Gregory N Fuller

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

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Publications (285)1462.73 Total impact

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    ABSTRACT: High-grade gliomas are notoriously heterogeneous regarding antigen expression, effector responses, and immunosuppressive mechanisms. Therefore, combinational immune therapeutic approaches are more likely to impact a greater number of patients and result in longer, durable responses. We have previously demonstrated the monotherapeutic effects of miR-124, which inhibits the signal transducer and activator of transcription 3 (STAT3) immune suppressive pathway, and immune stimulatory 4-1BB aptamers against a variety of malignancies, including genetically-engineered immune competent high-grade gliomas. To evaluate potential synergy, we tested an immune stimulatory aptamer together with miRNA-124, which blocks tumor-mediated immune suppression, and found survival to be markedly enhanced, including beyond that produced by monotherapy. The synergistic activity appeared to be not only secondary to enhanced CD3+ cell numbers but also to reduced macrophage immune tumor trafficking, indicating that a greater therapeutic benefit can be achieved with approaches that both induce immune activation and inhibit tumor-mediated immune suppression.
    No preview · Article · Dec 2015 · OncoImmunology
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    ABSTRACT: Gliomatosis peritonei, a rare condition often associated with immature ovarian teratoma, is characterized by the presence of mature glial tissue in the peritoneum. We retrospectively evaluated 21 patients with gliomatosis peritonei and studied their clinicopathologic features and immunophenotype. The patients' ages ranged from 5 to 42 years (median, 19 years). Their primary ovarian tumors consisted of immature teratoma (n=14), mixed germ cell tumors (n=6), and mature teratoma with a carcinoid tumor (n=1). Gliomatosis peritonei was diagnosed at the same time as primary ovarian neoplasm in 16 patients and secondary surgery in 5 patients. Also, 11 of 21 patients had metastatic immature teratoma (n=4), metastatic mature teratoma (n=2), or both (n=5). One patient developed glioma arising from gliomatosis peritonei. Seventeen patients had follow-up information and were alive with no evidence of disease (n=13), alive with disease (n=3), or alive with an unknown disease status (n=1). The follow-up durations ranged from 1 to 229 months (mean, 49 months; median, 23 months). Immunohistochemistry results demonstrated that SOX2 was expressed in all cases of gliomatosis peritonei and glioma with tissue available (nine of nine cases), whereas OCT4 and NANOG were negative in all cases with available tissue (eight of eight cases). In conclusion, both gliomatosis peritonei and glioma arising from it show a SOX2+/OCT4-/NANOG- immunophenotype. These findings demonstrated that gliomatosis peritonei is associated with favorable prognosis, although it is important to rule out potentially associated immature teratoma and malignant transformation. SOX2 may have an important role in the development of gliomatosis peritonei.Modern Pathology advance online publication, 13 November 2015; doi:10.1038/modpathol.2015.116.
    No preview · Article · Nov 2015 · Modern Pathology
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    ABSTRACT: Glioblastoma (GBM) is the most aggressive human brain tumor. Although several molecular subtypes of GBM are recognized, a robust molecular prognostic marker has yet to be identified. Here,wereport that the stemness regulator Sox2 is a new, clinically important target of microRNA-21 (miR-21) in GBM, with implications for prognosis. Using the MiR-21-Sox2 regulatory axis, approximately half of all GBM tumors present in the Cancer Genome Atlas (TCGA) and in-house patient databases can be mathematically classified into high miR-21/low Sox2 (Class A) or low miR-21/high Sox2 (Class B) subtypes. This classification reflects phenotypically and molecularly distinct characteristics and is not captured by existing classifications. Supporting the distinct nature of the subtypes, gene set enrichment analysis of the TCGA dataset predicted that Class A and Class B tumors were significantly involved in immune/inflammatory response and in chromosome organization and nervous system development, respectively. Patients with ClassBtumors had longer overall survival than those with Class A tumors. Analysis of both databases indicated that the Class A/Class B classification is a better predictor of patient survival than currently used parameters. Further, manipulation of MiR-21-Sox2 levels in orthotopic mouse models supported the longer survival of the Class B subtype. The MiR-21-Sox2 association was also found in mouse neural stem cells and in the mouse brain at different developmental stages, suggesting a role in normal development. Therefore, this mechanism-based classification suggests the presence of two distinct populations of GBM patients with distinguishable phenotypic characteristics and clinical outcomes.
