Amy B Heimberger

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

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Publications (101)629.42 Total impact

  • Cancer Research 08/2015; 75(15 Supplement):4291-4291. DOI:10.1158/1538-7445.AM2015-4291 · 9.28 Impact Factor
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    ABSTRACT: sec> Background: Fibrinogen-like protein 2 (FGL2) may promote glioblastoma multiforme (GBM) cancer development by inducing multiple immune-suppression mechanisms. Methods: The biological significance of FGL2 expression was assessed using the The Cancer Genome Atlast (TCGA) glioma database and tumor lysates analysis. The therapeutic effects of an anti-Fgl2 antibody and the role of immune suppression regulation by Fgl2 were determined in immune-competent, NOD-scid IL2Rgammanull (NSG), and Fc&b.gamma;RIIB-/- mice (n = 3–18 per group). Data were analyzed with two-way analysis of variance, log-rank survival analysis, and Pearson correlation. All statistical tests were two-sided. Results: In low-grade gliomas, 72.5% of patients maintained two copies of the FGL2 gene, whereas 83.8% of GBM patients had gene amplification or copy gain. Patients with high levels of FGL2 mRNA in glioma tissues had a lower overall survival ( P = .009). Protein levels of FGL2 in GBM lysates were higher relative to low-grade glioma lysates (11.48±5.75ng/mg vs 3.96±1.01ng/mg, P = .003). In GL261 mice treated with an anti-FGL2 antibody, median survival was 27 days compared with only 17 days for mice treated with an isotype control antibody ( P = .01). The anti-FGL2 antibody treatment reduced CD39+ Tregs, M2 macrophages, programmed cell death protein 1 (PD-1), and myeloid-derived suppressor cells (MDSCs). FGL2-induced increases in M2, CD39, and PD-1 were ablated in Fc&b.gamma;RIIB-/- mice. Conclusions: FGL2 augments glioma immunosuppression by increasing the expression levels of PD-1 and CD39, expanding the frequency of tumor-supportive M2 macrophages via the FcγRIIB pathway, and enhancing the number of MDSCs and CD39+ regulatory T cells. Collectively, these results show that FGL2 functions as a key immune-suppressive modulator and has potential as an immunotherapeutic target for treating GBM. </sec
    JNCI Journal of the National Cancer Institute 05/2015; 107(8). DOI:10.1093/jnci/djv137 · 15.16 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 05/2015; 136(9). DOI:10.1002/ijc.29264 · 5.01 Impact Factor
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    ABSTRACT: The growth factor PDGF controls the development of glioblastoma (GBM) but its contribution to the function of GBM stem-like cells (GSC) has been little studied. Here we report that the transcription factor FoxM1 promotes PDGFA-STAT3 signaling to drive GSC self-renewal and tumorigenicity. In GBM we found a positive correlation between expression of FoxM1 and PDGF-A. In GSC and mouse neural stem cells, FoxM1 bound to the PDGF-A promoter to upregulate PDGF-A expression, acting to maintain the stem-like qualities of GSC in part through this mechanism. Analysis of the human cancer genomic database TCGA revealed that GBM express higher levels of STAT3, a PDGF-A effector signaling molecule, as compared with normal brain. FoxM1 regulated STAT3 transcription through interactions with the β-catenin/TCF4 complex. FoxM1 deficiency inhibited PDGF-A and STAT3 expression in neural stem cells and GSC, abolishing their stem-like and tumorigenic properties. Further mechanistic investigations defined a FoxM1-PDGFA-STAT3 feed-forward pathway that was sufficient to confer stem-like properties to glioma cells. Collectively, our findings showed how FoxM1 activates expression of PDGF-A and STAT3 in a pathway required to maintain the self-renewal and tumorigenicity of glioma stem-like cells. Copyright © 2015, American Association for Cancer Research.
    Cancer Research 04/2015; 75(11). DOI:10.1158/0008-5472.CAN-14-2800 · 9.28 Impact Factor
  • Sherise D Ferguson · Visish M Srinivasan · Amy B Heimberger
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    ABSTRACT: The role of tumor-induced immune modulation in cancer progression is currently a focus of investigation. The signal transducer and activator of transcription 3 (STAT3) is an established molecular hub of immunosuppression, and its signaling pathways are classically overactivated within malignancies. This article will review STAT3 operational mechanisms within the immune system and the tumor microenvironment, with a focus on therapeutic strategies that may impact outcomes for patients with cancer.
    Journal of Neuro-Oncology 02/2015; 123(3). DOI:10.1007/s11060-015-1731-3 · 2.79 Impact Factor
