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Viral Therapeutics investigators

David Bartlett, MD
Contact:
Hillman Cancer Center
5115 Centre Avenue 1.46 HCCLB
Pittsburgh PA
Phone: 412-623-7723
Research Interests and Keywords:
  • Tumor selective oncolytic vaccinia viruses
  • immunotherapy
  • regional cancer therapies
  • HIPEC
  • peritoneal surface malignancies
  • translational research
  • peritoneal mesothelioma
  • therapeutic cancer vaccines
Summary
Although my overall group is very active in a wide range of clinical trials and translational/clinical research, my specialty is in the regional delivery of chemotherapy to manage regionally confined, unresectable metastatic cancers, and my laboratory-based program is in the development of oncolytic viruses for regional therapy. I have developed tumor selective oncolytic vaccinia viruses that have been tested in pre-clinical models and clinical trials and have a successful history of transitioning benchtop findings into clinical trial applications.
Yuan Chang, MD
Contact:
Hillman Cancer Center
5117 Centre Ave Suite 1.8
Pittsburgh PA
Research Interests and Keywords:
  • Tumor viruses
  • Kaposi's sarcoma associated herpesvirus (KSHV)
  • Merkel cell polyomavirus (MCV)
  • digital transcriptome subtraction
  • tumor virus discovery
Summary
The work of our group (jointly directed by Patrick Moore and Yuan Chang) has focused on human tumor viruses since the early 1990s when we identified Kaposi's sarcoma associated herpesvirus (KSHV/HHV8) and showed that this virus was causally associated with Kaposi's sarcoma, the most common AIDS-related cancer in the United States and the most common malignancy in parts of Africa. We sequenced the KSHV genome, developed serologic assays, determined its prevalence in human populations, and characterized many of its critical viral oncoproteins. We have continued to study virus-host cell interactions in the context of dysregulation of pro-proliferative and anti-apoptotic pathways. We recently identified the seventh human tumor virus, Merkel cell polyomavirus (MCV), from a Merkel cell carcinoma (MCC). We characterized the transcriptional products of MCV and described the early region viral T antigen oncoproteins. Our work has established that MCV causes ~80% of MCC: we determined that the virus is clonally integrated in MCC tumor cells; that human tumor-associated Large T (LT) antigens contain signature truncation mutations; that T antigen proteins are expressed in MCC tumor cells by novel antibodies we developed; and we are the first laboratory to show rodent cell transformation by MCV sT antigen but not the LT antigen. We have identified several novel cellular interactors for MCV T antigens that open new avenues of investigating critical oncogenic signaling pathways. We have focused on many aspects of cancer etiology as modeled through oncogenic tumor viruses.
Haitao Guo, PhD
Patrick Moore, MD, MPH
Contact:
Hillman Cancer Center
Lab 1.8
Pittsburgh PA
Research Interests and Keywords:
  • Human tumor virology (KSHV, MCV and digital transcriptome subtraction)
Saumendra Sarkar, PhD
Contact:
Hillman Cancer Center
Lab 1.7 5117 Centre Avenue
Pittsburgh PA
Research Interests and Keywords:
  • RIG-I-like receptors (RLR)
  • interferon (IFN)-stimulated genes
  • toll-like receptor 3 (TLR3)
  • innate immune signaling
  • anti-viral innate immunity
  • type I IFN; IFN signaling
  • IFN regulatory factor 3 (IRF3)
  • tumor microenvironment
Summary
Innate immunity of an organism is the inborn protection against invading pathogens. Because it is inborn, and entrusted with the protection of the host from a vast array of previously unknown invaders, the innate immune system generates a generalized alert response upon pathogen detection. This alert is chemically mediated by a class of molecules called cytokines, such as interferons. A critical task for this host protection system is to distinguish foreign or non-self, from self, and initiate their destruction or containment. The sensors or the receptors of the innate immune system accomplish this by recognizing specific molecular patterns, which are common to pathogens or pathogen associated molecules, but absent in the host. We focus on a particular subset of these sensors/receptors, which are involved in sensing virus infection. In order to protect the host from viral invasion, the innate immune system has evolved sensors to detect foreign nucleic acids. Several unique features of virally produced DNA or RNA are exploited to distinguish viral nucleic acids from that of the host. One such unique nucleic acid is double-stranded RNA (dsRNA) ' a common byproduct or intermediate in viral genome replication. In mammals, receptors like toll-like receptor 3 (TLR3), retinoic acid-inducible gene I (RIG-I), and melanoma differentiation-associated gene 5 (MDA5) are the three known sensors of dsRNA. Single-stranded viral RNA is sensed by toll-like receptors 7 and 8 (TLR7 and TLR8), while viral DNA is detected by toll-like receptor 9 (TLR9) and other cytoplasmic receptors. We study two related aspects of the signaling process involved in interferon production in the context of infectious disease and cancer: 1) modulation of viral RNA sensing mechanisms; and 2) alternative mechanisms of interferon induction in specific tumors.