    Full-text · Article · Nov 2015 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience

  • No preview · Article · Nov 2015 · Neuro-Oncology
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    ABSTRACT: Gliosarcoma is classified by the World Health Organization as a variant of glioblastoma. These tumors exhibit biphasic histologic and immunophenotypic features, reflecting both glial and mesenchymal differentiation. Gliosarcomas can be further classified into primary (de novo) tumors, and secondary gliosarcomas, which are diagnosed at recurrence after a diagnosis of glioblastoma. Using a retrospective review, patients seen at MD Anderson Cancer Center between 2004 and 2014 with a pathology-confirmed diagnosis of gliosarcoma were identified. 34 patients with a diagnosis of gliosarcoma seen at the time of initial diagnosis or at recurrence were identified (24 primary gliosarcomas (PGS), 10 secondary gliosarcomas (SGS)). Molecular analysis performed on fourteen patients revealed a high incidence of TP53 mutations and, rarely, EGFR and IDH mutations. Median overall survival (OS) for all patients was 17.5 months from the diagnosis of gliosarcoma, with a progression free survival (PFS) of 6.4 months. Comparing PGS with SGS, the median OS was 24.7 and 8.95 months, respectively (from the time of sarcomatous transformation in the case of SGS). The median OS in SGS patients from the initial diagnosis of GB was 25 months, with a PFS of 10.7 months. Molecular analysis revealed a higher than expected rate of TP53 mutations in GS patients and, typical of primary glioblastoma, IDH mutations were uncommon. Though our data shows improved outcomes for both PGS and SGS when compared to the literature, this is most likely a reflection of selection bias of patients treated on clinical trials at a quaternary center.
    No preview · Article · Sep 2015 · Journal of Neuro-Oncology
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    ABSTRACT: Ten to twenty percent of newly diagnosed glioblastoma (GBM) patients initially present with multiple lesions, termed multifocal or multicentric GBM (M-GBM). The prognosis of these patients is poorer than that of solitary GBM (S-GBM) patients. However, it is unknown whether multifocality has a genetic, epigenetic, or molecular basis. Here, we identified the genetic and epigenetic characteristics of M-GBM by performing a comprehensive analysis of multidimensional data, including imaging, genetic, epigenetic, and gene expression profiles, from 30 M-GBM cases in The Cancer Genome Atlas database and comparing the results with those of 173 S-GBM cases. We found that M-GBMs had no IDH1, ATRX, or PDGFRA mutations and were significantly associated with the mesenchymal subtype. We also identified the CYB5R2 gene to be hypo-methylated and overexpressed in M-GBMs. The expression level of CYB5R2 was significantly associated with patient survival in two major independent GBM cohorts, totaling 758 cases. The IDH1 mutation was markedly associated with CYB5R2 promoter methylation, but the survival influence of CYB5R2 was independent of IDH1 mutation status. CYB5R2 expression was significantly associated with collagen maturation and the catabolic process and immunoregulation pathways. These results reveal that M-GBMs have some underlying genetic and epigenetic characteristics that are associated with poor prognosis and that CYB5R2 is a new epigenetic marker for GBM prognosis.
    No preview · Article · Sep 2015 · Acta Neuropathologica
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    Full-text · Article · Jun 2015 · New England Journal of Medicine
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    ABSTRACT: BACKGROUND Diffuse low-grade and intermediate-grade gliomas (which together make up the lower-grade gliomas, World Health Organization grades II and III) have highly variable clinical behavior that is not adequately predicted on the basis of histologic class. Some are indolent; others quickly progress to glioblastoma. The uncertainty is compounded by interobserver variability in histologic diagnosis. Mutations in IDH, TP53, and ATRX and codeletion of chromosome arms 1p and 19q (1p/19q codeletion) have been implicated as clinically relevant markers of lower-grade gliomas. METHODS We performed genomewide analyses of 293 lower-grade gliomas from adults, incorporating exome sequence, DNA copy number, DNA methylation, messenger RNA expression, microRNA expression, and targeted protein expression. These data were integrated and tested for correlation with clinical outcomes. RESULTS Unsupervised clustering of mutations and data from RNA, DNA-copy-number, and DNA-methylation platforms uncovered concordant classification of three robust, nonoverlapping, prognostically significant subtypes of lower-grade glioma that were captured more accurately by IDH, 1p/19q, and TP53 status than by histologic class. Patients who had lower-grade gliomas with an IDH mutation and 1p/19q codeletion had the most favorable clinical outcomes. Their gliomas harbored mutations in CIC, FUBP1, NOTCH1, and the TERT promoter. Nearly all lower-grade gliomas with IDH mutations and no 1p/19q codeletion had mutations in TP53 (94%) and ATRX inactivation (86%). The large majority of lower-grade gliomas without an IDH mutation had genomic aberrations and clinical behavior strikingly similar to those found in primary glioblastoma. CONCLUSIONS The integration of genomewide data from multiple platforms delineated three molecular classes of lower-grade gliomas that were more concordant with IDH, 1p/19q, and TP53 status than with histologic class. Lower-grade gliomas with an IDH mutation either had 1p/19q codeletion or carried a TP53 mutation. Most lower-grade gliomas without an IDH mutation were molecularly and clinically similar to glioblastoma. (Funded by the National Institutes of Health)
