Elizabeth A Grimm

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

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Publications (258)1225.48 Total impact

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    ABSTRACT: COX-2 and its product PGE2 enhance carcinogenesis and tumor progression, which has been previously reported in melanoma. As most COX inhibitors cause much toxicity, the downstream microsomal PGE2 synthase-1 (mPGES1) is a consideration for targeting. Human melanoma TMAs were employed for testing mPGES1 protein staining intensity and percentage levels and both increased with clinical stage; employing a different Stage III TMA, mPGES1 intensity (not percentage) associated with reduced patient survival. Our results further show that iNOS was also highly expressed in melanoma tissues with high mPGES1 levels, and iNOS-mediated NO promoted mPGES1 expression and PGE2 production. An mPGES1specific inhibitor (CAY10526) as well as siRNA attenuated cell survival and increased apoptosis. CAY10526 significantly suppressed tumor growth and increased apoptosis in melanoma xenografts. Our findings support the value of a prognostic and predictive role for mPGES1, and suggest targeting this molecule in the PGE2 pathway as another avenue toward improving melanoma therapy. This article is protected by copyright. All rights reserved.
    No preview · Article · Jan 2016 · Pigment Cell & Melanoma Research
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    ABSTRACT: Purpose Inflammatory marker expression in stage III melanoma tumors was evaluated for association with outcome, using two independent cohorts of stage III melanoma patients' tumor tissues. Experimental Design Fifteen markers of interest were selected for analysis, and their expression in melanoma tissues was determined by immunohistochemistry. Proteins associating with either overall survival (OS) or relapse-free survival (RFS) in the retrospective discovery tissue microarray (TMA) (n = 158) were subsequently evaluated in an independent validation TMA (n = 114). Cox proportional hazards regression models were used to assess the association between survival parameters and covariates, the Kaplan-Meier method to estimate the distribution of survival, and the log-rank test to compare distributions. Results Expression of CD74 on melanoma cells was unique, and in the discovery TMA it associated with favorable patient outcome (OS: HR, 0.53, P = 0.01 and RFS: HR, 0.56; P = 0.01). The validation dataset confirmed the CD74 prognostic significance and revealed that the absence of MIF and iNOS was also associated with poor survival parameters. Consistent with the protein observation, tumor CD74 mRNA expression also correlated positively (p = 0.003) with OS in the melanoma TCGA data set. Conclusions Our data validate CD74 as a useful prognostic tumor cell protein marker associated with favorable RFS and OS in stage III melanoma. Low or negative expression of MIF in both TMAs, and of iNOS in the validation set also provided useful prognostic data. A disease-specific investigation of CD74's functional significance is warranted, and other markers appear intriguing to pursue.
    Full-text · Article · Jan 2016 · Clinical Cancer Research
  • Ivan H Chan · Victoria Wu · Scott McCauley · Elizabeth A Grimm · John B Mumm
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    ABSTRACT: Recent advances in immunoncology have dramatically changed the treatment options available to cancer patients. However, the fundamental challenges with this therapeutic modality are not new and still persist with the current wave of immunoncology compounds. These challenges are centered on the activation and expansion, induction of intratumoral infiltration and persistence of highly activated, cytotoxic, tumor antigen specific CD8+ T cells. We have investigated the anti-tumor mechanism of action of pegylated recombinant interleukin-10, (PEG-rIL-10) both pre-clinically with murine (PEG-rMuIL-10) and now clinically (AM0010) with human pegylated interleukin-10. The preponderance of data suggest that IL-10's engagement of its receptor on CD8+ T cells enhances their activation status leading to antigen specific expansion. Quantitation of CD8+ T cell tumor infiltration reveals that treatment of both humans and mice with pegylated rIL-10 results in 3-4 fold increases of intratumoral, cytotoxic, CD8+ T cells. In addition, mice cured of their tumors with PEG-rMuIL-10 exhibit long term immunological protection from tumor re-challenge and long term treatment of cancer patients with AM0010 results in the persistence of highly activated CD8+ T cells. Cumulatively, these data suggest the IL-10 represents an emerging therapeutic that specifically addresses the fundamental challenges of the current wave of immunoncology assets.
    No preview · Article · Dec 2015
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    ABSTRACT: Significance: The role of epigenetic regulators in cancer progression is being increasingly appreciated. We show novel roles for RNF2 in melanoma tumorigenesis and metastasis, albeit via different mechanisms. Our findings support the notion that epigenetic regulators, such as RNF2, directly and functionally control powerful gene networks that are vital in multiple cancer processes. Cancer Discov; 5(12); 1-14. ©2015 AACR.See related commentary by Black and Whetstine, p. 1241.
    Full-text · Article · Oct 2015 · Cancer Discovery

