Gregory N Fuller

University of Texas MD Anderson Cancer Center, Houston, Texas, United States

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Publications (224)1072.07 Total impact

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    ABSTRACT: Subependymomas are usually treated with surgical resection; however, no standard, defined alternative medical therapy is recommended for patients who are not surgical candidates, owing to a paucity of molecular, immunological, and genetic characterization. To address this, an ex vivo functional analysis of the immune microenvironment in subependymoma was conducted, a subependymoma cytokine/chemokine microarray was constructed for the evaluation of operational immune and molecular pathways, and a subependymoma cell line was derived and used to test a variety of cytotoxic agents that target operational pathways identified in subependymoma. We found that immune effectors are detectable within the microenvironment of subependymoma; however, marked immune suppression is not observed. The subependymoma tissue microarrays demonstrated tumor expression of p53, MDM2, HIF-1α, topoisomerase II-β, p-STAT3, and nucleolin, but not EGFRvIII, EphA2, IL-13RA2, CMV, CTLA-4, FoxP3, PD-1, PD-L1, EGFR, PDGF-α, PDGF-β, PDGFR-α, PDGFR-β, PTEN, IGFBP2, PI3K, MDM4, IDH1, mTOR, or Jak2. A topoisomerase inhibitor (WP744, IC50=0.83μM) and a p-STAT3/HIF-1α inhibitor (WP1066, IC50=3.15μM) demonstrated a growth inhibition of the subependymoma cell proliferation. Cumulatively, these data suggest that those agents that interfere with oncogenes operational in subependymoma may have clinical impact. Copyright © 2014 Elsevier B.V. All rights reserved.
    Journal of Neuroimmunology 10/2014; 277(1-2):168-175. · 2.79 Impact Factor
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    ABSTRACT: Signal transducer and activator of transcription 5b (STAT5b) is likely the relevant STAT5 isoform with respect to the process of malignant progression in gliomas. STAT5b is a latent cytoplasmic protein involved in cell signaling through the modulation of growth factors, apoptosis, and angiogenesis. Previous in vitro studies have shown increased STAT5b expression in glioblastomas relative to low-grade tumors and normal brain. We recently demonstrated that phosphorylated STAT5b associates with delta epidermal growth factor receptor in the nucleus and subsequently binds the promoters of downstream effector molecules, including aurora kinase A. Analysis of TCGA dataset reveals that STAT5b is predominantly expressed in proneural (PN) gliomas relative to mesenchymal and neural gliomas. Here, we modeled ectopic expression of STAT5b in vivo using a platelet-derived growth factor subunit B (PDGFB)-dependent mouse model of PN glioma to determine its effect on tumor formation and progression. We showed that co-expression of STAT5b and PDGFB in mice yielded a significantly higher rate of high-grade gliomas than PDGFB expression alone. We also observed shorter survival in the combined expression set. High-grade tumors from the STAT5b+PDGFB expression set were found to have a lower rate of apoptosis than those from PDGFB alone. Furthermore, we showed that increased expression of STAT5b+PDGFB led to increased expression of downstream STAT5b targets, including Bcl-xL, cyclin D1, and aurora kinase A in high-grade tumors when compared to tumors derived from PDGFB alone. Our findings show that STAT5b promotes the malignant transformation of gliomas, particularly the PN subtype, and is a potential therapeutic target. © 2014 Wiley Periodicals, Inc.
    International Journal of Cancer 10/2014; · 6.20 Impact Factor
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    ABSTRACT: The immune therapeutic potential of microRNAs (miRNAs) in the context of tumor-mediated immune suppression has not been previously described for monocyte-derived glioma-associated macrophages, which are the largest infiltrating immune cell population in glioblastomas and facilitate gliomagenesis.