    Full-text · Article · Jun 2015 · New England Journal of Medicine
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    ABSTRACT: To report a case of primary rhabdomyosarcoma (RMS) of the pineal gland in an adult, as well as review the literature on this rare entity. The case is compared with previous reports of similar entities, with emphasis on this patient's characteristics and clinical presentation, investigations, and management. Diagnosis of primary RMS of the pineal gland was based on the presence of strap cells and multinucleated myotube-like structures, as well as tumor cell expression of skeletal muscle markers consistent with myogenic differentiation. Multimodality treatment was initiated based on pediatric protocols. Unfortunately, the disease progressed on treatment, and the patient survived only 5 months from diagnosis. Pineal RMS is a rare disease with poor prognosis. Optimal management is unknown but likely to involve aggressive multimodality therapy. Copyright© by the American Society for Clinical Pathology.
    No preview · Article · May 2015 · American Journal of Clinical Pathology
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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.
    No preview · Article · May 2015 · International Journal of Cancer
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    ABSTRACT: Insulin-like growth factor binding protein 2 (IGFBP2) is a pleiotropic oncogenic protein that has both extracellular and intracellular functions. Despite a clear causal role in cancer development, the tumor-promoting mechanisms of IGFBP2 are poorly understood. The contributions of intracellular IGFBP2 to tumor development and progression are also unclear. Here we present evidence that both exogenous IGFBP2 treatment and cellular IGFBP2 overexpression lead to aberrant activation of epidermal growth factor receptor (EGFR), which subsequently activates signal transducer and activator of transcription factor 3 (STAT3) signaling. Furthermore, we demonstrate that IGFBP2 augments the nuclear accumulation of EGFR to potentiate STAT3 transactivation activities, via activation of the nuclear EGFR signaling pathway. Nuclear IGFBP2 directly influences the invasive and migratory capacities of human glioblastoma cells, providing a direct link between intracellular (and particularly nuclear) IGFBP2 and cancer hallmarks. These activities are also consistent with the strong association between IGFBP2 and STAT3-activated genes derived from The Cancer Genome Atlas database for human glioma. A high level of all three proteins (IGFBP2, EGFR and STAT3) was strongly correlated with poorer survival in an independent patient data set. These results identify a novel tumor-promoting function for IGFBP2 of activating EGFR/STAT3 signaling and facilitating EGFR accumulation in the nucleus, thereby deregulating EGFR signaling by two distinct mechanisms. As targeting EGFR in glioma has been relatively unsuccessful, this study suggests that IGFBP2 may be a novel therapeutic target.Oncogene advance online publication, 20 April 2015; doi:10.1038/onc.2015.131.
    No preview · Article · Apr 2015 · Oncogene
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    ABSTRACT: Papillary tumor of the pineal region (PTPR) is a rare neuroectodermal tumor first described in 2003 and formally codified by the WHO in 2007. Limited reports suggest surgical resection is the mainstay of treatment; however, the role of multimodality therapy is not well defined. We evaluated our institutional experience in the treatment of PTPR. Eight patients with pathologically confirmed PTPR diagnosed between 1999 and 2013 were retrospectively reviewed. The median age at diagnosis was 37 (range 25-56). After a median follow-up of 60 months (range 10-170), seven of eight patients were still living. All patients underwent maximum safe surgical resection; five received adjuvant radiation (63%). Overall and progression free survival 5 years from diagnosis were 100% and 51%, respectively. Progression free survival 5 years from completion of adjuvant radiotherapy was 64%. Crude recurrence rates for patients receiving adjuvant radiotherapy (n=5) vs. not (n=3) were 20% and 67%, respectively. Crude recurrence rate after gross total resection (GTR) and no adjuvant radiotherapy (n=2) was 100%, vs. 0% when adjuvant radiotherapy was administered after GTR (n=2). Three patients received adjuvant radiotherapy after subtotal resection, of which one had out-of-field recurrence at 46 months (crude recurrence rate 33%). In all cases, salvage with radiation at the time of recurrence was effective. Our institutional experience confirms a recent multicenter retrospective series showing excellent survival, but high risk of local recurrence for PTPR. Our findings suggest radiotherapy provides durable local control, particularly when administered in the adjuvant setting even after GTR. Copyright © 2015 Elsevier Inc. All rights reserved.
