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 Research 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 (3) development of novel pharmacodynamic assays, including assays for antiangiogenic therapy. (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. During this fiscal year we have finished development of a novel pharmacodynamic assay for assessment of HDAC inhibitor activity in vivo. 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. We have used this technology in 3 clinical trials, two of which have been written for publication. We have established a collaboration with Drs. Jay Bradner and Stuart Schreiber of the Broad Institute to use our technology to develop new HDAC inhibitors. (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. These data demonstrate that beta-catenin is controlled by the beta-TrCP1-associated ubiquitin ligase complex and that stabilization of beta-catenin with TCR ligation is achieved by calcium flux, calcineurin activation, and beta-catenin serine/threonine dephosphorylation, which blocks targeting of beta-catenin to the proteasome. This leads to accumulation of cytoplasmic and nuclear beta-catenin and activation of beta-catenin target genes. Furthermore we found that IL-2 is a beta-catenin-responsive gene and have begun mapping the responsive sites on the IL-2 promoter.We had published previously that beta-catenin promotes proliferation of the adult T-cell leukemia (ATL) cell line HUT102. We have now investigated the mechanism of beta-catenin signaling in ATL and discovered that beta-catenin is induced by HTLV-1 Tax and cooperates with Tax in transcriptional activation. In the ATL cell line HUT102 and Jurkat T-ALL cells, Tax expression increased activity of a luciferase reporter driven by the beta-catenin promoter. Real-time RT-PCR confirmed that Tax increased beta-catenin expression.

Agency
National Institute of Health (NIH)
Institute
Division of Clinical Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01SC006743-13
Application #
7331717
Study Section
(MOB)
Project Start
Project End
Budget Start
Budget End
Support Year
13
Fiscal Year
2006
Total Cost
Indirect Cost
Name
Clinical Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Pise-Masison, Cynthia A; Radonovich, Michael; Dohoney, Kathleen et al. (2009) Gene expression profiling of ATL patients: compilation of disease-related genes and evidence for TCF4 involvement in BIRC5 gene expression and cell viability. Blood 113:4016-26
Mushinski, J Frederic; Nguyen, Phuongmai; Stevens, Lisa M et al. (2009) Inhibition of tumor cell motility by the interferon-inducible GTPase MxA. J Biol Chem 284:15206-14
Kajiguchi, T; Chung, E J; Lee, S et al. (2007) FLT3 regulates beta-catenin tyrosine phosphorylation, nuclear localization, and transcriptional activity in acute myeloid leukemia cells. Leukemia 21:2476-84
Giubellino, Alessio; Gao, Yang; Lee, Sunmin et al. (2007) Inhibition of tumor metastasis by a growth factor receptor bound protein 2 Src homology 2 domain-binding antagonist. Cancer Res 67:6012-6
Xu, W; Soga, S; Beebe, K et al. (2007) Sensitivity of epidermal growth factor receptor and ErbB2 exon 20 insertion mutants to Hsp90 inhibition. Br J Cancer 97:741-4
Gojo, Ivana; Jiemjit, Anchalee; Trepel, Jane B et al. (2007) Phase 1 and pharmacologic study of MS-275, a histone deacetylase inhibitor, in adults with refractory and relapsed acute leukemias. Blood 109:2781-90
Niedermeier, Andrea; Talanin, Nickolai; Chung, Eun Joo et al. (2006) Histone Deacetylase Inhibitors Induce Apoptosis with Minimal Viral Reactivation in Cells Infected with Kaposi's Sarcoma-Associated Herpesvirus. J Invest Dermatol 126:2516-24
Athauda, Gagani; Giubellino, Alessio; Coleman, Jonathan A et al. (2006) c-Met ectodomain shedding rate correlates with malignant potential. Clin Cancer Res 12:4154-62
Marcu, Monica G; Jung, Yun-Jin; Lee, Sunmin et al. (2006) Curcumin is an inhibitor of p300 histone acetylatransferase. Med Chem 2:169-74
Chung, Eun Joo; Lee, Min-Jung; Lee, Sunmin et al. (2006) Assays for pharmacodynamic analysis of histone deacetylase inhibitors. Expert Opin Drug Metab Toxicol 2:213-30

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