  • No preview · Article · Jul 2015 · Cancer Research

  • No preview · Article · Jul 2015 · Cancer Research
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    ABSTRACT: While melanoma is believed to be a highly immunogenic tumor and recent developments in immunotherapies are promising. Interferon-γ (IFN-γ) produced by immune cells plays a crucial role in tumor immune surveillance; however, it has also been reported to be pro-tumorigenic. In the current study, we found that IFN-γ enhances the expression of CD74, which interacts with its ligand, macrophage migration inhibitory factor (MIF), and thereby activates the PI3K/AKT pathway in melanoma, promoting tumor survival. IFN-γ increased phosphorylation of AKT Ser473 and upregulated total and cell surface expression of CD74 in human melanoma cell lines tested. CD74 was highly expressed in melanoma tissues. Moreover, the expression of CD74 on tumor cells correlated with plasma IFN-γ levels in melanoma patient samples. In our analysis of melanoma cell lines, all produced MIF constitutively. Blockade of CD74-MIF interaction reduced AKT phosphorylation and expression of pro-tumorigenic molecules, including interleukin-6, interleukin-8 and BCL-2. Inhibition of CD74-MIF interaction significantly suppressed tumor growth in the presence of IFN-γ in our xenograft mouse model. Thus, we conclude that IFN-γ promotes melanoma cell survival by regulating CD74-MIF signaling, suggesting that targeting the CD74-MIF interaction under IFN-γ-stimulatory conditions would be an effective therapeutic approach for melanoma.Journal of Investigative Dermatology accepted article preview online, 03 June 2015. doi:10.1038/jid.2015.204.
    Full-text · Article · Jun 2015 · Journal of Investigative Dermatology
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    ABSTRACT: Primary uveal melanoma tumors have been shown to harbor activating mutations in the heterotrimeric G-alpha protein subunits GNAQ or GNA11 genes in approximately 85% of samples.(Van Raamsdonk et al., 2009, Van Raamsdonk et al., 2010) Mutations in GNAQ or GNA11 are mutually exclusive, and result in amino acid changes at either the R183 or Q209 sites. GNAQ or GNA11 mutations have also been identified in uveal melanoma liver metastases suggesting that the metastatic cells in the liver are derived from primary tumor cell clones with these mutations.(Carvajal et al. 2014) In addition, the many uveal melanoma cell lines derived from metastatic sites also harbor GNAQ or GNA11 mutations.(Griewank et al., 2012)This article is protected by copyright. All rights reserved.
    No preview · Article · Dec 2014 · Pigment Cell & Melanoma Research
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    ABSTRACT: c-Jun N-terminal kinase (JNK) known as the stress activated protein kinase, is a key mediator of a variety of stress stimuli, including proinflammatory cytokines, reactive oxygen species, and ultraviolet radiation (Bogoyevitch et al., 2010). By phosphorylating crucial molecules such as c-Jun, p53, and Bcl-2, active JNK regulates cell growth, differentiation, apoptosis, and autophagy (Bogoyevitch et al., 2010). Previous studies of JNK in cancer cells have produced paradoxical findings, with some supporting a pro-oncogenic function and others demonstrating its role as a tumor suppressor (Bogoyevitch et al., 2010; Tournier, 2013). To date, the role of JNK in melanoma remains ambiguous.This article is protected by copyright. All rights reserved.
    No preview · Article · Dec 2014 · Pigment Cell & Melanoma Research
  • Zhen Ding · Yong Qin · John E Wiktorowicz · Elizabeth A Grimm