    No preview · Article · Mar 2015 · World Neurosurgery
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    ABSTRACT: Akt is a robust oncogene that plays key roles in the development and progression of many cancers, including glioma. We evaluated the differential propensities of the Akt isoforms toward progression in the well-characterized RCAS/Ntv-a mouse model of PDGFB-driven low grade glioma. A constitutively active myristoylated form of Akt1 did not induce high-grade glioma (HGG). In stark contrast, Akt2 and Akt3 showed strong progression potential with 78% and 97% of tumors diagnosed as HGG, respectively. We further revealed that significant variations in polarity and hydropathy values among the Akt isoforms in both the pleckstrin homology domain (P domain) and regulatory domain (R domain) were critical in mediating glioma progression. Gene expression profiles from representative Akt-derived tumors indicated dominant and distinct roles for Akt3, consisting primarily of DNA repair pathways. TCGA data from human GBM closely reflected the DNA repair function, as Akt3 was significantly correlated with a 76-gene signature DNA repair panel. Consistently, compared with Akt1 and Akt2 overexpression models, Akt3-expressing human GBM cells had enhanced activation of DNA repair proteins, leading to increased DNA repair and subsequent resistance to radiation and temozolomide. Given the wide range of Akt3-amplified cancers, Akt3 may represent a key resistance factor.
    Full-text · Article · Mar 2015 · Proceedings of the National Academy of Sciences
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    ABSTRACT: Dynamic contrast-enhanced perfusion MR imaging has proved useful in determining whether a contrast-enhancing lesion is secondary to recurrent glial tumor or is treatment-related. In this article, we explore the best method for dynamic contrast-enhanced data analysis. We retrospectively reviewed 24 patients who met the following conditions: 1) had at least an initial treatment of a glioma, 2) underwent a half-dose contrast agent (0.05-mmol/kg) diagnostic-quality dynamic contrast-enhanced perfusion study for an enhancing lesion, and 3) had a diagnosis by pathology within 30 days of imaging. The dynamic contrast-enhanced data were processed by using model-dependent analysis (nordicICE) using a 2-compartment model and model-independent signal intensity with time. Multiple methods of determining the vascular input function and numerous perfusion parameters were tested in comparison with a pathologic diagnosis. The best accuracy (88%) with good correlation compared with pathology (P = .005) was obtained by using a novel, model-independent signal-intensity measurement derived from a brief integration beginning after the initial washout and by using the vascular input function from the superior sagittal sinus for normalization. Modeled parameters, such as mean endothelial transfer constant > 0.05 minutes(-1), correlated (P = .002) but did not reach a diagnostic accuracy equivalent to the model-independent parameter. A novel model-independent dynamic contrast-enhanced analysis method showed diagnostic equivalency to more complex model-dependent methods. Having a brief integration after the first pass of contrast may diminish the effects of partial volume macroscopic vessels and slow progressive enhancement characteristic of necrosis. The simple modeling is technique- and observer-dependent but is less time-consuming. © 2015 American Society of Neuroradiology.
