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An NCI-designated Comprehensive Cancer Center, affiliated with the University of Pittsburgh School of Medicine
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As a clinician investigator, I am interested in the development of novel, biologically-informed therapies for relapsed/refractory high grade lymphoma. In particular, my clinical research is focused on understanding the molecular genomic profile of each tumor in order to match it to cognate therapeutic agents, an approach that provides a foundation for precision medicine trials that create individualized treatment regimens for each patient. As part of this effort, I would like to align my research with the investigators in the Precision Medicine Institute and the Center for Immunotherapy. Additionally, I’m interested in investigating the biological underpinnings of virally-mediated malignancies including EBV-driven Hodgkin lymphoma and HIV associated cancers. To that effect, I have studied the effects of checkpoint blockade (CPB) in HIV-associated Kaposi’s sarcoma. This study was the first report to demonstrate the high efficacy and tolerability of CPB in this disease space and was subsequently recognized in an AACR press release. The development of novel agents and new effective combinations based on improved understanding of tumorigenesis has been the main goal of my academic career.
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Most cells can not divide indefinitely due to a process termed cellular senescence. Because cancer cells need to escape cellular senescence in order to proliferate and eventually form tumors, it is well accepted that cellular senescence is a powerful tumor suppressive mechanism. In addition, since several molecular changes that are observed in senescent cells occur in somatic cells during the aging process, investigating the molecular mechanisms underlying cellular senescence will also allow us to better understand the more complicated aging process. Thus, molecules that regulate cellular senescence represent potential therapeutic targets for the prevention and treatment of cancer as well as the fight against aging. Our work is directed at unraveling the role of caveolin-1 as a novel mediator of cellular senescence. Caveolin-1 is the structural protein component of caveolae, invaginations of the plasma membrane involved in signal transduction. Caveolin-1 acts as a scaffolding protein to concentrate, organize, and functionally modulate signaling molecules within caveolar membranes. Our laboratory was the first to demonstrate that caveolin-1 plays a pivotal role in oxidative stress-induced premature senescence. We found that oxidative stress upregulates caveolin-1 protein expression through the p38 MAPK/Sp1-mediated activation of the caveolin-1 gene promoter. We also demonstrated that upregulation of caveolin-1 protein expression promotes premature senescence through activation of the p53/p21Waf1/Cip1 pathway by acting as a regulator of Mdm2, PP2A-C, TrxR1 and Nrf2. Moreover, we found that caveolin-1-mediated premature senescence regulates cell transformation and contributes to cigarette smoke-induced pulmonary emphysema, directly linking caveolin-1's function to age-related diseases. Taken together, our findings indicate that caveolin-1 plays a central role in the signaling events that lead to cellular senescence. Our current main research interest is the identification, at the molecular level, of novel signaling pathways that link caveolin-1 to oxidative stress-induced premature senescence and the characterization of their relevance to aging and age-related diseases using both cellular and animal models. These investigations will provide novel insights into the cellular and molecular mechanisms underlying aging and cancerous cell transformation and will identify novel molecular targets that can be exploited for the development of alternative therapeutic options in the context of age-related diseases, including cancer.
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Dr. Deborah Galson's laboratory is focused on two main areas:
(1) Determining the mechanism by which multiple myeloma (MM) cells reduce bone formation via suppression of the differentiation capacity of osteoblast progenitor cells in a manner that persists even after removal of the myeloma cells. These MM-altered bone marrow stromal cells also enhance osteoclastogenesis and microenvironmental support of myeloma growth. We have shown that myeloma cells induce the upregulation of expression of the transcriptional repressor Gfi1 in osteoblast precursor cells and that Gfi1 has a role in repressing Runx2, the key osteoblast transcription factor. We are currently investigating the mechanisms by which Gfi1 represses Runx2; MM cells and TNF-alpha/IL-7 regulate Gfi1 expression and activity; and roles for Gfi1 in MM cells and osteoclasts. Our preliminary data suggests that Gfi1 may prove to be a useful 3-way therapeutic target in MM bone disease. We are also expanding these studies into other cancer-induced bone disease models and into inflammatory diseases that cause bone formation suppression.
