David T Curiel

Washington University in St. Louis, San Luis, Missouri, United States

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Publications (780)4202.6 Total impact

  • Cancer Research 08/2015; 75(15 Supplement):5210-5210. DOI:10.1158/1538-7445.AM2015-5210 · 9.33 Impact Factor

  • Cancer Research 08/2015; 75(15 Supplement):4376-4376. DOI:10.1158/1538-7445.AM2015-4376 · 9.33 Impact Factor
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    ABSTRACT: The dismal clinical context of advanced-grade glioma demands the development of novel therapeutic strategies with direct patient impact. Adenovirus-mediated virotherapy represents a potentially effective approach for glioma therapy. In this research, we generated a novel glioma specific adenovirus by instituting more advanced genetic modifications which can maximize the efficiency and safety of therapeutic adenoviral vectors. In this regard, a glioma-specific targeted fiber was developed through the incorporation of previously published glioma-specific, phage-panned peptides (VWT peptide) on a fiber fibritin-based chimeric fiber, designated as 'GliomaFF.' We showed that the entry of this virus was highly restricted to glioma cells, supporting the specificity imparted by the phage-panned peptide. Additionally, the stability of the targeting moiety presented by fiber fibritin structure permitted greatly enhanced infectivity. Furthermore, the replication of this virus was restricted in glioma cells by controlling the expression of E1 gene under the activity of the tumor-specific survivin promoter. Utilizing this approach, we were able to explore the combinatorial efficacy of different adenoviral modifications that could amplify the specificity, infectivity, and exclusive replication of this therapeutic adenovirus in glioma. Finally, the virotherapy with this modified virus resulted in up to a 70% extended survival in an in vivo murine glioma model. These data demonstrate this novel adenoviral vector is a safe and efficient to treat this difficult malignancy.
    Human gene therapy 05/2015; 26(9). DOI:10.1089/hum.2015.008 · 3.76 Impact Factor
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    M Beatty · L Timares · DT Curiel ·

  • Gynecologic Oncology 04/2015; 137. DOI:10.1016/j.ygyno.2015.01.150 · 3.77 Impact Factor

