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My research has focused on several basic and translational aspects of cancer biology. From a basic science perspective, my lab cloned NOL7, a novel gene that induces an anti-angiogenic phenotype and suppresses in vivo tumor growth. NOL7 acts as a master regulator of angiogenesis by modulating the expression of angiogenesis-associated mRNAs via both steady-state downregulation and posttranscriptional upregulation. NOL7 itself is positively regulated by the retinoblastoma (Rb) gene, supporting the paradigm shift that Rb can act as a positive regulator of gene transcription. Our long-term goal is to understand how transcriptional and posttranscriptional regulation of angiogenesis-related mRNAs contributes to the expression of the phenotype and to leverage this knowledge to develop novel therapeutic approaches. Our central hypothesis is that Rb positively regulates NOL7 expression and that loss of NOL7 protein expression results in decreased regulation of NOL7 target mRNA transcripts, the gain of expression of the pro-angiogenic phenotype and the loss of tumor growth inhibition. This research is innovative because it will define the mechanisms by which NOL7 acts as a master regulator of angiogenesis. Further, it provides fundamental insights into the poorly understood area of posttranscriptional regulation of angiogenesis. This research is expected to have a positive impact on human health because it may provide new therapeutic avenues for targeting angiogenesis in both physiologic and pathologic conditions. We have also been pursuing a number of translational research aspects of tumor angiogenesis using head and neck squamous cell carcinoma as a model. For example, we have been testing the hypothesis that inhibitors of angiogenesis are effective chemopreventive agents. The expression of the angiogenic phenotype is both an early and an essential step in the development of cancer, making it an attractive target for cancer prevention. The long-term goal of our work is to develop novel, nontoxic chemopreventive strategies for cancer that are based upon the inhibition of angiogenesis. These investigations have resulted in a number of clinical trials. Finally, we are currently using animal models and tissue derived from the clinical trials to investigate mechanisms of acquired resistance in response prolonged chemopreventive therapy. Such modeling will enable us to test the hypothesis that acquired resistance to inhibitors of angiogenesis can be reversed, thereby prolonging a drug’s chemopreventive activity.
From a patient care perspective, I have played a leading role in defining the clinical utility of oral cancer screening adjuncts/tests. I have served on the American Dental Association (ADA) Council of Scientific Affairs (CSA). In that capacity, I was a member and Chair of CSA Expert Panels that developed evidence-based guideline recommendations for the evaluation of potentially malignant disorders of the orders of the oral cavity. In addition, I was also a member of Cochrane Systematic Reviews Expert Panels that performed systematic reviews and made clinical guideline recommendations with respect to oral cancer screening. We have also sought ways to improve our ability to diagnose, prognosticate and monitor/predict response to therapy. As such, we have been involved in large scale genomic analyses to understand how treatment of head and neck tumors influences the transcriptome. In addition, we are seeking to establish a molecularly-based saliva screening test for the identification of high-risk patients that are likely to progress to cancer. We have performed targeted sequencing to determine the mutation rate of the most commonly altered genes in moderate dysplasia, severe dysplasia, and reactive hyperplasia (control group). These analyses identified dysplasia-specific molecular changes that underlie the pathogenesis of cancer development. Using the candidate mutations identified in dysplastic tissues, we are developing assays to determine their expression levels in saliva/tissue samples from a retrospective cohort of patients with oral dysplasia with known outcomes. Finally, in the future, the dysplasia-specific biomarkers will be tested using prospective samples derived from an ongoing oral dysplasia natural history study to validate the diagnostic accuracy of a salivary screening test. These studies are conceptually innovative because they are defining the mutational landscape oral premalignancy. In addition, they will determine if diagnostic efficacy of a non-invasive molecular salivary screening platform for oral dysplasia. The research will benefit human health by improving our ability to identify the subset of molecularly/biologically important premalignant oral lesions that are likely to progress to cancer, thereby allowing for more rapid and personalized intervention when the disease is at a more treatable stage.
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Lingen, Mark W.