    JNCI Journal of the National Cancer Institute 08/2014; 106(8). · 15.16 Impact Factor
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    ABSTRACT: Rosette-forming glioneuronal tumor (WHO grade I) is a rare neoplasm primarily arising in young adults that is characterized by distinctive neurocytic rosette formation, a spindled glial component resembling pilocytic astrocytoma, and a high incidence of PIK3CA mutation. Low-grade diffuse astrocytoma (WHO grade II), on the other hand, is far more common and is characterized by a high incidence of IDH mutation. Here we report a patient with simultaneous presentation of a midbrain-cerebellar rosetteforming glioneuronal tumor and a cerebral diffuse astrocytoma. Molecular characterization of both tumors confirmed characteristic, mutually exclusive, distinct signatures, with the rosette-forming glioneuronal tumor exhibiting a previously unreported novel PIK3CA gene mutation.
    Clinical neuropathology 07/2014; 33(11). · 1.31 Impact Factor
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    ABSTRACT: Major discoveries in the biology of nervous system tumors have raised the question of how non-histological data such as molecular information can be incorporated into the next World Health Organization (WHO) classification of central nervous system tumors. To address this question, a meeting of neuropathologists with expertise in molecular diagnosis was held in Haarlem, The Netherlands, under the sponsorship of the International Society for Neuropathology (ISN). Prior to the meeting, participants solicited input from clinical colleagues in diverse neuro-oncological specialties. The present “white paper” catalogues the recommendations of the meeting, at which a consensus was reached that incorporation of molecular information into the next WHO classification should follow a set of provided “ISN-Haarlem” guidelines. Salient recommendations include that: 1) diagnostic entities should be defined as narrowly as possible to optimize interobserver reproducibility, clinicopathological predictions and therapeutic planning; 2) diagnoses should be “layered” with histologic classification, WHO grade, and molecular information listed below an “integrated diagnosis”; 3) determinations should be made for each tumor entity as to whether molecular information is required, suggested or not needed for its definition; 4) some pediatric entities should be separated from their adult counterparts; 5) input for guiding decisions regarding tumor classification should be solicited from experts in complementary disciplines of neuro-oncology and 6) entity-specific molecular testing and reporting formats should be followed in diagnostic reports. It is hoped that these guidelines will facilitate the forthcoming update of the 4th Edition of the WHO classification of central nervous system tumors.
    Brain Pathology 07/2014; · 4.35 Impact Factor
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    ABSTRACT: While World Health Organization (WHO) grading of meningioma stratifies patients according to recurrence risk overall, there is substantial within-grade heterogeneity with respect to recurrence-free survival (RFS). Most meningiomas are graded according to mitotic counts per unit area on H&E sections, a method potentially confounded by tumor cellularity, as well as potential limitations of accurate mitotic figure detection on routine histology. To refine mitotic figure assessment we evaluated 363 meningiomas with phospho-histoneH3(Ser10), and determined the mitotic index (number of mitoses per 1000 tumor cells). The median mitotic indices among WHO grades I (n=268), II (n=84), and III (n=11) tumors were 1, 4, and 12, Classification and regression tree analysis to categorize cutoffs identified 3 subgroups defined by mitotic indices of 0-2, 3-4, and ≥5, which on univariate analysis were associated with RFS (p<0.01). In multivariate analysis, mitotic index subgrouped in this manner was significantly associated with RFS (p<0.01) after adjustment for Simpson grade, WHO grade, and MIB-1 index. Mitotic index was then examined within individual WHO grade, showing that for grade I and II meningiomas, mitotic index can add additional information to RFS risk. The results suggest that the use of a robust mitotic marker in meningioma could refine risk stratification.
    Brain Pathology 07/2014; · 4.35 Impact Factor
  • Neuro-Oncology 07/2014; 16 Suppl 3:iii39. · 5.29 Impact Factor
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    ABSTRACT: The addition of anti-angiogenic therapy to the few treatments that are available to patients with malignant gliomas was based on the fact that these tumors are highly vascularized and on findings from initial preclinical and clinical studies which showed encouraging results. However, tumors that initially respond to this therapy invariably recur with the acquisition of highly aggressive and invasive phenotype. Although several myeloid populations have been associated to the recurrence of these tumors, a specific targetable population has not been yet identified as responsible for the heightened invasion observed upon antiangiogenesis therapies.