  • Gynecologic Oncology 04/2015; 137:133. DOI:10.1016/j.ygyno.2015.01.331 · 3.77 Impact Factor
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    ABSTRACT: The NAD(+)-dependent protein deacetylase SIRT1 regulates energy metabolism, responses to stress, and aging by deacetylating many different proteins, including histones and transcription factors. The mechanisms controlling SIRT1 enzymatic activity are complex and incompletely characterized, yet essential for understanding how to develop therapeutics that target SIRT1. Here, we demonstrate that the N-terminal domain of SIRT1 (NTERM) can trans-activate deacetylation activity by physically interacting with endogenous SIRT1 and promoting its association with the deacetylation substrate NF-κB p65. Two motifs within the NTERM domain contribute to activation of SIRT1-dependent activities, and expression of one of these motifs in mice is sufficient to lower fasting glucose levels and improve glucose tolerance in a manner similar to overexpression of SIRT1. Our results provide insights into the regulation of SIRT1 activity and a rationale for pharmacological control of SIRT1-dependent activities. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 03/2015; 10(10). DOI:10.1016/j.celrep.2015.02.036 · 8.36 Impact Factor
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    M S Beatty · L Timares · DT Curiel ·
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    ABSTRACT: Adenoviruses are currently used in a variety of bench and bedside applications. However, their employment in gene delivery to lymphocyte lineages is hampered by the lack of coxsackie virus and adenovirus receptor (CAR) on the cell surface. Exploitation of an alternative receptor on the surface of T lymphocytes can allow for utilization of adenovirus in a variety of T lymphocyte-based diseases and therapies. Here, we describe how resistance to infection can be overcome by the utilization of a bi-specific fusion protein, soluble CAR murine interleukin 2 (sCAR-mIL-2), that retargets adenovirus to the murine IL-2 receptor (IL-2R). Infection of a murine T-cell line, CTLL-2, with a sCAR-mIL-2/Adenovirus conjugate provided a ninefold increase in both green fluorescence protein-positive cells and luciferase expression. In addition, this increase in infection was also seen in isolated primary murine T lymphocytes. In this context, the sCAR-mIL-2 adapter provided a fourfold gene transduction increase in activated primary murine T lymphocytes. Our results show that recombinant sCAR-mIL-2 fusion protein promotes IL-2R-targeted gene transfer to murine T lymphocytes and that alternative targeting can abrogate their native resistance to infection. Correction to: Cancer Gene Therapy (2013) 20, 445–452;doi:10.1038/cgt.2013.39; published online 9 August 2013
    Cancer gene therapy 03/2015; in press(4). DOI:10.1038/cgt.2015.13 · 2.42 Impact Factor
  • W H Everett · D T Curiel ·
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    ABSTRACT: Radiation therapy is a critical component of cancer treatment with over half of patients receiving radiation during their treatment. Despite advances in image-guided therapy and dose fractionation, patients receiving radiation therapy are still at risk for side effects due to off-target radiation damage of normal tissues. To reduce normal tissue damage, researchers have sought radioprotectors, which are agents capable of protecting tissue against radiation by preventing radiation damage from occurring or by decreasing cell death in the presence of radiation damage. Although much early research focused on small-molecule radioprotectors, there has been a growing interest in gene therapy for radioprotection. The amenability of gene therapy vectors to targeting, as well as the flexibility of gene therapy to accomplish ablation or augmentation of biologically relevant genes, makes gene therapy an excellent strategy for radioprotection. Future improvements to vector targeting and delivery should greatly enhance radioprotection through gene therapy.Cancer Gene Therapy advance online publication, 27 February 2015; doi:10.1038/cgt.2015.8.
    Cancer Gene Therapy 02/2015; 22(4). DOI:10.1038/cgt.2015.8 · 2.42 Impact Factor
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    ABSTRACT: Conditionally replicative adenoviruses are promising agents for oncolytic virotherapy. Various approaches have been attempted to retarget adenoviruses to tumor-specific antigens to circumvent deficiency of receptor for adenoviral binding and to provide an additional level of tumor specificity. Functional incorporation of highly specific targeting molecules into the viral capsid can potentially retarget adenoviral infection. However, conventional antibodies are not compatible with the cytoplasmic adenovirus capsid synthesis. The goal of this study was to evaluate the utility of single variable domains derived from heavy chain camelid antibodies for retargeting of adenovirus infection. We have combined transcriptional targeting using a tumor-specific promoter with transductional targeting through viral capsid incorporation of antihuman carcinoembryonic antigen single variable domains. Obtained data demonstrated that employment of a single variable domain genetically incorporated into an adenovirus fiber increased specificity of infection and efficacy of replication of single variable domain-targeted oncolytic adenovirus. The double targeting, both transcriptional through the C-X-C chemokine receptor type 4 promoter and transductional using the single variable domain, is a promising means to improve the therapeutic index for these advanced generation conditionally replicative adenoviruses. A successful strategy to transductional retargeting of oncolytic adenovirus infection has not been shown before and therefore we believe this is the first employment of transductional targeting using single variable domains derived from heavy chain camelid antibodies to enhance specificity of conditionally replicative adenoviruses.
    02/2015; 2:15001. DOI:10.1038/mto.2015.1