    No preview · Article · Nov 2014 · Nitric Oxide

  • No preview · Article · Nov 2014 · European Journal of Cancer
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    ABSTRACT: An obstacle to effective gene-based cancer therapies is the limited number of cancer-specific growth suppressing and apoptosis-inducing genes. Using a differentiation induction subtraction hybridization (DISH) approach with human melanoma cells, melanoma differentiation associated (mda) genes were isolated that display elevated expression as a function of irreversible growth arrest, cancer reversion and terminal differentiation. This screening paradigm resulted in the cloning of mda-7 in the context of terminal differentiation of human melanoma cells. Based on its structure, chromosomal location, sequence homology and cytokine-like properties, mda-7 has now been renamed IL-24 and classified as a member of the expanding IL-10 cytokine gene family. Expression of mda-7/IL-24 inversely correlates with melanoma progression and administration of mda-7/IL-24 by means of a replication incompetent adenovirus, Ad.mda-7, results in growth suppression and apoptosis in melanoma cells as well as in a broad-spectrum of additional cancer cell types. In contrast, Ad.mda-7 does not elicit deleterious effects in normal cells, including those of epithelial, fibroblast, astrocyte, melanocyte or endothelial origin. Based on these distinctive properties and anti-tumor and anti-angiogenic activities in human tumor xenograft animal models, mda-7/IL-24 has now entered the clinical arena. A Phase I/II clinical trial in patients with advanced carcinomas involving intratumoral administration of mda-7/IL-24 [using a replication incompetent adenovirus; ING241 (Ad.mda-7)] has documented that this gene is safe and well tolerated by patients and a single virus injection elicits apoptosis in a majority of the tumor. Current data suggests that mda-7/IL-24 may function as a dual-acting cytokine in which its normal physiological functions may be related to specific aspects of the immune system and over-expression culminates in cancer-specific apoptosis. This review will provide a prospectus of our current understanding of mda-7/IL-24.
    No preview · Article · Oct 2014 · Cancer biology & therapy
  • Sun-Hee Kim · Yuuri Hashimoto · Suhendan Ekmekcioglu · Elizabeth A. Grimm