    Neuro-Oncology 07/2014; 16 Suppl 3:iii15. · 5.29 Impact Factor
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    ABSTRACT: The addition of anti-angiogenic therapy to the few treatments available to patients with malignant gliomas was based on the fact that these tumors are highly vascularized and on encouraging results from preclinical and clinical studies. However, tumors that initially respond to this therapy invariably recur with the acquisition of a highly aggressive and invasive phenotype. Although several myeloid populations have been associated to this pattern of recurrence, a specific targetable population has not been yet identified. Here, we present evidence for the accumulation of Tie2-expressing monocytes/macrophages (TEMs) at the tumor/normal brain interface of mice treated with anti-VEGF therapies in regions with heightened tumoral invasion. Furthermore, we describe the presence of TEMs in malignant glioma surgical specimens that recurred after bevacizumab treatment. Our studies showed that TEMs enhanced the invasive properties of glioma cells and secreted high levels of gelatinase enzymatic proteins. Accordingly, Tie2+MMP9+ monocytic cells were consistently detected in the invasive tumor edge upon anti-VEGF therapies. Our results suggest the presence of a specific myeloid/monocytic subpopulation that plays a pivotal role in the mechanism of escape of malignant gliomas from anti-VEGF therapies and therefore constitutes a new cellular target for combination therapies in patients selected for anti-angiogenesis treatment.
    Oncotarget 04/2014; 5(8):2208-20. · 6.63 Impact Factor
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    ABSTRACT: MIR-491 is commonly co-deleted with its adjacent CDKN2A on chromosome 9p21.3 in glioblastoma multiforme (GBM). However, it is not known whether deletion of MIR-491 is only a passenger event or has an important role. Small-RNA sequencing of samples from GBM patients demonstrated that both mature products of MIR-491 (miR-491-5p and -3p) are downregulated in tumors compared with the normal brain. The integration of GBM data from The Cancer Genome Atlas (TCGA), miRNA target prediction and reporter assays showed that miR-491-5p directly targets EGFR, CDK6 and Bcl-xL, whereas miR-491-3p targets IGFBP2 and CDK6. Functionally, miR-491-3p inhibited glioma cell invasion; overexpression of both miR-491-5p and -3p inhibited proliferation of glioma cell lines and impaired the propagation of glioma stem cells (GSCs), thereby prolonging survival of xenograft mice. Moreover, knockdown of miR-491-5p in primary Ink4a-Arf-null mouse glial progenitor cells exacerbated cell proliferation and invasion. Therefore, MIR-491 is a tumor suppressor gene that, by utilizing both mature forms, coordinately controls the key cancer hallmarks: proliferation, invasion and stem cell propagation.Oncogene advance online publication, 21 April 2014; doi:10.1038/onc.2014.98.