  • Toxicon 01/2015; 93:S46. DOI:10.1016/j.toxicon.2014.11.151 · 2.49 Impact Factor
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    ABSTRACT: Purpose: We decided to construct a novel oncolytic adenovirus whose replication was driven by the CDC25B promoter for its use in preclinical models of pancreatic cancer. Experimental design: We placed the essential E1A gene under control of the CDC25B promoter. Based on preliminary data we pseudotyped the adenovirus with a chimeric fiber of serotypes 5/3. We investigated the in vitro lytic effect and the in vivo therapeutic efficacy in combination with gemcitabine, on human pancreatic tumor xenografts orthotopically growing in nude mice, and in tumors growing in Syrian hamsters. We also assessed biochemical markers of hepatic toxicity and CA19.9 levels. Results: AV25CDC exhibited a strong in vitro lytic effect on pancreatic cancer cells. In vivo administration of AV25CDC combined with gemcitabine in mice harboring s.c. growing SW1990 pancreatic tumors, almost abrogated tumor growth. Nude mice harboring 15-days old orthotopic tumors, treated i.t. or systemically with AV25CDC combined with gemcitabine, exhibited 70%-80% reduction in tumor size compared to control mice that lasted for at least 60 days. Chemo-virotherapy treatment induced a return to normal levels of biochemical parameters of hepatic toxicity; these mice exhibited more than 90% reduction in CA19.9 serum levels compared to control. Chemo-virotherapy efficacy was confirmed in mice harboring Mia PaCa-2 tumors and in Syrian hamster harboring HaP-T1 tumors. We observed that viral treatment disrupted tumor architecture and induced an increase in MMP-9 activity that might facilitate gemcitabine penetrability. Conclusions: These data demonstrates that AV25CDC is an effective oncolytic agent candidate for pancreatic cancer chemo-virotherapy combination. Copyright © 2015, American Association for Cancer Research.
    Clinical Cancer Research 01/2015; 21(7). DOI:10.1158/1078-0432.CCR-14-2316 · 8.72 Impact Factor
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    ABSTRACT: Hemolytic uremic syndrome (HUS), caused by Shiga toxin-(Stx) produced by E. coli (STEC), remains untreatable. Human Stx monoclonal antibodies, which are highly effective in preventing Stx- sequelae in animal models, are languishing due to cost and logistics. We previously reported the production and evaluation of a camelid VHH-based neutralizing agent (VNA) targeting Stx1 and Stx2 (VNA-Stx), protected mice from Stx1 and Stx2 intoxications. Here we report that a single intramuscular (IM) injection of a non-replicating adenovirus (Ad) vector, carrying a secretory transgene of VNA-Stx (Ad/VNA-Stx), protected mice challenged with Stx2, and gnotobiotic piglets infected with STEC from fatal systemic intoxication. One IM dose of Ad/VNA-Stx virus given to piglets 24 hours after bacterial challenge prevented fatal central nervous system (CNS) symptoms in 9 of 10 animals, and in 5 of 9 when it was given 48 hours after bacterial challenge, just prior to the onset of CNS symptoms. All 6 placebo animals died or were euthanized with severe CNS symptoms. Ad/VNA-Stx treatment had no impact on the diarrhea. In conclusion, Ad/VNA-Stx treatment is effective in protecting piglets against Stx2-mediated fatal CNS complications following STEC challenge. With low production cost and further development, this could presumably be an effective treatment for patients with HUS and/or individuals with high risk of developing HUS due to exposure to STEC.
    Infection and Immunity 11/2014; 83(1). DOI:10.1128/IAI.02360-14 · 3.73 Impact Factor
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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.
    Cancer biology & therapy 10/2014; 2(4 Suppl 1):S23-37. DOI:10.4161/cbt.458 · 3.07 Impact Factor
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    Y I Kawamura · Y Adachi · D T Curiel · R Kawashima · R Kannagi · N Nishimoto · T Dohi ·
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    ABSTRACT: Increased expression of sialyl Lewis(x/a) carbohydrates, ligands for E-selectin, correlates with clinically advanced stages and metastasis of gastric and colon cancers. In contrast, Sd(a) carbohydrate is abundantly detected in the normal gastrointestinal mucosa but dramatically reduced or lost in cancer tissues. A glycosyltransferase, β1,4N-acetylgalactosaminyltransferase 2 (B4GALNT2) that catalyzes Sd(a) carbohydrate synthesis, is silenced in cancer. In the present study, we aimed at reducing the expression of sialyl Lewis(x/a) of cancer cells in vivo by forced expression of B4GALNT2 and Sd(a), thereby preventing dissemination/metastasis, especially metastasis triggered by surgical maneuvers. We used a fiber-modified adenovirus (Ad) vector that contained a chimeric construct with a serotype 5 shaft and a serotype 3 knob. Using this Ad5/3 vector, we successfully introduced the B4GALNT2 gene into a human gastric cancer cell line KATO III in vitro and confirmed replacement of sialyl Lewis(x) to Sd(a) with a decrease in E-selectin-dependent adhesion. Administration of Ad5/3-B4GALNT2 vectors into the peritoneal cavity of mice after inoculation of KATO III cells with laparotomy significantly reduced the incidence of metastasis. Our results indicate that the transfer of a single gene encoding B4GALNT2 modified carbohydrate chains of cancer cells in vivo and decreased tumor dissemination and metastasis.Cancer Gene Therapy advance online publication, 12 September 2014; doi:10.1038/cgt.2014.46.
    Cancer Gene Therapy 09/2014; 21(10). DOI:10.1038/cgt.2014.46 · 2.42 Impact Factor
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    ABSTRACT: AbstractA significant limiting factor to the human clinical application of conditionally replicative adenovirus (CRAd)-based virotherapy is the inability to noninvasively monitor these agents and their potential persistence. To address this issue, we proposed a novel imaging approach that combines transient expression of the human somatostatin receptor (SSTR) subtype 2 reporter gene with genetic labeling of the viral capsid with mCherry fluorescent protein. To test this dual modality system, we constructed the Ad5/3Δ24pIXcherry/SSTR CRAd and validated its capacity to generate fluorescent and nuclear signals in vitro and following intratumoral injection. Analysis of 64Cu-CB-TE2A-Y3-TATE biodistribution in mice revealed reduced uptake in tumors injected with the imaging CRAd relative to the replication-incompetent, Ad-expressing SSTR2 but significantly greater uptake compared to the negative CRAd control. Optical imaging demonstrated relative correlation of fluorescent signal with virus replication as determined by viral genome quantification in tumors. Positron emission tomography/computed tomography studies demonstrated that we can visualize radioactive uptake in tumors injected with imaging CRAd and the trend for greater uptake by standardized uptake value analysis compared to control CRAd. In the aggregate, the plasticity of our dual imaging approach should provide the technical basis for monitoring CRAd biodistribution and persistence in preclinical studies while offering potential utility for a range of clinical applications.