    No preview · Article · Oct 2014 · Cancer Research
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    ABSTRACT: The role of inflammation in cancer has been reported in various adult malignant neoplasms. By contrast, its role in pediatric tumors has not been as well studied. In this study, we have identified and characterized the infiltration of various inflammatory immune cells as well as inflammatory markers in Wilms tumor (WT), the most common renal malignancy in children. Formalin-fixed paraffin-embedded blocks from tumors and autologous normal kidneys were immunostained for inflammatory immune cells (T cells, B cells, macrophages, neutrophils, and mast cells) and inflammatory markers such as cyclooxygenase-2 (COX-2), hypoxia-inducible factor 1α, phosphorylated STAT3, phosphorylated extracellular signal–related kinases 1 and 2, inducible nitric oxide synthase, nitrotyrosine, and vascular endothelial growth factor expression. Overall, we found that there was predominant infiltration of tumor-associated macrophages in the tumor stroma where COX-2 was robustly expressed. The other tumor-associated inflammatory markers were also mostly localized to tumor stroma. Hence, we speculate that COX-2–mediated inflammatory microenvironment may be important in WT growth and potential therapies targeting this pathway may be beneficial and should be tested in clinical settings for the treatment of WTs in children.
    Full-text · Article · Aug 2014 · Translational oncology
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    ABSTRACT: Mutagen sensitivity assay, which measures the enhanced cellular response to DNA damage induced in vitro by mutagens/carcinogens, has been used in the study of cancer susceptibility. 4-Nitroquinoline-1-oxide (4-NQO), an ultraviolet (UV) radiation-mimetic chemical, can produce chromosomal breaks in mammalian cells and induce cancer. Given the potential role of 4-NQO as the experimental mutagen substituting for UV as the etiological carcinogen of cutaneous melanoma (CM), we tested the hypothesis that cellular sensitivity to 4-NQO is associated with the risk of developing CM in a case-control study of 133 patients with primary CM and 176 cancer-free controls. Short-term blood cultures were treated with 4-NQO at a final concentration of 10 μmol/l for 24 h and scored chromatid breaks in 50 well-spread metaphases. Multivariate logistic regression was used to calculate odds ratios and 95% confidence intervals. We found that the log-transformed frequency of chromatid breaks was significantly higher in 133 patients than in 176 controls (P=0.004) and was associated with an increased risk for CM (adjusted odds ratio=1.78, 95% confidence interval: 1.12-2.84) after adjustment for age and sex. Moreover, as the chromatid break values increased, the risk for CM increased in a dose-dependent manner (Ptrend=0.003). Further analysis explored a multiplicative interaction between the sensitivity to 4-NQO and a family history of skin cancer (Pinteraction=0.004) on the risk of CM. Therefore, our findings suggest that sensitivity to 4-NQO may be a risk factor for the risk of CM, which is more sensitive than UV-induced chromotid breaks.
    Full-text · Article · Jun 2014 · Melanoma Research
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    Jacob Yo · Peter Hu · Yong Qin · Elizabeth A. Grimm
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    ABSTRACT: Cutaneous melanoma is one of the most aggressive forms of skin cancer. In the United States, its incidence rate increased on average 2.7% annually between 1985 and 2010. Targeted molecular chemotherapy drugs, such as BRAF and MEK inhibitors, significantly improve survival and quality of life among late-stage patients; but oftentimes de novo or acquired resistance render these therapies ineffective. Therefore, ongoing search for novel therapies for advanced melanoma is imperative. In laboratory studies, we found that Zyflamend (New Chapter, Inc., Brattleboro, VT), a promising anticancer multi-herbal extract, inhibited melanoma proliferation by regulating the autophagy-apoptosis switch. Based on our preliminary findings, we speculated that a combination of Zyflamend and vemurafenib, a mutant BRAF inhibitor, may synergistically inhibit melanoma proliferation. To test this hypothesis, we prepared 3 concentrations of Zyflamend (low [LZ], 0.001 µL/mL; medium [MZ], 0.025 µL/mL; high [HZ], 0.050 µL/mL) and vemurafenib (low [LV], 0.1 µM; medium [MV], 1.0 µM; high [HV], 5.0 µM) each, and 4 combinations—LZLV, LZMV, MZMV, MZLV. HZ and HV concentrations were not used in combination treatments due to their individual extensive toxicity. A375 (BRAF mutant) and MeWo (BRAF wild type) melanoma cells and normal BJ fibroblasts were diluted to 50,000 cells/mL, seeded in 24-well plates, and incubated with the treatments for 48 hours. Our controls (50,000 cells/mL each) included media with DMSO (HV concentration), media with DMSO and olive oil (HZ concentration), and media only in each experiment. All media solutions were prepared with Dulbecco’s modified Eagle’s medium supplemented with 5% fetal bovine serum. Trypan blue and Cellometer Auto T4 (Nexcelom Bioscience, Lawrence, MA) were used for cell counting. Each preparation was done in duplicate, and each experiment was conducted in duplicate at separate times. We observed that the MZLV combination had the greatest synergistic effect against our melanoma cell lines: this combination resulted in a 54% reduction in A375 cells compared with a predicted reduction of 22%, while having less than 20% reduction in BJ fibroblasts. The proliferation of BJ fibroblasts incubated with MZ (70%) was lower than expectation; but surprisingly, vemurafenib (LV) appeared to rescue partially this inhibition (MZLV, 86%). We also observed similar phenomenon with MeWo Cells. These findings with MeWo cells are in agreement with BRAF wild-type studies showing BRAF inhibitor resistance via MEK and ERK signaling. In our study, we found that a combination of Zyflamend and vemurafenib may be a novel therapy for late-stage cutaneous melanoma. Further studies should focus on elucidating the mechanism behind this dosage-dependent synergistic effect on BRAF-mutant cells and the partial rescue of Zyflamend’s toxic effect on normal human fibroblasts.
    Full-text · Conference Paper · Jun 2014
  • S. Ekmekcioglu · R. Kurzrock · E.A. Grimm

