrated genomic approach revealed an unexpected utilization of immuno-regulatory signals by pancreatic cancer epithelial cells. In particular, the nuclear hormone receptor retinoic-acid-receptor-related orphan receptor gamma (RORγ), known to drive inflammation and T cell differentiation, was upregulated during pancreatic cancer progression, and its genetic or pharmacologic inhibition led to a striking defect in pancreatic cancer growth and a marked improvement in survival. Further, a large-scale retrospective analysis in patients revealed that RORγ expression may predict pancreatic cancer aggressiveness, as it positively correlated with advanced disease and metastasis. Collectively, these data identify an orthogonal co-option of immuno-regulatory signals by pancreatic cancer stem cells, suggesting that autoimmune drugs should be evaluated as novel treatment strategies for pancreatic cancer patients.
    Keywords: Msi ; Musashi ; Pdac ; Rorg ; Cancer ; Cancer Stem Cells ; Cytokines ; Immune ; Pancreatic Cancer ; Stem Cells
    ISSN: 00928674
    E-ISSN: 1097-4172
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  • 9
    Language: Spanish
    In: Religión y sociedad en el área maya, 1995-01-01, ISBN 84-605-3226-7, pags. 93-108, 1995, pp.93-108
    Source: Fundación Dialnet
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  • 10
    Language: English
    In: Clinical Therapeutics, August 2015, Vol.37(8), pp.e35-e36
    Description: To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.clinthera.2015.05.111 Byline: J. Reyes-Esparza, A. Gomez Solis, Lourdes Rodriguez-Fragoso Author Affiliation: Universidad Autonoma del Estado de Morelos, Cuernavaca, Morelos, Mexico
    Keywords: Medicine ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 0149-2918
    E-ISSN: 1879-114X
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