    No preview · Article · Dec 2014 · American Journal of Neuroradiology
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    ABSTRACT: BACKGROUND: Methylation profiling of solid tumors has revealed biologic subtypes, often with clinical implications. Methylation profiles of meningioma and their clinical implications are not well understood. METHODS: Ninety-two meningioma samples (n = 44 test set and n = 48 validation set) were profiled using the Illumina HumanMethylation450 BeadChip. Unsupervised clustering and analyses for recurrence-free survival (RFS) were performed. RESULTS: Unsupervised clustering of the test set using approximately 900 highly variable markers identified two clearly defined methylation subgroups. One of the groups (n = 19) showed global hypermethylation of a set of markers, analogous to CpG island methylator phenotype (CIMP). These findings were reproducible in the validation set, with 18/48 samples showing the CIMP-positive phenotype. Importantly, of 347 highly variable markers common to both the test and validation set analyses, 107 defined CIMP in the test set and 94 defined CIMP in the validation set, with an overlap of 83 markers between the two datasets. This number is much greater than expected by chance indicating reproducibly of the hypermethylated markers that define CIMP in meningioma. With respect to clinical correlation, the 37 CIMP-positive cases displayed significantly shorter RFS compared to the 55 non-CIMP cases (hazard ratio 2.9, p = 0.013). In an effort to develop a preliminary outcome predictor, a 155-marker subset correlated with RFS was identified in the test dataset. When interrogated in the validation dataset, this 155-marker subset showed a statistical trend (p < 0.1) towards distinguishing survival groups. CONCLUSIONS: This study defines the existence of a CIMP phenotype in meningioma, which involves a substantial proportion (37/92, 40%) of samples with clinical implications. Ongoing work will expand this cohort and examine identification of additional biologic differences (mutational and DNA copy number analysis) to further characterize the aberrant methylation subtype in meningioma. CIMP-positivity with aberrant methylation in recurrent/malignant meningioma suggests a potential therapeutic target for clinically aggressive cases.
    Full-text · Article · Nov 2014 · Neuro-Oncology
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    ABSTRACT: Antibody therapeutic targeting of the immune checkpoints CTLA-4 and PD-1 has demonstrated marked tumor regression in clinical trials; however, this requires multimodality treatment and has known toxicity. MicroRNAs (miRNAs) can modulate gene transcripts, including those of tumor-mediated immune suppressive pathways. MiRNAs can be delivered to the systemic immune compartment, which can initiate anti-tumor immune response, overcoming the issue of miRNA delivery to the tumor. To identify potential miRNA therapeutics, we exploited human glioblastoma miRNA expression assays followed by a screening process of predicted binding sites in the 3' UTR of immune suppressive pathways and immune checkpoints. MiR-138 emerged as a leading candidate with binding sites in the 3' UTR of CTLA-4 and PD-1, which were functionally confirmed with luciferase expression assays. The miR-138 targeting of CTLA-4 and PD-1 was further validated by expression analysis of transfected human CD4+ T cells. Using human glioma tumor microarrays and in situ hybridization, heterogeneous expression of miR-138 was found amongst all glioma grades and pathological subtypes. The PD-1 ligand, PD-L1, was frequently expressed in glioblastomas based on immunohistochemistry and ex vivo flow cytometry from human glioblastoma. Analysis of TCGA database revealed that co-expression of PD-1 and PD-L1 impacts glioblastoma survival. The role of CTLA-4 in glioblastoma-mediated immune suppression is well documented, suggesting that targeting of CTLA-4 and PD-1 with miR-138 in glioblastoma patients may have anti-tumor activity. In vivo treatment with miR-138 in immune-competent mice with GL261 gliomas demonstrated marked tumor regression, a 43% increase in median survival (P = 0.011), and an associated decrease in intratumoral FoxP3+ Tregs, CTLA-4, and PD-1 expression. Conversely, in an immune-incompetent animal background, miR-138 failed to exert any therapeutic effect, indicating that miR-138 mediates in vivo activity via the immune system. Cumulatively, our data indicate that miR-138 may be an active and novel immunotherapeutic agent for human glioblastoma patients.
    Full-text · Article · Nov 2014 · Neuro-Oncology
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    ABSTRACT: Aggressive cancer cells are characterized by high rates glycolysis and lactate production, a metabolic reprogramming event known as the Warburg effect. This ultimately provides tumor cells including GBM the most malignant and common primary brain tumor with intermediate metabolites for anabolic processes, cell proliferation and invasion. However, these biological processes generate oxidative stress that must be balanced through detoxification of reactive oxygen species (ROS). Using an unbiased retroviral loss of function screen in pre-disposed but non-transformed astrocytes, we demonstrate that PTEN Induced Kinase 1 (PINK1), a mitochondrial kinase is a crucial regulator of the Warburg effect. Mechanistically, loss of PINK1 mediates metabolic reprogramming in normal human astrocytes through ROS dependent hypoxia-inducible factor-1α (HIF1α) stabilization, a transcription factor that controls expression of several aerobic glycolysis genes. Overexpression of PINK1 in GBM cells suppresses ROS, HIF1a and the Warburg effect in vitro and in vivo. Surprisingly, loss of PINK1 in GBM cells that retain PINK1 expression increases oxidative stress and reduces cell viability suggesting ROS balance and maintenance is critical in tumor cells and can be therapeutically exploited. PINK1 loss was observed in GBM and correlated with poor patient survival. Collectively, we demonstrate that PINK1 is a negative regulator of the Warburg effect.