    Molecular Imaging 09/2014; 13:1-19. DOI:10.2310/7290.2014.00024 · 1.96 Impact Factor
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    ABSTRACT: Current therapies for most acute toxin exposures are limited to administration of polyclonal antitoxin serum. We have shown that VHH-based neutralizing agents (VNAs) consisting of two or more linked, toxin-neutralizing heavy-chain-only VH domains (VHHs), each binding distinct epitopes, can potently protect animals from lethality in several intoxication models including Botulinum neurotoxin serotype A1 (BoNT/A1). Appending a 14 amino acid albumin binding peptide (ABP) to an anti-BoNT/A1 heterodimeric VNA (H7/B5) substantially improved serum stability and resulted in an effective VNA serum half-life of 1 to 2 days. A recombinant, replication-incompetent, adenoviral vector (Ad/VNA-BoNTA) was engineered that induces secretion of biologically active VNA, H7/B5/ABP (VNA-BoNTA), from transduced cells. Mice administered a single dose of Ad/VNA-BoNTA, or a different Ad/VNA, via different administration routes led to a wide range of VNA serum levels measured four days later; generally intravenous > intraperitoneal > intramuscular > subcutaneous. Ad/VNA-BoNTA treated mice were 100% protected from 10 LD50 of BoNT/A1 for more than six weeks and protection positively correlated with serum levels of VNA-BoNTA exceeding about 5 ng/ml. Some mice developed antibodies that inhibited VNA binding to target but these mice displayed no evidence of kidney damage due to deposition of immune complexes. Mice were also successfully protected from 10 LD50 BoNT/A1 when Ad/VNA-BoNTA was administered up to 1.5 hours post-intoxication, demonstrating rapid appearance of the protective VNA in serum following treatment. Genetic delivery of VNAs promises to be an effective method of providing prophylactic protection and/or acute treatments for many toxin-mediated diseases.
    PLoS ONE 08/2014; 9(8):e106422. DOI:10.1371/journal.pone.0106422 · 3.23 Impact Factor
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    ABSTRACT: Gene-based therapies for neurological diseases continue to develop briskly. As disease mechanisms are elucidated, flexible gene delivery platforms incorporating transcriptional regulatory elements, therapeutic genes and targeted delivery are required for the safety and efficacy of these approaches. Adenovirus serotype 5 (Ad5)-based vectors can carry large genetic payloads to provide this flexibility, but do not transduce neuronal cells efficiently. To address this, we have developed a tropism-modified Ad5 vector with neuron-selective targeting properties for evaluation in models of Parkinson disease therapy. A panel of tropism-modified Ad5 vectors was screened for enhanced gene delivery in a neuroblastoma cell line model system. We used these observations to design and construct an unbiased Ad vector platform, consisting of an unmodified Ad5 and a tropism-modified Ad5 vector containing the fiber knob domain from canine Ad serotype 2 (Ad5-CGW-CK2). Delivery to the substantia nigra or striatum showed that this vector produced a neuronally-restricted pattern of gene expression. Many of the transduced neurons were from regions with afferent projections to the injection site, implicating that OPEN ACCESS Viruses 2014, 6 3294 the vector binds the presynaptic terminal resulting in presynaptic transduction. We show that Ad5-CGW-CK2 can selectively transduce neurons in the brain and hypothesize that this modular platform is potentially adaptable to clinical use.
    Viruses 08/2014; 6(8):3293-3310. DOI:10.3390/v6083293 · 3.35 Impact Factor
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    ABSTRACT: We used stable isotope labelling of amino acids in cell culture and high throughput quantitative mass spectrometry to analyse the protein composition of highly purified wild type adenoviruses, mutant adenoviruses lacking an internal protein component (protein V) and recombinant adenoviruses of the type commonly used in gene therapy including one virus which had been used in a clinical trail. We found that the viral protein abundance and composition was consistent across all types of virus examined except for the virus lacking protein V which also had reduced amounts of another viral core protein, protein VII. In all the samples analysed we found no evidence of consistent packaging or contamination with cellular proteins. We believe this technique makes a powerful method to analyse the protein composition of this important gene therapy vector and genetically engineered or synthetic virus like particles. The raw data have been deposited at ProteomeXchange, identifier PXD001120.
    Journal of General Virology 08/2014; 95(Pt 11). DOI:10.1099/vir.0.068221-0 · 3.18 Impact Factor
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    ABSTRACT: Using adenovirus (Ad)-based vectors is a promising strategy for novel cancer treatments; however, current tracking approaches in vivo are limited. The C-terminus of the Ad minor capsid protein IX (pIX) can incorporate heterologous reporters to monitor biodistribution. We incorporated metallothionein (MT), a low-molecular-weight metal-binding protein, as a fusion to pIX. We previously demonstrated 99mTc binding in vitro to a pIX-MT fusion on the Ad capsid. We investigated different fusions of MT within pIX to optimize functional display. We identified a dimeric MT construct fused to pIX that showed significantly increased radiolabeling capacity. After Ad radiolabeling, we characterized metal binding in vitro. We explored biodistribution in vivo in control mice, mice pretreated with warfarin, mice preimmunized with wild-type Ad, and mice that received both warfarin pretreatment and Ad preimmunization. Localization of activity to liver and bladder was seen, with activity detected in spleen, intestine, and kidneys. Afterwards, the mice were euthanized and selected organs were dissected for further analysis. Similar to the imaging results, most of the radioactivity was found in the liver, spleen, kidneys, and bladder, with significant differences between the groups observed in the liver. These results demonstrate this platform application for following Ad dissemination in vivo.
    Molecular Imaging 07/2014; 13:1-12. · 1.96 Impact Factor

