Louise C. Showe, Ph.D.

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 patients contain a tumor-relevant gene signature that accurately predicts whether a lung nodule detected by LDCT is benign or malignant based on a 29-gene expression signature they identified. They also demonstrated that information in blood gene expression patterns could predict patient survival and thus provide clinicians with information that could inform further treatments. They have now moved these studies forward to clinical application with initial studies again funded by the PA DOH. In achieving these goals, they have adopted a sample collection system that simplifies and standardizes collection and have moved their assay to the Nanostring platform that has already been approved by the FDA for another biomarker test.  BY moving this work forward, they have processed over 700 samples and licensed the technology.  The present study is funded by a grant from the NCI Early Detection Research Network, which is focused on developing methods to detect and diagnose cancers early when they are more easily and successfully treated.  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 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 S├ęzary syndrome (SS), which 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 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 identified some specific cellular defects not previously known.  They also identified a signature of poor prognosis that was independent of stage or circulating malignant cell numbers.  These studies were published in the Journal of Experimental Medicine and Blood. The Showe lab's work on CTCL continues with clinical collaborators at the University of Pennsylvania (Drs. Alain Rook and Ellen Kim Dermatology) and Drs. Susan Bates and Richard Piekarz (Colombia and NCI, respectively). 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 and next-generation sequencing with recent studies moving to single cell analyses, they are defining parameters that distinguish responders from non-responders and identifying markers to detect low levels of residual disease in patients in apparent remission as early signs of recurrence.

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. 

Gene Expression and Vaccines

Studies with the Ertl lab have examined gene expression changes in young and aged populations as a function of yealy flu vaccination to try to understand the poorer responses to vaccinations in general in a growing elderly population.  In addition, they examined potential effects of race, timing of repeated vaccination and effects of hour of vaccination on response.  Additional studies using mouse models have explored protocols that increase response and, as a result, vaccine efficacy in the elderly.