Dr. Towia Libermann
Dr. Liberman is the director of the BIDMC Genomics Center. He is a molecular biologist and immunologist who is studying the genes that are involved in the pathogenesis of autoimmune diseases such as rheumatoid arthritis, as well as cancer and diabetes. Dr. Libermann has been the recent recipient of an N.I.H. Center grant to create a Genomics Center at BIDMC. This resource, which is located at the Harvard Institutes of Medicine, is available to the entire research faculty at the medical center, as well as investigators at Harvard Medical School and beyond.
Genomic and proteomic technologies have the promise to rapidly generate multiple disease hypotheses due to the parallel query of hundreds of thousands of data points. We use proteomics, transcriptional profiling and genotyping approaches together with novel bioinformatics tools to define disease mechanisms at a molecular level, with particular emphasis on the role of epithelial-specific transcription factors of the Ets transcription factor/oncogene family in epithelial cell differentiation and human cancer, as well as inflammatory diseases, and autoimmune diseases such as rheumatoid arthritis, Type I diabetes and multiple sclerosis. Most cancers originate as a result of aberrant gene expression in epithelial tissues, leading to defects in epithelial cell differentiation and proliferation. The latter is governed by distinct sets of tightly controlled transcriptional regulators. The Ets family encodes proteins involved in normal development as well as in human cancer. During the last years the laboratory successfully cloned and characterized four new members of the Ets family, PDEF, ESE-1, ESE-2, and ESE-3, that are restricted to different subsets of epithelial cells. Both ESE-1 and ESE-2 play a role during terminal differentiation of keratinocytes and mammary gland development, whereas PDEF is exclusively expressed in hormone-regulated epithelia. All four Ets factors are aberrantly expressed in various types of cancer such as prostate and breast cancer indicating an important function of these factors in human cancer. A role for PDEF in prostate cancer is apparent, since PDEF acts as a positive regulator of the prostate cancer marker prostate specific antigen (PSA) and directly interacts and cooperates with the androgen receptor. Our goals are to determine the roles of these transcription factors in epithelial cell differentiation and cancer formations using targeted disruption, transgenic mice, and in vitro epithelial cell differentiation approaches. We are also applying various cutting edge technologies for proteomics, transcriptional profiling and genotyping in order to define and compare gene profiles and genomic DNA in kidney, ovarian, prostate and breast cancer tissues, correlate gene profiles and mutations with biological activities and disease, and define disease mechanisms at a molecular level. We are using these technologies in particular to identify the target genes for our Ets factors in cancer and to determine whether SNPs within these genes are linked to the etiology of any of these diseases. Results from these studies have already enabled us to gain new insights into the functional and regulatory pathways of these Ets factors and into their potential function in cancer pathogenesis. Due to the importance of the Ets family in regulation of various tissue- and differentiation-specific genes and due to the direct implication of several members of the Ets family in various human cancers, these epithelial-restricted Ets factors are expected to play a role in prostate, kidney, ovarian and mammary gland epithelial cell transformation or cancer progression. Together with Drs. Peter Oettgen Dr. Libermann's team identified two of these Ets transcription factors as novel mediators of the inflammatory response to pro-inflammatory cytokines. Additional research efforts have focused on gene therapy approaches for the treatment of autoimmune diseases and the prevention of organ allograft rejection through controlled and local release of immunosuppressive agents.
IL-6 is a pleiotropic cytokine whose expression under normal physiological conditions is tightly controlled. However, aberrant constitutive IL-6 gene expression has been implicated in prostate and renal cancer progression and resistance to apoptosis induction as well as chemotherapy, and has been directly linked to prostate and renal cancer morbidity and mortality. Particularly striking is the tremendous increase in expression of IL-6 in hormone-refractory prostate cancer or advanced renal cancer. IL-6, in addition to its role as an immunomodulatory cytokine, functions as a growth factor for cancer cells and may exert effects on bone formation upon metastasis to the bone. Nevertheless, the importance of IL-6 per se for cancer progression is not entirely clear and it is possible that IL-6 is only one of several genes that act in a similar fashion in synergy, but are regulated by the same upstream signals. Thus, IL-6 may represent a surrogate marker for cancer progression, but interference with IL-6 as a therapeutic modality may not work, since IL-6 is only one of several factors with a similar function. We, therefore, argued that understanding the regulation of IL-6 gene expression in prostate and renal cancer may elucidate the upstream factors that deregulate expression of a whole set of genes involved in advanced prostate and renal cancer. These upstream factors should be far more desirable points of interference for novel therapies than IL-6 itself. As a first step to delineate the molecular mechanisms leading to deregulated IL-6 gene expression in advanced prostate and renal cancer we defined the transcription factors that constitutively activate the IL-6 gene as NF-B and AP-1. To evaluate the functional consequences of NF-B and AP-1 activation and to explore the possibility that NF-B and AP-1 play a role in the survival of prostate and renal cancer cells, we have demonstrated that blockage of these regulatory mechanisms can inhibit IL-6 expression and induce apoptosis and inhibition of tumor growth in nude mice. We are now in the process to carefully delineate the molecular mechanisms of apoptosis induction. Since IL-6 and possibly other genes with similar functions may be regulated by AP-1 and NF-B, combined interference with these transcription factors may give rise to novel therapeutic modalities in the fight against prostate and renal cancer. As a proof of principle we are now in the process to apply a novel high throughput drug screening approach using microarrays in 384 well microtiter plates and small molecule combinatorial libraries to find inducers of apoptosis specific for prostate cancer cells. Dr. Libermann's team has also described the molecular signals that control the genes for several potent proinflammatory cytokines, including interleukin-6 and interleukin-10, and has pinpointed the pathways that turn these genes on and off, thus providing potential strategies for controlling inflammatory responses.
Additional studies in the prostate cancer area are focused on prostate cancer metastasis to the bone using coculture systems with osteoblasts and bone metastatic animal models. Further studies in the lab are focused on mechanisms of action of anti-cancer drugs on prostate, renal, ovarian and breast cancer cells using transcriptional profiling and genotyping approaches in order to identify putative novel points of entry for rational drug design, target validation, and identification of potential genes involved in adverse drug responses or drug resistance. We are also using transcriptional profiling approaches to identify predictive markers for ovarian cancer patients resistance or sensitivity to chemotherapy. In addition, we are using transcriptional profiling and proteomics approaches to define the molecular mechanisms involved in renal cancer development and progression as well as to define predictive markers for disease free and overall survival of renal cancer patients. Finally we are applying proteomics approaches using the Ciphergen system to identify protein profiles in cancer patients that are prognostic markers for cancer progression or metastasis as well as for drug response.