Publication Stats

29k Citations
4,202.60 Total Impact Points


  • 2011-2015
    • Washington University in St. Louis
      • • Division of Cancer Biology
      • • Department of Radiation Oncology
      San Luis, Missouri, United States
  • 1994-2014
    • University of Alabama at Birmingham
      • • Department of Medicine
      • • Department of Surgery
      • • Comprehensive Cancer Center
      Birmingham, Alabama, United States
  • 2013
    • Washington State University
      پولمن، واشینگتن, Washington, United States
  • 2004-2011
    • Virginia Commonwealth University
      • • Department of Human and Molecular Genetics
      • • Department of Biochemistry and Molecular Biology
      • • Department of Radiation Oncology
      Richmond, VA, United States
    • Hadassah Medical Center
      • Department of Medicine
      Yerushalayim, Jerusalem, Israel
  • 2007
    • Royal Adelaide Hospital
      • Department of Thoracic Medicine
      Tarndarnya, South Australia, Australia
    • Columbia University
      New York, New York, United States
  • 2006
    • University of Chicago
      Chicago, Illinois, United States
    • University of Groningen
      Groningen, Groningen, Netherlands
  • 2002-2004
    • VU University Medical Center
      • • Department of Orthopedic Surgery
      • • Department of Neurosurgery
      Amsterdam, North Holland, Netherlands
    • Tulane University
      • Section of Hematology and Medical Oncology
      New Orleans, LA, United States
  • 2001-2004
    • VU University Amsterdam
      • • Department of Orthopaedic Surgery
      • • Department of Medical Oncology
      Amsterdamo, North Holland, Netherlands
    • National Hospital Organization Kyushu Cancer Center
      Hukuoka, Fukuoka, Japan
    • University of Glasgow
      • School of Medicine
      Glasgow, Scotland, United Kingdom
  • 2003
    • University of Kuopio
      Kuopio, Eastern Finland Province, Finland
  • 1994-2000
    • University of Alabama
      Tuscaloosa, Alabama, United States
  • 1991-1993
    • University of North Carolina at Chapel Hill
      • Department of Medicine
      North Carolina, United States
  • 1992
    • Research Institute of Molecular Pathology
      Wien, Vienna, Austria
  • 1990
    • National Cancer Institute (USA)
      베서스다, Maryland, United States