    Oncogene 04/2014; · 8.56 Impact Factor
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    ABSTRACT: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT: The addition of anti-angiogenic therapy to the few treatments available to patients with malignant gliomas was based on the fact that these tumors are highly vascularized and on encouraging results from preclinical and clinical studies. However, tumors that initially respond to this therapy invariably recur with the acquisition of a highly aggressive and invasive phenotype. Although several myeloid populations have been associated to this pattern of recurrence, a specific targetable population has not been yet identified. Here, we present evidence for the accumulation of Tie2-expressing monocytes/macrophages (TEMs) at the tumor/normal brain interface of mice treated with anti-VEGF therapies in regions with heightened tumoral invasion. Furthermore, we describe the presence of TEMs in malignant glioma surgical specimens that recurred after bevacizumab treatment. Our studies showed that TEMs enhanced the invasive properties of glioma cells and secreted high levels of gelatinase enzymatic proteins. Accordingly, Tie2 +
    Oncotarget 04/2014; 1. · 6.63 Impact Factor
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    ABSTRACT: The influence of survivin isoforms on outcome in glioblastoma is poorly understood. We analyzed the dominant anti-apoptotic transcript variants of survivin using expression data and modeled them in vivo to determine their impact on glioma formation and progression. Using data from low- and high-grade glioma knowledge bases, we expressed the anti-apoptotic isoforms of survivin (transcript variants 1 and 2) in vivo using the RCAS/Ntv-a model of murine glioma. In low-grade gliomas, survivin RNA expression was increased in 22 of 167 (13.2%) of cases and was associated with shortened survival (P = .005). Survivin RNA was preferentially expressed in proneural (PN) relative to mesenchymal high-grade gliomas (P < .0001). In proneural gliomas, survivin was expressed in 94 of 141 (67%) of cases and was associated with shorter disease-free survival (P = .04). In a platelet-derived growth factor subunit B-dependent murine model of PN glioma, ectopic expression of variant 1 yielded tumors in 28 of 30 (93%) of mice, of which 25% were high-grade tumors, whereas ectopic expression of variant 2 yielded tumors in 27 of 28 (96%), of which 81% were high-grade tumors (P < .0001). Microvascular proliferation was significantly more prominent (P < .0001), and tumor-free survival was shorter in mice with variant 2 than variant 1-derived tumors (P = .01). Survivin expression in low-grade gliomas is associated with poor survival and is preferentially expressed in PN gliomas. Compared with variant 1, variant 2 was associated with poorer survival and promoted malignant progression, angiogenesis, and shorter tumor-free survival in the PN murine model. Inhibiting survivin transcript variant 2, rather than variant 1 (the common isoform), may be an effective treatment strategy for glioma.
    Neuro-Oncology 03/2014; · 5.29 Impact Factor
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    ABSTRACT: PURPOSE/AIM To describe the common spread pattern behavior of gliomas of the posterior cingulate and retro-cingulate cortex using confocal reconstructions of MR images and Brodmann nomenclature. CONTENT ORGANIZATION Twenty diffuse gliomas cases involving the posterior cingulate (Brodmann area [BA] 23 & 31) and 5 cases involving the retro-cingulate cortex (BA 26,29,&30) were retrospectively analyzed. The posterior cingulate spread pattern follows the white matter pathways with an often discontinuous, sagittal, “double barrel” pattern. This must be differentiated from primary or secondary involvement of the callosal fibers which can rapidly disseminate tumor to the superomedial frontoparietal lobes coronally. In 3 cases, growth of a callosal tumor will cause herniation through the thin callosal isthmus into the ventricles. Retrosplenial tissues can be reached by the spread from the posterior parahippocampus, optic radiations, or the posterior callosum. Functional and neurosurgical importance will be discussed. SUMMARY Posterior cingulate gliomas spread via white matter tracts in predictable patterns with clinical ramifications.