Massahiro Shuda
Contact:
UPCI Research Pavilion at Hillman Cancer Center, 1.9
5117 Centre Avenue
Pittsburgh PA
Phone: 412-623-7733
Gutian Xiao, PhD
Contact:
Hillman Cancer Center
Lab 1.19A 5117 Centre Avenue
Pittsburgh PA
Research Interests and Keywords:
  • Signal transduction in immunity and tumorigenesis
Moses Bility, PhD
Contact:
2136 Parran Hall
130 DeSoto Street
Pittsburgh PA
Phone: 412-648-8058
Research Interests and Keywords:
  • Hepatitis
  • HIV
  • HCV
  • HBV
  • liver disease
  • innate immunity
  • inflammation
  • macrophage activation
  • humanized mouse models
Summary
Over 500 million people worldwide are infected with chronic liver pathogens including chronic hepatitis viruses and zoonotic liver flukes, which leads to severe liver diseases. Additionally, several studies have demonstrated that HIV co-infection exacerbate chronic HBV/HCV-induced liver diseases, resulting in increased mortality. The increased prevalence of obesity and metabolic syndrome-associated non-alcoholic fatty liver disease in the United States and other developed countries also contributes to the global liver disease burden, with approximately 25% of the US population affected. The development of therapeutics against these diseases has been hindered by the lack of robust small animal models that accurately recapitulates human disease; in most cases rodents are not susceptible to infections or are resistant to disease. The lack of robust small animal models of human infectious diseases also poses a major hindrance in studying emerging diseases such as Zika virus. Innate immune cell infiltration including macrophage infiltration is a major component of the inflammatory milieu associated with chronic liver infections, non-alcoholic steatohepatitis and most human infections. Importantly, macrophages play a critical role in innate immune response, modulating gut microbiota, macronutrients (i.e., iron, lipids, etc.) sensing and metabolism, and tissue integrity/remodeling; therefore, elucidating the role of macrophage activation in human infectious diseases and metabolic syndrome-associated diseases will provide novel insight into the mechanisms of immune dysregulation and tissue pathogenesis. The Bility lab is broadly interested in elucidating the role of macrophage polarization in human infectious diseases and obesity/metabolic syndrome-associated diseases utilizing humanized mouse models carrying autologous functional human immune system, human liver cells and other human organ systems along with strong emphasis on collaborative translational research with clinical investigators. Major research efforts are: 1) Elucidating the role of macrophage polarization in chronic liver infections (HBV, HCV, liver fluke), HIV-hepatitis virus co-infections and associated liver diseases; 2) Elucidating the nexus between macrophage polarization and gut microbiota in fatty diet-induced non-alcoholic steatohepatitis and associated liver diseases; 3) Developing humanized mouse model for human diseases, including viral hepatitis, HIV, arbovirus, etc. In addition to his biomedical research, Dr. Bility also has strong interests in health security and pandemic/disaster response and management. Dr. Bility has extensive training and expertise in medical planning and operations for various contingencies including pandemic, chemical, biological, radiological, and nuclear (CBRN) disaster events in both domestic and international conditions.