    No preview · Article · Mar 2014
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    Chandrani Chattopadhyay · Elizabeth A Grimm · Scott E Woodman
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    ABSTRACT: Nearly all primary uveal melanoma (UM) that metastasize involve the liver. Hepatocyte growth factor (HGF) is proposed to be an important microenvironmental element in attracting/supporting UM metastasis through activation of MET. The majority (>85%) of UM express mutations in the G-alpha proteins, that drive the MEK-ERK1/2 pathway. Thus, we proposed that the combination of MET and MEK inhibition would inhibit the growth and migration of G-alpha protein mutant versus non-mutant UM cells. Western-blots demonstrated the relative protein levels of ERK1/2 and MET in UM cells. Cells were treated with the small molecule inhibitors AZD6244 (MEKi) and/or MK-8033 (METi) and downstream markers evaluated. Further studies determined the effect of combination MEKi and METi treatment on cell growth, apoptosis and migration. All G-alpha protein mutant UM cell lines express MET mRNA and protein. The level of mRNA expression correlates with protein expression. MEKi, but not METi treatment results in markedly reduced ERK1/2 phosphorylation. Either MEKi or METi treatment alone results in reduced cell proliferation, but only modest induction of apoptosis. The combination MEKi+METi results in significant reduction of proliferation in G-alpha protein mutant cells. UM cell migration was blocked by METi, but not MEKi treatment. MET protein expression showed no correlation with G-alpha protein mutation status. Combining MEKi with METi treatment has added benefit to either treatment alone in reducing G-alpha protein mutant UM cell growth. Combining METi with MEKi treatment adds the effect of limiting uveal melanoma cell migration.
    Full-text · Article · Feb 2014 · PLoS ONE
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    ABSTRACT: Melanoma is one of the cancers of fastest-rising incidence in the world. iNOS is overexpressed in melanoma and other cancers, and previous data suggest that iNOS and nitric oxide (NO) drive survival and proliferation of human melanoma cells. However, specific mechanisms through which this occurs are poorly defined. One candidate is the PI3K/AKT/mTOR pathway, which plays a major role in proliferation, angiogenesis, and metastasis of melanoma and other cancers. We used the chick embryo chorioallantoic membrane (CAM) assay to test the hypothesis that melanoma growth is regulated by iNOS-dependent mTOR pathway activation. Both pharmacologic inhibition and siRNA-mediated gene silencing of iNOS suppressed melanoma proliferation and in vivo growth on the CAM in human melanoma models. This was associated with strong downregulation of mTOR pathway activation by Western blot analysis of p-mTOR, p-P70S6K, p-S6RP, and p-4EBP1. iNOS expression and NO were associated with reversible nitrosylation of TSC2, and inhibited dimerization of TSC2 with its inhibitory partner TSC1, enhancing GTPase activity of its target Rheb, a critical activator of mTOR signaling. Immunohistochemical analysis of tumor specimens from stage III melanoma patients showed a significant correlation between iNOS expression levels and expression of mTOR pathway members. Exogenously-supplied NO was also sufficient to reverse mTOR pathway inhibition by the B-Raf inhibitor Vemurafenib. In summary, covalent modification of TSC2 by iNOS-derived NO is associated with impaired TSC2/TSC1 dimerization, mTOR pathway activation, and proliferation of human melanoma. This model is consistent with the known association of iNOS overexpression and poor prognosis in melanoma and other cancers.
    Full-text · Article · Jan 2014 · Cancer Research
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    Preview · Article · Nov 2013

Publication Stats

12k Citations
1,225.48 Total Impact Points


  • 1988-2015
    • University of Texas MD Anderson Cancer Center
      • • Department of Melanoma Medical Oncology
      • • Department of Experimental Therapeutics
      • • Department of Bioimmunotherapy
      • • Department of Molecular and Cellular Oncology
      • • Department of Cancer Biology
      • • Department of Thoracic Cardiovascular Surgery
      • • Department of General Surgery
      Houston, Texas, United States
  • 1993-2011
    • University of Houston
      Houston, Texas, United States
  • 2005
    • University of California, San Francisco
      • Department of Medicine
      San Francisco, California, United States
  • 1996
    • Baylor College of Medicine
      Houston, Texas, United States
  • 1995-1996
    • Houston Zoo
      Houston, Texas, United States
  • 1992
    • University of Texas Health Science Center at Houston
      • Division of General Surgery (LBJ)
      Houston, TX, United States
  • 1987
    • National Eye Institute
      Maryland, United States
  • 1981-1987
    • National Cancer Institute (USA)
      • • Metabolism Branch
      • • Surgery Branch
      베서스다, Maryland, United States
  • 1982-1986
    • National Institutes of Health
      • Branch of Surgery
      베서스다, Maryland, United States
  • 1983
    • Nevada cancer institute
      Las Vegas, Nevada, United States
  • 1980-1983
    • University of California, Los Angeles
      • Department of Medicine
      Los Ángeles, California, United States
  • 1979
    • Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
      • Department of Medicine
      Torrance, California, United States