The Showe Laboratory
The Showe laboratory applies genomics approaches to answer complex questions in the context of the interaction between the immune system and cancer, with the ultimate goal of developing novel tools for early diagnosis, markers of therapy response and 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, glioblastoma multiforme and cutaneous T cell lymphoma. The team conducts collaborative efforts on HIV and influenza infections, and an international collaboration on multiple sclerosis. The lab’s diverse interests are shown by a long-term collaboration with the University of Fairbanks to understand how hibernating black bears and Alaskan ground squirrels modify gene expression in various tissues during hibernation.
Senior Staff Scientist
Kiran Gummireddy, Ph.D.
Kunchithapadam Swaminathan, 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 patented and 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, Roswell Park, NYU, Temple University, The Helen F. Graham Cancer Center, Fox Chase Cancer Center, Meridian Health, N.J. and the Barzilai Medical Center, Israel.
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.
Development of a Gene Expression Signature to Distinguish Glioblastoma Multiforme (GBM) Subtypes
Glioblastoma multiforme (GBM) is the most common and severe form of primary malignant brain cancer. GBM is an aggressive cancer with no effective treatments and the median survival time for patients diagnosed with GBM is only 15 months from diagnosis. GMB is a heterogenous tumor having multiple disease subtypes, so it is important for clinicians to understand how these various GBM subtypes respond to emerging therapies that may one day be useful to glioblastoma patients in the future.
Building on collaborative studies initiated with Ramana Davuluri, Ph.D. and Donald O’Rourke, MD, the Showe lab is developing a diagnostic platform to help classify GBM tumor subtypes to match to more efficacious treatments.
ISOMA Therapeutics, a start-up spun out of Wistar in 2017 based on intellectual property jointly owned by Wistar and The University of Pennsylvania, is developing a glioblastoma diagnostic subtyping assay in tandem with a clinical stage glioblastoma therapy to help advance personalized treatment options for patients diagnosed with GBM.
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.
Kossenkov, A.V., Qureshi, R., Dawany, N.B., Wickramasinghe, J., Liu, Q., Majumdar, R.S., Chang, C., Widura, S., Kumar, T., Horng, W.H., et al. “A Gene Expression Classifier from Whole Blood Distinguishes Benign from Malignant Lung Nodules Detected by Low-Dose CT.”Cancer Res. 2019 Jan 1;79(1):263-273. doi: 10.1158/0008-5472.CAN-18-2032. Epub 2018 Nov 28.
Kurupati, R.K., Kossenkoff, A., Kannan, S., Haut, L.H., Doyle, S., Yin, X., Schmader, K.E., Liu, Q., Showe, L., Ertl, H.C.J. “The effect of timing of influenza vaccination and sample collection on antibody titers and responses in the aged.” Vaccine. 2017 Jun 27;35(30):3700-3708. doi: 10.1016/j.vaccine.2017.05.074. Epub 2017 Jun 2.
Jariwala, N., Benoit, B., Kossenkov, A.V., Oetjen, L.K., Whelan, T.M., Cornejo, C.M., Takeshita, J., Kim, B.S., Showe, L.C., Wysocka, M., et al. “TIGIT and Helios Are Highly Expressed on CD4+ T Cells in Sézary Syndrome Patients.” J Invest Dermatol. 2017 Jan;137(1):257-260. doi: 10.1016/j.jid.2016.08.016. Epub 2016 Sep 1.
Gumireddy, K., Li, A., Kossenkov, A.V., Sakurai, M., Yan, J., Li, Y., Xu, H., Wang, J., Zhang, P.J., Zhang, L., et al. "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.
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.