Sylvester Comprehensive Cancer Center

Glen N. Barber, Ph.D.

Glen N. Barber, Ph.D.

Professor and Chair Cell Biology Department; Associate Director for Basic Research, Sylvester Comprehensive Cancer Center

Description of Research

Dr. Barber’s research focuses on understanding mechanisms of innate immunity to virus infection and malignant disease. Gaining insight into the innate immune process allows investigators to develop translational research comprising the design of novel vaccines and therapeutics to combat these diseases. One of the laboratory’s interests involves analyzing the function of interferons (IFNs), which can be produced in response to virus infection. The IFNs are secreted from the cell, and following interaction with specific cellular receptors, mediate their action by inducing the expression of numerous genes, many of which exert potent antiviral and antitumor activity.

Dr. Barber’s laboratory has been responsible for discovering mechanisms that help explain how IFN production is triggered in response to infection by microbes. In 2004 researchers from his laboratory demonstrated that activation of IFN required the ‘death domain’ containing proteins receptor interacting protein 1 (RIP1) and the Fas-associated death domain molecule (FADD). FADD/RIP1 interactions facilitate RLR (Rig-I like Receptor) pathways essential triggering host defense countermeasures in response to infection with RNA viruses, such as vesicular stomatitis virus (VSV) and influenza virus. Recently, Dr. Barber's laboratory has also elucidated how the cell responds to infection by DNA pathogens such as cancer causing viruses, intracellular bacteria and perhaps certain parasites. A molecule in his lab, referred to as STING (Stimulator of IFN genes) was found to be essential for producing IFN in response to a variety of DNA pathogens. Mice lacking STING are extremely sensitive to virus infection. The importance of STING in innate immunity, cancer and autoimmunity is presently ongoing. Finally, the laboratory has demonstrated another important component of host defense involving molecules called the NFAR (nuclear factors associated with dsRNA). These proteins were found to prevent virus replication by blocking protein synthesis. Understanding mechanisms of innate immune signaling in the cell could enable the development of new strategies to inhibit pathogen replication as well as stimulate the host immune response to avoid disease.

Interestingly, these studies revealed that the innate immune system appeared defective in many types of tumor cells. Accordingly, studies indicated that viruses such as VSV, a relatively non-pathogenic RNA virus, can selectively replicate in and induce the killing of malignant cells, but not normal cells. Genetically engineered VSVs now have been generated by the laboratory and are being evaluated as a novel approach to cancer therapy. Dr. Barber is also interested in studying how viruses such as the human T cell lymphotropic virus (HTLV1), hepatitis C virus (HCV), Epstein-Barr virus (EBV), human papillomavirus (HPV), and human herpes virus type-8 (HHV-8) contribute towards tumorigenesis, which may involve inhibiting innate immune pathways to avoid host defense countermeasures. Understanding these processes could lead to an improvement of current treatments as well as generate new therapeutics and vaccines that may help eradicate infection and cancer.

Highlights

  • Discovered new innate immune recognition pathways. These pathways are important for recognizing RNA and DNA virus infection and for activating host defense countermeasures. Understanding such pathways will generate new ideas to help combat disease.
  • Discovered that vesicular stomatitis virus (VSV) has potent oncolytic (anti-tumor) properties. Dr. Barber’s laboratory has shown that VSV replicates to high levels in tumorigenic cells (but not normal cells), and has identified defects in IFN signaling and translational control in tumorigenic cells as possible reasons for this uncontrolled replication.
  • Developed recombinant VSV that express other virus proteins, such as from hepatitis C virus and human papillomavirus (implicated in tumorigenesis) as possible vaccines for these viruses.
  • Has designed new mechanisms to detect virus infection in cancer.

Selected Cancer-Related Publications

  • Heiber JF, Barber GN. Evaluation of innate immune signaling pathways in transformed cells. Methods Mol Biol 797:217-38, 2012. Read more »
  • Gall A, Treuting P, Elkon KB, Loo YM, Gale M Jr, Barber GN, Stetson DB. Autoimmunity Initiates in Nonhematopoietic Cells and Progresses via Lymphocytes in an Interferon-Dependent Autoimmune Disease. Immunity 36:120-31, 2012. Read more »
  • Naik S, Nace R, Barber GN, Russell SJ. Potent systemic therapy of multiple myeloma utilizing oncolytic vesicular stomatitis virus coding for interferon-beta. Cancer Gene Ther 19:443-50, 2012. Read more »
  • Wang L, Toomey NL, Diaz LA, Walker G, Ramos JC, Barber GN, Ning S. Oncogenic IRFs Provide a Survival Advantage for Epstein-Barr Virus- or Human T-Cell Leukemia Virus Type 1-Transformed Cells through Induction of BIC Expression. J Virol 85:8328-37, 2011. Read more »
  • Ning S, Pagano JS, Barber GN. IRF7: activation, regulation, modification and function. Genes Immun 12:399-414, 2011. Read more »
  • Heiber JF, Xu XX, Barber GN. Potential of vesicular stomatitis virus as an oncolytic therapy for recurrent and drug-resistant ovarian cancer. Chin J Cancer 30:805-14, 2011. Read more »
  • Kelly EJ, Nace R, Barber GN, Russell SJ. Attenuation of vesicular stomatitis virus encephalitis through microRNA targeting. J Virol 84:1550-62, 2010. Read more »
  • Capo-Chichi CD, Yeasky TM, Heiber JF, Wang Y, Barber GN, Xu XX. Explicit targeting of transformed cells by VSV in ovarian epithelial tumor-bearing Wv mouse models. Gynecol Oncol 116:269-275, 2010. Read more »
  • Galivo F, Diaz RM, Wongthida P, Thompson J, Kottke T, Barber G, Melcher A, Vile R. Single-cycle viral gene expression, rather than progressive replication and oncolysis, is required for VSV therapy of B16 melanoma. Gene Ther 17:158-70, 2010. Read more »
  • Ishikawa H, Ma Z, Barber GN. STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature 461:788-92,2009. Read more »
  • Willmon CL, Saloura V, Fridlender ZG, Wongthida P, Diaz RM, Thompson J, Kottke T, Federspiel M, Barber G, Albelda SM, Vile RG. Expression of IFN-beta enhances both efficacy and safety of oncolytic vesicular stomatitis virus for therapy of mesothelioma. Cancer Res 69:7713-20,2009. Read more »
  • Chakraborty P, Seemann J, Mishra RK, Wei JH, Weil L, Nussenzveig DR, Heiber J, Barber GN, Dasso M, Fontoura BM. Vesicular stomatitis virus inhibits mitotic progression and triggers cell death. EMBO Rep 10:1154-60,2009. Read more »
  • Parisien JP, Bamming D, Komuro A, Ramachandran A, Rodriguez JJ, Barber G, Wojahn RD, Horvath CM. A shared interface mediates paramyxovirus interference with antiviral RNA helicases MDA5 and LGP2. J Virol 83:7252-60, 2009. Read more »
  • Barber GN. The NFAR's (nuclear factors associated with dsRNA): Evolutionarily conserved members of the dsRNA binding protein family. RNA Biol 6:35-39, 2009. Read more »
  • Barral PM, Sarkar D, Su ZZ, Barber GN, Desalle R, Racaniello VR, Fisher PB. Functions of the cytoplasmic RNA sensors RIG-I and MDA-5: Key regulators of innate immunity. Pharmacol Ther 124:219-34, 2009. Read more »

Programs

Leader of the Multidisciplinary Research Program: Viral Oncology Program

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