The Showe Laboratory
The Showe laboratory applies genomics approaches to answer complex questions in the context of immunology and cancer with the ultimate goal of developing novel diagnostic tools and markers of therapy response and disease relapse. Through an extensive network of collaborations with other laboratories at Wistar and several other institutions, the lab focuses on a diversified group of diseases, including lung cancer and cutaneous T cell lymphoma, HIV and influenza infections, and multiple sclerosis. The lab’s diverse interests are shown by a long-term collaboration with the University of Fairbanks to study how hibernating black bears modify gene expression in various tissues during hibernation.
Senior Staff Scientist
Kiran Gummireddy, Ph.D.
Biomarkers for Early diagnosis of Non-Small Cell Lung Cancer
The Showe lab has been a pioneer in the development of cancer biomarkers from blood. In 2009, they published novel findings showing how mononuclear white blood cells (PBMC) from lung cancer patients contain a 29-gene, tumor-relevant gene signature that accurately predicts whether a lung nodule detected by CT scan is benign or malignant. They also demonstrated that information in blood gene expression patterns could predict patient survival and inform further treatments. In moving these studies forward to clinical application the lab has adopted a simplified and standardized sample collection and moved their assay to the Nanostring platform, a variation of the DNA microarray technology. The technology has been licensed and is in development for commercialization.
Ongoing effort: As part of the NCI Early Detection Network the lab will developing new methods to detect and diagnose cancers early, when they are more easily and successfully treated, and develop new methods to predict outcomes after treatment. This is a collaborative study with investigators at The University of Pennsylvania, NYU, Temple University, The Helen Graham Cancer Center, Fox Chase Cancer Center and Meridian Health.
Gene Expression in Cutaneous T-Cell Lymphoma
Cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of non-Hodgkin lymphomas with characteristics of “skin-homing” T lymphocytes. The most common forms of CTCL are the skin associated Mycosis Fungoides (MF) and a more aggressive leukemic form,Sezary Syndrome (SS),.. SS has been the focus of the laboratory studies. Early interest in this cancer was based on the observation that patients were severely deficient in the production of interleukin 12, a cytokine originally identified and characterized at The Wistar Institute, and on availability of a unique collection of patients being treated at the University of Pennsylvania Department of Dermatology. Based on initial studies, Showe was awarded one of the first National Cancer Institute Director’s Challenge grants to develop molecular diagnostics for CTCL using microarray platforms. This study led to the identification of a small number of genes that could detect SS by microarray or Q-rtPCR and identified some new specific cellular defects and a signature of poor prognosis that was independent of stage or circulating malignant cell numbers.
Ongoing studies: in collaboration with clinicians at the University of Pennsylvania (Alain Rook and Ellen Kim), Columbia University (Susan Bates) and NCI (Richard Piekarz), present work focuses on understanding mechanisms of therapeutic response both in vitro and in vivo to combined treatments such as toll-receptor agonists and interferon as well recently FDA-approved treatments with histone deacetylase inhibitors. Combining data from gene and microRNA expression, produced using microarrays and next-generation sequencing, the lab is defining parameters that distinguish responders from non-responders and markers of residual disease that can be monitored to detectrecurrences before they are clinically evident. Using single cell analysis they are probing malignant cell heterogeneity and therapeutic response. A recent award from GSK focuses on the CTCL work and potential cancer therapies.
Functional Genomics of HIV
In a long term collaboration with the lab of Luis J. Montaner, D.V.M., D.Phil., at Wistar, the Showe lab applies functional genomic approaches to understand mechanisms of immune evasion in HIV infections and explore new ways to manage current HIV-1 infections, including the possibility of using immune-mediated control of virus infection upon interrupting drug therapy. Additional studies have focused on developing biomarkers to assess secondary infections, such as Tuberculosis, in the presence of an active HIV infection She is a Co-Investigator on the BEAT-HIV Delaney Collaboratory grant to continue these studies.
Gene Expression in Multiple Sclerosis
In collaboration with Cris Constantinescu, M.D., Ph.D., at The University of Nottingham, UK, the Showe laboratory is examining gene expression profiles in blood samples from multiple sclerosis patients involved in clinical trials with immuno-modulatory drugs. The aim is to determine whether it is possible to identify gene expression patterns that correlate with responsiveness and non-responsiveness to therapy.
Gene Expression and Vaccines
Studies in collaboration with Hildegund C.J. Ertl, M.D., at Wistar, have examined gene expression changes in young and aged populations as a function of flu vaccination to try to understand the poorer responses to vaccinations in general in the elderly population in particular. In addition, potential effects of race and timing of repeated vaccination on response were examined. Additional studies using mouse models have explored protocols that increase vaccine response with the potential benefit resof improving vaccine efficacy in the growing elderly population.
Dawany, N., Parzych, E.M., Showe, L.C., Ertl, H.C. "Age-related changes in the gene expression profile of antigen-specific mouse CD8+ T cells can be partially reversed by blockade of the BTLA/CD160 pathways during vaccination." Aging (Albany NY). 2016 Nov 9;8(12):3272-3297. doi: 10.18632/aging.101105.
Gumireddy, K., Li, A., Kossenkov, A.V., Sakurai, M., Yan, J., Li, Y., Xu, H., Wang, J., Zhang, P.J., Zhang, L., Showe, L.C., Nishikura, K., Huang, Q. "The mRNA-edited form of GABRA3 suppresses GABRA3-mediated Akt activation and breast cancer metastasis." Nat Commun. 2016 Feb 12;7:10715. doi: 10.1038/ncomms10715.
Iwasaki, O., Tanizawa, H., Kim, K.D., Yokoyama, Y., Corcoran, C.J., Tanaka, A., Skordalakes, E., Showe, L.C., Noma, K. "Interaction between TBP and Condensin Drives the Organization and Faithful Segregation of Mitotic Chromosomes." Mol Cell. 2015 Sep 3;59(5):755-67. doi: 10.1016/j.molcel.2015.07.007. Epub 2015 Aug 6.
Bates, S.E., Eisch, R., Ling, A., Rosing, D., Turner, M., Pittaluga, S., Prince, H.M., Kirschbaum, M.H., Allen, S.L., Zain, J., Geskin, L.J., Joske, D., Popplewell, L., Cowen, E.W., Jaffe, E.S., Nichols, J., Kennedy, S., Steinberg, S.M., Liewehr, D.J., Showe, L.C., Steakley, C., Wright, J., Fojo, T., Litman, T., Piekarz, R.L. "Romidepsin in peripheral and cutaneous T-cell lymphoma: mechanistic implications from clinical and correlative data." Br J Haematol. 2015 Jul;170(1):96-109. doi: 10.1111/bjh.13400. Epub 2015 Apr 19.
Tavecchio, M., Lisanti, S., Lam, A., Ghosh, J.C., Martin, N.M., O'Connell, M., Weeraratna, A.T., Kossenkov, A.V., Showe, L.C., Altieri, D.C. "Cyclophilin D extramitochondrial signaling controls cell cycle progression and chemokine-directed cell motility." J Biol Chem. 2013 Feb 22;288(8):5553-61. doi: 10.1074/jbc.M112.433045. Epub 2013 Jan 9.