This project is designed to develop a new approach to cancer treatment through the study of growth, survival, and metastasis regulatory signal transduction events that identify molecular targets for anticancer drug development. Our work is divided into basic research and translational research through the Preclinical Development Scientific Core, a translational drug development facility that we have established. Our work is currently focused on (1) histone deacetylase as a target for anticancer drug development, and (2) the molecular mechanisms of hematopoietic cell regulation by beta-catenin and the identification of beta-catenin as a target in hematologic malignancies. (1) Our basic research on signal transduction pathways that can inhibit the growth of hormone-refractory prostate cancer cells led us to the identification of histone deacetylase as a critical target in this neoplasm. We have performed studies of the impact of signaling pathways on histone acetylase complexes regulating the promoter of the cyclin-dependent kinase inhibitor p21, which is an important transcriptional target of the anticancer histone deacetylase inhibitors. We are performing the translational science and pharmacodynamic studies on the phase I trial of the histone deacetylase inhibitor MS-275, that is being run in solid tumors at the NCI and in hematologic malignancies at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins and the University of Maryland Greenebaum Cancer Center. We have studied the pharmacodynamic response to the butyrate prodrug tributyrin in a phase II study at the University of Maryland, and we are working with translational oncologists at the Mayo Clinic and Karmanos Cancer Institute on pharmacodynamic approaches to the new HDAC inhibitor PXD101. For all of these studies we have set up an immunocytochemistry assay with image analysis for quantification, and in the past year we have developed a novel multiparameter flow cytometric assay for protein acetylation. The NCI has applied for a patent for our work, which is uniquely capable of analyzing HDAC inhibitor activity in as little blood as in a finger-stick, and can look at combination therapy pharmacodynamic responses by examining 7 parameters simultaneously. The Preclinical Development Scientific Core has been working with intramural investigators on a range of phase I and phase II clinical trials. I am an associate investigator on 4 currently active clinical trials. For each of these trials we work with the PI to develop novel pharmacodynamic endpoints, including analysis of circulating epithelial tumor cells. This year we completed analysis of circulating epithelial tumor cells for an intramural Phase II trial of perifosine in androgen-independent prostate cancer.(2) While studying the anticancer action of lovastatin, a drug that was brought to Phase I clinical trial at the NCI as a direct translation of our research, we found that a critical determinant of sensitivity to the proapoptotic activity of lovastatin was the integrity of beta-catenin protein. This led us to examine the role of beta-catenin in apoptosis. We used hematologic malignancies as our model and found that beta-catenin plays an unexpectedly vital role in these cells. Our data demonstrated that beta-catenin regulates leukemia cell survival, proliferation, and adhesive properties. These data identified beta-catenin as a novel target for anticancer drug development in hematologic malignancies. We are also studying the role of beta-catenin in mature peripheral lymphocytes, where we found that beta-catenin is critical in peripheral T-cell activation. Our data suggest that a burst of beta-catenin signaling is required for T-cell activation, and that failure to appropriately down-regulate beta-catenin signaling promotes transformation. Furthermore we delineated the pathway for posttranslational regulation of beta-catenin in human PBL.
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