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    ABSTRACT: The epidermal growth factor receptor variant III deletion mutation, EGFRvIII, is expressed in ∼30% of primary glioblastoma and linked to poor long-term survival. Rindopepimut consists of the unique EGFRvIII peptide sequence conjugated to keyhole limpet hemocyanin. In previous phase II trials (ACTIVATE/ACT II), rindopepimut was well tolerated with robust EGFRvIII-specific immune responses and promising progression-free and overall survival. This multicenter, single-arm phase II clinical trial (ACT III) was performed to confirm these results. Rindopepimut and standard adjuvant temozolomide chemotherapy were administered to 65 patients with newly diagnosed EGFRvIII-expressing (EGFRvIII+) glioblastoma after gross total resection and chemoradiation. Progression-free survival at 5.5 months (∼8.5 mo from diagnosis) was 66%. Relative to study entry, median overall survival was 21.8 months, and 36-month overall survival was 26%. Extended rindopepimut vaccination (up to 3.5+ years) was well tolerated. Grades 1-2 injection site reactions were frequent. Anti-EGFRvIII antibody titers increased ≥4-fold in 85% of patients, and increased with duration of treatment. EGFRvIII was eliminated in 4/6 (67%) tumor samples obtained after >3 months of therapy. This study confirms, in a multicenter setting, the preliminary results seen in previous phase II trials of rindopepimut. A pivotal, double-blind, randomized, phase III trial ("ACT IV") is under way. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
    Neuro-Oncology 01/2015; 17(6). DOI:10.1093/neuonc/nou348 · 5.29 Impact Factor
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    Peter E Fecci · Amy B Heimberger · John H Sampson
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    ABSTRACT: Immunotherapy for cancer continues to gain both momentum and legitimacy as a rational mode of therapy and a vital treatment component in the emerging era of personalized medicine. Gliomas, and their most malignant form, glioblastoma, remain as a particularly devastating solid tumor for which standard treatment options proffer only modest efficacy and target specificity. Immunotherapy would seem a well-suited choice to address such deficiencies given both the modest inherent immunogenicity of gliomas and the strong desire for treatment specificity within the confines of the toxicity-averse normal brain. This review highlights the caveats and challenges to immunotherapy for primary brain tumors, as well as reviewing modalities that are currently used or are undergoing active investigation. Tumor immunosuppressive countermeasures, peculiarities of central nervous system immune access, and opportunities for rational treatment design are discussed. See all articles in this CCR Focus section, "Discoveries, Challenges, and Progress in Primary Brain Tumors." Clin Cancer Res; 20(22); 5620-9. ©2014 AACR.
    Clinical Cancer Research 11/2014; 20(22):5620-9. DOI:10.1158/1078-0432.CCR-14-0832 · 8.19 Impact Factor
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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. DOI:10.1016/j.jneuroim.2014.10.008 · 2.79 Impact Factor
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    ABSTRACT: Immunotherapeutic approaches to cancer have shown remarkable promise. A critical barrier to successfully executing such immune-mediated interventions is the selection of safe yet immunogenic targets. As patient deaths have occurred when tumor-associated antigens shared by normal tissue have been targeted by strong cellular immunotherapeutic platforms, route of delivery, target selection and the immune-mediated approach undertaken must work together to maximize efficacy with safety. Selected tumor-specific targets can spare potential toxicity to normal tissue; however, they are far less common than tumor-associated antigens and may not be present on all patients. In the context of immunotherapy for high-grade glioma, 2 of the most prominently studied antigens are the tumor-associated epidermal growth factor receptor and its tumor-specific genetic deletion variant III. In this review, we will summarize the immune-mediated strategies employed against these targets as well as the caveats particular to these approaches.
    Neuro-Oncology 10/2014; 16(suppl 8):viii20-viii25. DOI:10.1093/neuonc/nou236 · 5.29 Impact Factor
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    ABSTRACT: Fibrinogen-like protein 2 (Fgl2), a member of the fibrinogen family, can be expressed as a membrane-associated protein with coagulation activity or in a secreted form possessing unique immune suppressive functions. The biological importance of Fgl2 is evident within viral-induced fibrin depositing inflammatory diseases and malignancies and provides a compelling rationale for Fgl2 expression to not only be considered as a disease biomarker but also as a therapeutic target. This article will provide a comprehensive review of the currently known biological properties of Fgl2 and clarifies future scientific directives.