(2) Determining the mechanism by which measles virus nucleocapsid protein (MVNP) activates cellular genes and alters osteoclast differentiation. MVNP has been shown to be able to induce a Pagetic phenotype when transduced into osteoclast precursors and there is increasing evidence that it can play a role in the development of Paget's disease. Understanding the mechanisms involved may aid in developing additional treatments for Paget's disease as well as increase our understanding of how viral proteins alter cells. We have made the important discovery that MVNP signals through the IKK family members TBK1 and IKKepsilon to increase IL-6, a key player in creating the pagetic microenvironment. We are also studying MVNP regulation of C/EBPbeta and FoxO proteins, as well as autophagy, in generating aberrant osteoclasts. We have found that MVNP alters both the level of C/EBPbeta expression as well as the translation regulation of the C/EBPbeta LAP/LIP isoforms ratio. MVNP also alters the regulation of FoxO1 cellular localization, preventing nuclear localization, which increases autophagy, Further, MVNP alters the stability of FoxO3a, leading to rapid degradation and loss of SIRT1 expression, which thereby increases NF-kappaB activity. We are expanding the investigation of TBK1 and IKKepsilon signal transduction into other disease models that elevate osteoclasts including cancer-induced bone disease and arthritis.
My current research focuses on the role of the tumor microenvironment in regulation of kidney cancer. In particular, I am interested in exploring the therapeutic benefit of targeting Profilin-1, an actin-binding protein, in endothelial cells in the tumor microenvironment as a potential treatment for kidney cancer. Kidney cancer is a pathology characterized by excessive vascularization of the tumor microenvironment. My previous work has demonstrated that Profilin-1 plays a key role in regulating the angiogenic potential of endothelial cells. Using small molecule inhibitors I developed during my PhD against Profilin-1 and dendritic cell vaccine against Profilin-1, I am investigating if Profilin-1 can serve as a therapeutic target for vascular normalization in kidney cancer and thus improve current line therapy response.
Dr. Geyer’s research interests include the design, implementation, and analyses of phase III clinical trials in early breast cancer that evaluate new therapeutics and diagnostics with potential for changing existing standards of care. More broadly, his focuses include immunology and immunotherapy, cancer therapeutics, biology and virology, and genome stability. Dr. Geyer has co-authored more than 100 peer-reviewed publications and served as co-chair of steering committees for practice-changing international phase III studies such as the KATHERINE and OlympiA trials.
Dr. Glorioso has spent his career studying the molecular biology and immunology of HSV and the last 20 years developing HSV gene vectors for local and systemic therapies. He is a world-wide leader in this field and has 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-related and arthritis pain. Dr. Glorioso has also focused his attention on neurodegenerative diseases that include SCA1 deficiency Alzheimer’s 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 systemic delivery for treatment of metastatic cancer and muscular dystrophy. He has also recently developed HSV vectors for the creation and neuronal differentiation of human iPS cells derived from fetal brain and human dermal fibroblasts. His vector technology has been licensed to numerous biotech companies in which Dr. Glorioso serves as founder and/or consultant.
I am an assistant professor of immunology at the University of Pittsburgh and member of Tumor Microenvironment Center at UPMC Hillman Cancer Center. My research focuses on the mechanisms that control cell death and how the quality of cell death can modulate the immune response, especially anti-tumor immunity. I have actively pursued research in cell death and immunology for fifteen years, at Beijing Normal University and National Institute of Biological Sciences, Beijing, China as a graduate student, St. Jude Children’s Research Hospital as a postdoc, and the University of Pittsburgh as principal investigator.
My work has initially focused on apoptosis/apoptosome and pyroptosis/inflammasome activation in macrophages, monocytes, and dendritic cells. I have identified bromoxone as a pan-inflammasome inhibitor and revealed mechanisms of inflammasome action against bacterial pathogen infection. I continued working on the programmed cell death, mainly necroptosis; I discovered the role of ESCRT- III in necroptosis and its immune responses. ESCRT-III machinery can rescue the necroptotic cells via shedding and repairing broken plasma membrane, thus, sustain cell survival. As a consequence, cells undergoing necroptosis can express chemokines and other regulatory molecules to promote dendritic cell-mediated cross-priming of CD8+ T cells. In collaboration with clinical investigators, I revealed ESCRT-III keeps cells from lysis, especially in kidneys from the transplantation procedures.
After becoming an independent researcher, I continue to work on the mechanisms of programmed cell death and its role in regulating immune responses, including auto-immunity and cancer immunology. We keep exploring novel signaling pathways of programmed cell death. We are also focusing on new drug target discoveries in the cell death pathway. Our goal is to use these targets to overcome the tumor cell death resistance upon chemotherapies. We are also deciphering the central roles of various types of programmed cell death in anti-tumor immunity, auto-immune diseases, and transplantation. We will reprogram cell death to modulate the immune response.