    No preview · Article · Nov 2014 · Neuro-Oncology
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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.
    No preview · Article · Oct 2014 · Journal of Neuroimmunology

  • No preview · Article · Oct 2014 · Cancer Research
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    ABSTRACT: Antibody therapeutic targeting of the immune checkpoints CTLA-4 and PD-1 has demonstrated marked tumor regression in clinical trials; however, this requires multimodality treatment and has known toxicity. Furthermore, the targeting of one checkpoint often results in the up-regulation of another. MicroRNAs (miRNAs) can modulate gene transcripts, including those of tumor-mediated immune suppressive pathways and networks. Additionally, miRNAs can be delivered to the systemic immune compartment, which can initiate anti-tumor immune response, including within the central nervous system, thereby overcoming the confounding issue of miRNA delivery to the tumor. To identify potential immune modulatory miRNA therapeutics, we exploited human glioblastoma miRNA expression assays followed by a screening process of predicted binding sites in the 3' UTR of immune suppressive pathways and immune checkpoints. MiR-138 emerged as a leading candidate with three predicted binding sites in the 3' UTR of CTLA-4 and one within PD-1, which was functionally confirmed with luciferase expression assays. The miR-138 targeting of CTLA-4 and PD-1 was further validated by expression analysis of transfected human CD4+ T cells. Using human glioma tumor microarrays and in situ hybridization, heterogeneous expression of miR-138 was found amongst all glioma grades and pathological subtypes. The PD-1 ligand, PD-L1, was frequently expressed in glioblastomas based on immunohistochemistry and ex vivo flow cytometry from fresh human glioblastoma. Analysis of TCGA database revealed that co-expression of PD-1 and PD-L1 impacts glioblastoma survival. Given the previously documented role of CTLA-4 as an operational mechanism of glioblastoma-mediated immune suppression, this cumulative data suggests that dual targeting of CTLA-4 and PD-1 with miR-138 in glioblastoma patients may have anti-tumor activity. In vivo treatment with miR-138 in immune-competent mice with GL261 gliomas demonstrated marked tumor regression, a 43% increase in median survival (P = 0.011), and an associated decrease in intratumoral FoxP3+ Tregs, CTLA-4, and PD-1 expression. Conversely, in an immune-incompetent animal background, miR-138 failed to exert any therapeutic effect, indicating that miR-138 mediates in vivo activity via the immune system. Cumulatively, our data indicate that miR-138 may be an active and novel immunotherapeutic agent for human glioblastoma patients.
    Full-text · Article · Sep 2014 · Neuro-Oncology

Publication Stats

10k Citations
1,462.73 Total Impact Points

Institutions

  • 1984-2015
    • University of Texas MD Anderson Cancer Center
      • • Department of NeuroSurgery
      • • Department of Pathology
      • • Department of Biomathematics
      Houston, Texas, United States
  • 1984-2011
    • University of Houston
      Houston, Texas, United States
  • 2010
    • Cairo University
      Al Qāhirah, Al Qāhirah, Egypt
  • 2007
    • Houston Methodist Hospital
      Houston, Texas, United States
    • University of Aberdeen
      Aberdeen, Scotland, United Kingdom
  • 2006
    • Mount Sinai School of Medicine
      • Department of Radiology
      Manhattan, NY, United States
  • 2003-2006
    • University of California, San Francisco
      San Francisco, California, United States
  • 2004
    • IDIBAPS August Pi i Sunyer Biomedical Research Institute
      Barcino, Catalonia, Spain
  • 2002
    • Texas A&M University
      • Department of Electrical and Computer Engineering
      College Station, TX, United States
    • University of Barcelona
      Barcino, Catalonia, Spain
  • 2001-2002
    • Memorial Sloan-Kettering Cancer Center
      • Division of Cell Biology
      New York City, NY, United States
  • 2000
    • National Institutes of Health
      Maryland, United States
  • 1998
    • Huntington Hospital
      Huntington, New York, United States
  • 1978-1988
    • University of Texas Medical School
      • • Department of Neurobiology and Anatomy
      • • Department of Psychiatry & Behavioral Sciences
      Houston, Texas, United States