    International Reviews Of Immunology 09/2014; DOI:10.3109/08830185.2014.956360 · 5.28 Impact Factor
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    ABSTRACT: Background 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. Methods An miRNA microarray was used to compare expression profiles between human glioblastoma-infiltrating macrophages and matched peripheral monocytes. The effects of miR-142-3p on phenotype and function of proinflammatory M1 and immunosuppressive M2 macrophages were determined. The therapeutic effect of miR-142-3p was ascertained in immune-competent C57BL/6J mice harboring intracerebral GL261 gliomas and in genetically engineered Ntv-a mice bearing high-grade gliomas. Student t test was used to evaluate the differences between ex vivo datasets. Survival was analyzed with the log-rank test and tumor sizes with linear mixed models and F test. All statistical tests were two-sided. Results miR-142-3p was the most downregulated miRNA (approximately 4.95-fold) in glioblastoma-infiltrating macrophages. M2 macrophages had lower miR-142-3p expression relative to M1 macrophages (P =.03). Overexpression of miR-142-3p in M2 macrophages induced selective modulation of transforming growth factor beta receptor 1, which led to subsequent preferential apoptosis in the M2 subset (P = .01). In vivo miR-142-3p administration resulted in glioma growth inhibition (P = .03, n = 5) and extended median survival (miR-142-3p-treated C57BL/6J mice vs scramble control: 31 days vs 23.5 days, P =.03, n = 10; miR-142-3p treated Ntv-a mice vs scramble control: 32 days vs 24 days, P =.03, n = 9), with an associated decrease in infiltrating macrophages (R-2 =.303). Conclusions These data indicate a unique role of miR-142-3p in glioma immunity by modulating M2 macrophages through the transforming growth factor beta signaling pathway.
    JNCI Journal of the National Cancer Institute 08/2014; 106(8). DOI:10.1093/jnci/dju162 · 15.16 Impact Factor
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    ABSTRACT: Despite the recent successes of using immune modulatory antibodies in cancer patients, autoimmune pathologies resulting from the activation of self self-reactive T cells preclude the dose escalations necessary to fully exploit their therapeutic potential. To reduce the observed and expected toxicities associated with immune modulation, here we describe a clinically feasible and broadly applicable approach to limit immune costimulation to the disseminated tumor lesions of the patient whereby an agonistic 4-1BB oligonucleotide aptamer is targeted to the tumor stroma by conjugation to an aptamer that binds to a broadly expressed stromal product, vascular endothelial growth factor (VEGF). The approach was predicated on the premise that by targeting the costimulatory ligands to products secreted into the tumor stroma the T cells will be costimulated prior to their engagement of the MHC/peptide complex on the tumor cell, thereby obviating the need to target the costimulatory ligands to non-internalizing cell cell-surface products expressed on the tumor cells. Underscoring the potency of stroma stroma-targeted costimulation and the broad spectrum of tumors secreting VEGF, in preclinical murine tumor models systemic administration of the VEGF VEGF-targeted 4-1BB aptamer conjugates engendered potent antitumor immunity against multiple unrelated tumors in subcutaneous, post post-surgical lung metastasis, methylcholantrene-induced fibrosarcoma, and oncogene-induced autochthonous glioma models, and exhibited a superior therapeutic index compared to non-targeted administration of an agonistic 4-1BB antibody or 4-1BB aptamer.
    06/2014; 2(9). DOI:10.1158/2326-6066.CIR-14-0007
  • Cancer Research 04/2014; 73(1 Supplement):B62-B62. DOI:10.1158/1538-7445.TUMIMM2012-B62 · 9.28 Impact Factor
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    11/2013; 1(Suppl 1):P177. DOI:10.1186/2051-1426-1-S1-P177
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    ABSTRACT: Despite extensive study, few therapeutic targets have been identified for glioblastoma (GBM). Here we show that patient-derived glioma sphere cultures (GSCs) that resemble either the proneural (PN) or mesenchymal (MES) transcriptomal subtypes differ significantly in their biological characteristics. Moreover, we found that a subset of the PN GSCs undergoes differentiation to a MES state in a TNF-a/ NF-kB-dependent manner with an associated enrichment of CD44 subpopulations and radioresistant phenotypes. We present data to suggest that the tumor microenvironment cell types such as macro-phages/microglia may play an integral role in this process. We further show that the MES signature, CD44 expression, and NF-kB activation correlate with poor radiation response