Dr. Gopalakrishnan is a tenured associate professor of biomedical Informatics. Her primary research focus over the past two decades has been on biomarker discovery from multiple types of biomedical data via novel integrative modeling using hybrid machine learning methods being developed and tested in her lab. She is fundamentally interested in technologies for data mining and discovery that allow incorporation of prior knowledge. Her lab has applied novel variants of rule learning techniques for biomarker discovery, prediction and monitoring of diverse diseases including neurodegenerative and cardiovascular diseases, lung, breast and esophageal cancers, and parasitic infectious disease such as Helminths. Multiple types of 'omic' data obtained from genomics, proteomics, metabolomics and microbiome profiling have been analyzed, leading to insights regarding biomarkers and molecular mechanisms that underlie chronic disease. Biomarkers for early detection of lung and esophageal cancers have been validated across institutional studies. Dr. Gopalakrishnan was a co-leader of the Bioinformatics and Biostatistics core for a decade as part of the NCI-funded Lung SPORE project. She also was the first formal director of the CoSBBI (Computer Science, Biology, and Biomedical Informatics) program which now forms a core part of the Hillman Academy that trains rising high school juniors and seniors in cancer related STEM research.
Dr. Gopalakrishnan also served recently as the director of the Intelligent Systems Program in the School of Computing and Information, which is a highly selective multidisciplinary applied AI graduate degree program at the University of Pittsburgh.
Understanding how extracellular signals are linked to gene expression is a fundamental challenge in biology, and more specifically, macrophage signal integration is central to understanding healthy versus aberrant regulation of inflammation. My laboratory uses quantitative approaches to address these problems, with major projects including (1) computational modeling of signaling-to-transcription in macrophages, (2) interrogating tissue-specific macrophage signaling, and (3) dissecting molecular determinants of macrophage inflammatory function. We use both data-driven and mechanistic modeling approaches to integrate transcription factor activity, global phosphorylation, and transcriptomic data to explore signaling mechanisms that shape macrophage function. In the tissue context, we use a combination of network-based approaches and hypothesis driven in vivo experiments to identify mechanisms linking tissue stimuli (e.g. cytokines and lipids) to transcription factor activity, and ultimately macrophage function. We hope these efforts will yield insights into dysregulation of signaling and inflammation, while informing therapeutic strategies.
Dr. Greenberger is examining the use of manganese superoxide dismutase (MnSOD) plasmid liposome gene therapy and GS-nitroxides, and other new second generation probiotics LR-IL22 and LR-IFN-B as agents to protect the normal tissues in the esophagus and lung from damage during radiation therapy. Damage to normal tissues during radiation therapy has been a major limitation to the effective treatment of lung cancer. The goal of his research is to improve the quality of life for cancer patients by potentially allowing the use of higher doses of radiation or chemotherapy to effectively treat lung cancer without the damaging side effects.
Research in my lab combines nuclear magnetic resonance (NMR) spectroscopy and other structural biology methodologies with biophysics, biochemistry, and chemistry to investigate cellular processes at the molecular and atomic levels in relation to human disease. We presently focus on two main areas in biology: gene regulation and HIV pathogenesis. To understand how biological macromolecules work and intervene with respect to activity and function, detailed knowledge of their architecture and dynamic features is required. Evaluation of the major determinants for stability and conformational specificity of normal and disease-causing forms of these molecules will allow us to unravel the complex processes associated with disease. Our group is also developing new NMR methods, such as 19F in-cell NMR.
Research in my lab is focused on the viral pathogenesis of hepatitis B virus (HBV) and antiviral discovery. HBV is the etiologic agent of viral hepatitis B, a disease affecting approximately 300 million people worldwide who suffer the high risk of liver failure, cirrhosis, and liver cancer. My laboratory aims at understanding the molecular mechanisms of HBV DNA replication and morphogenesis, with special focus on the biosynthesis and regulation of HBV covalently closed circular (ccc) DNA, which is the persistent form of HBV infection, and is the culprit for the failure of current antiviral therapies. Making use of the HBV cccDNA reporter cell line systems recently established by us, we are screening small molecule compound libraries for cccDNA inhibitors in a high throughput fashion, and two identified cccDNA formation inhibitors are currently under preclinical development. In addition, we are studying the innate immunity and oncogenic signaling pathways that regulate HBV replication, as well as identification and characterization of host restriction factors that inhibit HBV infection and propagation in human hepatocytes. We are also investigating the molecular mechanisms of HBV-induced liver cancer and finding therapeutic targets.