Andrea Gambotto, MD
Contact:
206 CNBIO
300 Technology Drive
Pittsburgh PA
Research Interests and Keywords:
  • Development of adenoviral vector based vaccines for HIV-1 and influenza
Joseph Glorioso, PhD
Contact:
450 Technology Drive
Suite 300
Pittsburgh PA
Research Interests and Keywords:
  • HSV vectors, glioblastoma, chronic pain
Summary

Dr. Glorioso has spent his career studying the molecular biology of HSV and the last 20 years developing HSV gene vectors. He is a world-wide leader in this field and has to the expertise to develop the technology related to the treatment of diseases of the peripheral and central nervous system. His interest in peripheral nerve disease has included nerve degeneration due to diabetes and cancer drug therapies that have led to treatments of animal models. Studies to understand the pathophysiology of chronic pain and the identification of gene therapy interventions that create effective pain therapies have been long standing interests and he was among the first to develop HSV vectors to treat pain. This research has culminated in clinical trials for treatment of cancer pain. Dr. Glorioso has also focused his attention on neurodegenerative diseases that include SCA1 and Huntington's disease and the development of oncolytic vectors to treat brain tumors. Part of this research extends his application of HSV vectors for vector delivery across the blood brain barrier and for targeting specific neuronal cell populations in animals. He has also recently developed HSV vectors for the creation and neuronal differentiation of human iPS cells derived from fetal brain and human fibroblasts.

John Mellors, MD
Charles Rinaldo, PhD
Contact:
A419C Crabtree Hall
130 DeSoto Street
Pittsburgh PA
Phone: 412-624-3928
Research Interests and Keywords:
  • Cellular immunity to human immunodeficiency virus (HIV) and Kaposi's sarcoma associated herpesvirus (KSHV
  • human herpesvirus 8)
  • clinical virology
Summary
Dr. Rinaldo's research is focused on the relation of disease progression to dendritic cell function and reactivity of CD8 killer T cells to HIV and human herpesvirus 8 (HHV-8, or KSHV, the cause of Kaposi's sarcoma).
Kathy Shair, PhD
Thomas Smithgall, PhD
Contact:
530 Bridgeside Point II
450 Technology Drive
Pittsburgh PA
Research Interests and Keywords:
  • Protein-tyrosine kinases
  • Src-family kinase
  • Abl
  • Fes
  • AML
  • CML
  • myeloma
  • HIV
  • AIDS
  • drug discovery
  • chemical biology
Summary
In theory, inhibition of undesirable enzymatic activity responsible for disease can be accomplished either directly at the active site or indirectly at a distance (allostery). Important examples of selective enzyme inhibition come from the field of protein-tyrosine kinases, an emerging therapeutic target class for cancer and infectious diseases. Virtually all clinically useful kinase inhibitors to date compete for ATP binding at the kinase domain active site. However, the high degree of protein kinase sequence and structural homology limits the development of highly selective ATP-competitive kinase inhibitors. Alternative drug discovery avenues include allosteric inhibitors that target structural features outside of the kinase domain active site that are unique to individual kinase subfamilies. Allosteric inhibitor mechanisms are likely to exhibit greater specificity for their intended kinase targets, and may also stabilize kinase domain conformations that promote the action of existing inhibitors targeting the active site. Based on these principles, we are actively engaged in a drug discovery campaign to find small molecules that enhance the natural allosteric mechanisms associated with kinase domain regulation. We have developed high-throughput screening approaches based on this concept to identify selective inhibitors for protein-tyrosine kinases of the non-receptor class, including members of the Src, Fes/Fps and Abl kinase families. Selective inhibitors emerging from these screens have promise for future development in the treatment of several forms of leukemia, multiple myeloma, and HIV/AIDS.
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