    Radiological Society of North America 2013 Scientific Assembly and Annual Meeting; 12/2013
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    ABSTRACT: Antiangiogenic therapy is effective in blocking vascular permeability, inhibiting vascular proliferation, and slowing tumor growth, but studies in multiple cancer types have shown that tumors eventually acquire resistance to blockade of blood vessel growth. Currently, the mechanisms by which this resistance occurs are not well understood. In this study, we evaluated the effects of neutrophils on glioma biology both in vitro and in vivo and determined target genes by which neutrophils promote the malignant glioma phenotype during anti-VEGF therapy. We found that an increase in neutrophil infiltration into tumors is significantly correlated with glioma grade and in glioblastoma with acquired resistance to anti-VEGF therapy. Our data demonstrate that neutrophils and their condition media increased the proliferation rate of Glioblastoma-initating cells (GICs). In addition, neutrophils significantly increased GICs transwell migration compared to controls. Consistent with this behavior, co-culture with neutrophils promoted GICs to adopt morphologic and gene expression changes consistent with a mesenchymal signature. Neutrophil-promoting tumor progression could be blocked by S100A4 down-regulation in vitro and in vivo. Furthermore, S100A4 depletion increased the effectiveness of anti-VEGF therapy in glioma. Collectively, these data suggest that increased recruitment of neutrophils during anti-VEGF therapy promotes glioma progression and may promote treatment resistance. Tumor progression with mesenchymal characteristics is partly mediated by S100A4, the expression of which is increased by neutrophil infiltration. Targeting granulocytes and S100A4 may be effective approaches to inhibit the glioma malignant phenotype and diminish antiangiogenic therapy resistance.
    Clinical Cancer Research 11/2013; · 8.19 Impact Factor
  • Histopathology 07/2013; · 3.30 Impact Factor
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    ABSTRACT: MicroRNAs (miRs) have been shown to modulate critical gene transcripts involved in tumorigenesis, but their role in tumor-mediated immune suppression is largely unknown. On the basis of miRNA gene expression in gliomas using tissue microarrays, in situ hybridization, and molecular modeling, miR-124 was identified as a lead candidate for modulating signal transducer and activator of transcription 3 (STAT3) signaling, a key pathway mediating immune suppression in the tumor microenvironment. miR-124 is absent in all grades and pathological types of gliomas. Upon up regulating miR-124 in glioma cancer stem cells (gCSCs), the STAT3 pathway was inhibited, and miR-124 reversed gCSC-mediated immune suppression of T-cell proliferation and induction of Foxp3+ regulatory T-cells (Tregs). Treatment of T-cells from immunosuppressed glioblastoma patients with miR-124 induced marked effector response including up regulation of IL-2, IFN-γ, and tumor necrosis factor (TNF)-α. Both systemic administration of miR-124 or adoptive miR-124-transfected T-cell transfers exerted potent anti-glioma therapeutic effects in clonotypic and genetically engineered murine models of glioblastoma and enhanced effector responses in the local tumor microenvironment. These therapeutic effects were ablated in both CD4+ and CD8+ depleted mice and nude mouse systems, indicating that the therapeutic effect of miR-124 depends on the presence of a T-cell-mediated antitumor immune response. Our findings highlight the potential application of miR-124 as a novel immunotherapeutic agent for neoplasms and serve as a model for identifying miRNAs that can be exploited as immune therapeutics.
    Cancer Research 05/2013; · 9.28 Impact Factor
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    ABSTRACT: Brain metastasis from papillary thyroid carcinoma (PTC) is extremely rare and carries a poor prognosis. We report nine cases (five females and four males) of brain metastasis of PTC. The age of patients ranged from 46 to 87 years old. The patients presented with nonspecific symptoms such as headaches. Brain metastasis was the first clinical presentation in three of nine patients; two of which had the aggressive tall cell variant of PTC. Six patients had prior history of PTC (four classic, one oncocytic variant, and one columnar cell variant) for 2 to 17 years with a median of 12 years. Gross total resection of brain metastasis was achieved for eight of our patients. Eight patients were treated with radioactive iodine. The median follow-up time was 12 months, ranging from 1 month to 4 years. Three patients died of their disease in 6 months, 21 months and 4 years, respectively after their first presentation of brain metastasis. It seems that these rare aggressive variants of PTC, such as tall cell variant, not only have higher propensity to develop brain metastasis, but also more frequently present with brain metastasis as their first clinical presentation than classic PTC. Furthermore, patients with PTC can develop brain metastasis even after many years.
    Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 03/2013; · 2.56 Impact Factor
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    ABSTRACT: Fusion genes are chromosomal aberrations that are found in many cancers and can be used as prognostic markers and drug targets in clinical practice. Fusions can lead to production of oncogenic fusion proteins or to enhanced expression of oncogenes. Several recent studies have reported that some fusion genes can escape microRNA regulation via 3'-untranslated region (3'-UTR) deletion. We performed whole transcriptome sequencing to identify fusion genes in glioma and discovered FGFR3-TACC3 fusions in 4 of 48 glioblastoma samples from patients both of mixed European and of Asian descent, but not in any of 43 low-grade glioma samples tested. The fusion, caused by tandem duplication on 4p16.3, led to the loss of the 3'-UTR of FGFR3, blocking gene regulation of miR-99a and enhancing expression of the fusion gene. The fusion gene was mutually exclusive with EGFR, PDGFR, or MET amplification. Using cultured glioblastoma cells and a mouse xenograft model, we found that fusion protein expression promoted cell proliferation and tumor progression, while WT FGFR3 protein was not tumorigenic, even under forced overexpression. These results demonstrated that the FGFR3-TACC3 gene fusion is expressed in human cancer and generates an oncogenic protein that promotes tumorigenesis in glioblastoma.
    The Journal of clinical investigation 01/2013; · 15.39 Impact Factor
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    ABSTRACT: Diffuse gliomas are a heterogenous group of neoplasms traditionally classified as grades II to IV based on histologic features, and with prognosis determined mainly by histologic grade and pretreatment clinical factors. Our understanding of the molecular basis of glioma initiation, tumor progression, and treatment failure is rapidly evolving. A molecular profile of diffuse gliomas is emerging. Studies evaluating gene expression and DNA methylation profile have found multiple glioma subtypes and an association between subtype and survival. The recent discovery of isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) mutations in glioma has provided reproducible prognostic biomarkers and novel therapeutic targets. Glioblastomas that exhibit CpG island hypermethylator phenotype, proneural gene expression, or IDH1 mutation identify a subset of patients with markedly improved prognosis. Accumulated evidence supports the stratification of both low-grade and anaplastic diffuse gliomas into prognostic groups using 1p/19q codeletion and IDH mutation status. A classification scheme incorporating clinical, pathologic, and molecular information may facilitate improved prognostication for patients treated in the clinic, the development of more effective clinical trials, and rational testing of targeted therapeutics.
    Neurology 10/2012; 79(18):1917-26. · 8.30 Impact Factor

Publication Stats

7k Citations
1,072.07 Total Impact Points


  • 1993–2014
    • University of Texas MD Anderson Cancer Center
      • • Department of Pathology
      • • Brain Tumor Center
      • • Department of NeuroSurgery
      Houston, Texas, United States
  • 2011–2012
    • Hofstra North Shore-LIJ School of Medicine
      New York City, New York, United States
    • Houston Methodist Hospital
      Houston, Texas, United States
  • 2010
    • Cairo University
      Al Qāhirah, Al Qāhirah, Egypt
    • University of Houston
      Houston, Texas, United States
  • 2009
    • University of California, Davis
      • Department of Pathology, Microbiology and Immunology (VM)
      Davis, CA, United States
  • 2006
    • Mount Sinai School of Medicine
      • Department of Radiology
      Manhattan, NY, United States
  • 2005
    • Yale University
      New Haven, Connecticut, United States
  • 2002–2005
    • Memorial Sloan-Kettering Cancer Center
      • • Department of Neurology
      • • Division of Cell Biology
      New York City, New York, United States
    • University of Barcelona
      Barcino, Catalonia, Spain
    • Texas A&M University
      • Department of Electrical and Computer Engineering
      College Station, TX, United States
  • 2004
    • IDIBAPS August Pi i Sunyer Biomedical Research Institute
      Barcino, Catalonia, Spain
  • 2000
    • National Institutes of Health
      Maryland, United States
  • 1998
    • Huntington Hospital
      Huntington, New York, United States