This project is designed to develop a new approach to cancer treatment through the study of growth-regulatory signal transduction events that identify molecular targets for anticancer drug development. This work is currently focused on (1) histone deacetylase as a target for anticancer drug development, and (2) the molecular mechanism 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 are taking a two-pronged approach to this project. Firstly we are performing basic 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. Secondly, we are performing all of the translational science and pharmacodynamic studies on the phase I trial of a new histone deacetylase inhibitor MS-275, that is being run in solid tumors at the NCI and in hematologic malignancies at the University of Maryland Cancer Center. (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 demonstrate that beta-catenin regulates leukemia cell survival, proliferation, and adhesive properties. These data identify 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, and have evidence that beta-catenin is crucial in peripheral T-cell activation. Our data suggest the hypothesis that a burst of beta-catenin signaling is required for T-cell activation, and that failure to appropriately down-regulate beta-catenin signaling is transforming.

Agency
National Institute of Health (NIH)
Institute
Division of Clinical Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01SC006743-09
Application #
6756753
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2002
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

Showing the most recent 10 out of 29 publications