and shorter survival in patients with GBM. Significance In this study, we characterize plasticity between the proneural (PN) and mesenchymal (MES) transcriptome signatures observed in glioblastoma (GBM). Specifically, we show that PN glioma sphere cultures (GSCs) can be induced to a MES state with an associated enrichment of CD44 expressing cells and a gain of radioresistance, in an NF-kB-dependent fashion. Newly diagnosed GBM samples show a direct correlation among radiation response, higher MES metagene, CD44 expres-sion, and NF-kB activation, and we propose macrophages/microglia as a potential microenvironmental component that can regulate this transition. Our results reveal a mechanistic link between transcriptome plasticity, radiation resistance, and NF-kB signaling. Inhibition of NF-kB activation can directly affect radioresistance and presents an attractive therapeutic target for GBM.
    Cancer Cell 09/2013; 24:331-346. · 23.89 Impact Factor
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    ABSTRACT: Despite extensive study, few therapeutic targets have been identified for glioblastoma (GBM). Here we show that patient-derived glioma sphere cultures (GSCs) that resemble either the proneural (PN) or mesenchymal (MES) transcriptomal subtypes differ significantly in their biological characteristics. Moreover, we found that a subset of the PN GSCs undergoes differentiation to a MES state in a TNF-α/NF-κB-dependent manner with an associated enrichment of CD44 subpopulations and radioresistant phenotypes. We present data to suggest that the tumor microenvironment cell types such as macrophages/microglia may play an integral role in this process. We further show that the MES signature, CD44 expression, and NF-κB activation correlate with poor radiation response and shorter survival in patients with GBM.
    Cancer cell 08/2013; 24(3). DOI:10.1016/j.ccr.2013.08.001 · 23.89 Impact Factor
  • Cancer Research 08/2013; 73(8 Supplement):3251-3251. DOI:10.1158/1538-7445.AM2013-3251 · 9.28 Impact Factor
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    ABSTRACT: The molecular heterogeneity of glioblastoma has been well recognized and has resulted in the generation of molecularly defined subtypes. These subtypes (classical, neural, mesenchymal, and proneural) are associated with particular signaling pathways and differential patient survival. Less understood is the correlation between these glioblastoma subtypes with immune system effector responses, immune suppression and tumor-associated and tumor-specific antigens. The role of the immune system is becoming increasingly relevant to treatment as new agents are being developed to target mediators of tumor-induced immune suppression which is well documented in glioblastoma. To ascertain the association of antigen expression, immune suppression, and effector response genes within glioblastoma subtypes, we analyzed the Cancer Genome Atlas (TCGA) glioblastoma database. We found an enrichment of genes within the mesenchymal subtype that are reflective of anti-tumor proinflammatory responses, including both adaptive and innate immunity and immune suppression. These results indicate that distinct glioma antigens and immune genes demonstrate differential expression between glioblastoma subtypes and this may influence responses to immune therapeutic strategies in patients depending on the subtype of glioblastoma they harbor.
    08/2013; 1(112). DOI:10.1158/2326-6066.CIR-13-0028
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    Amy B Heimberger · Mark Gilbert · Ganesh Rao · Jun Wei
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    ABSTRACT: A large unmet need exists for cost-effective, widely available antineoplastic immunotherapeutic agents with a robust translational potential. MicroRNAs (miRNAs) that regulate tumor-mediated immunosuppression or immune checkpoints can induce robust therapeutic immune responses, indicating that miRNAs may ultimately become part of the portfolio of anticancer immunotherapeutics.
    OncoImmunology 08/2013; 2(8):e25124. DOI:10.4161/onci.25124 · 6.28 Impact Factor

Publication Stats

4k Citations
629.42 Total Impact Points

Institutions

  • 2002–2015
    • University of Texas MD Anderson Cancer Center
      • • Department of NeuroSurgery
      • • Department of Cancer Biology
      Houston, Texas, United States
  • 2008–2013
    • University of Houston
      Houston, Texas, United States
    • Baylor College of Medicine
      Houston, Texas, United States
  • 2000–2011
    • Duke University Medical Center
      • • Division of Neurosurgery
      • • Department of Surgery
      Durham, North Carolina, United States
  • 2007
    • University of California, San Francisco
      San Francisco, California, United States
    • University of Aberdeen
      Aberdeen, Scotland, United Kingdom