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The Wistar Institute

3601 Spruce Street

Room 214-10

Philadelphia, PA 19104

 

Office: 215-898-3791

Research

Recent Scientific Advances

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, from studies supported by the Pennsylvania Department of Health, which show how mononuclear white blood cells (PBMC) from lung cancer patientscontain a tumor-relevant gene signature that accurately predicts early-stage lung cancer. Using microarray data from 267 individuals, they developed a 29-gene signature that predicts the presence of lung cancer with 86% accuracy when compared to controls with non-malignant, smoking-related lung disease. They also demonstrated that they could predict patient survival based on information found in PBMC gene expression patterns, and that removal of a tumor from the lung has significant effects on the tumor induced blood gene expression.  This suggests that monitoring blood based gene expression after tumor resection may provide an alternative method to monitor for recurrence. These initial studies also identified defects based on gene expression in the anti-cancer Natural Killer (NK) cells of patients with lung cancer. Recent studies in mouse models by other investigators confirm that defects in NK cell function to be an important factor in lung cancer susceptibility and progression (Kriessel et al. Cancer Reearch 2012). Ongoing studies are focused on the development of a clinically useful test that uses a simplified sample collection system that does not require PBMC purification and to develop a better classifier through the integration of data from different levels of gene regulation.  This is a collaborative study with investigators at The University of Pennsylvania, NYU, Temple University, The Helen Graham Cancer Center, FCCC and Harvard.  

Figure 1. Genes specific to T-cell and myeloid lineages significantly associated with survival. Genes significantly associated with survival were found to be enriched for genes specific to myeloid cells (21 genes, all with hazard ratio, HR, > 1) and T cells (15 genes with HR > 1, 8 genes with HR < 1), indicating an association of those lineages with the survival signature. While our samples were derived from the peripheral blood, 6 T cell-specific genes have also been found by other studies to be differentially expressed in lung adenocarcinoma tumor samples, reflecting the infiltration of T cells into lung lesions. These are shown in the T cell overlap with the lung. Cytokines and chemokines detected in the serum of lung cancer patients that can promote or interfere with immune responses are also indicated.
Showe, et al. Oncoimmunology. 2012 November 1;1(8):1414-1416.

 

Gene Expression in Cutaneous T-Cell Lymphoma

Cutaneous T-Cell lymphomas (CTCL) are a group of rare lymphoproliferative disorders characterized by localization of the neoplastic T lymphocytes to the skin at presentation with a more aggressive leukemic form presenting with blood involvement. Although a variety of causative factors have been subsequently investigated, the etiology of CTCL remains unknown. The two main subtypes of CTCL are skin associated mycosis fungoides (MF) and leukemic Sézary syndrome (SS) which has been the focus of the laboratory studies.  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 Wistar and the unique collection of patients being treated by Dr. Alain Rook at the University of Pennsylvania Department of Dermatology. Initial studies which made some new important observations led to a successful competition for a NCI Directors challenge award to develop molecular diagnostics for CTCL using microarray platforms.  The successful completion of these studies led to the identification of a small number of genes that could detect SS by microarray or Q-rtPCR and also identified a signature of poor prognosis that was independent of stage or circulating malignant cell numbers published in the J. Exp. Med and Blood journals. The Showe lab's work on CTCL continues  with clinical collaborators at the University of Pennsylvania (Drs. Alain Rook and Ellen Kim Dermatology). Present work has focused on understanding mechanisms of therapeutic response both in vitro and in vivo using combined treatments such a Toll-receptor agonists and Interferon as well recently FDA approved treatments with Histone deacetylase inhibitors. Using approaches that combine data from gene and microRNA expression produced using microarrays or by Nex-gen sequencing they are defining parameters that distinguish responders from non-responders and identifying markers to monitor residual disease in patients in remission.

Functional genomics of HIV

In collaboration with Dr. Luis Montaner, head of the Wistar HIV-1 Immunopathogenesis Laboratory, the Showe lab has been applying functional genomic approaches to understanding mechanisms of immune evasion in HIV infections and exploring 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 TB in the presence of an active HIV infection.

Gene expression in multiple sclerosis

In collaboration with Dr. Cris Constantenescu, Nottingham, U.K., 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 in blood samples that correlate with responsiveness and non-responsiveness to therapy.