Signal Transduction Events and the Regulation of Cell Gr

该项目旨在通过研究生长调节信号转导事件，确定抗癌药物开发的分子靶点，开发一种新的癌症治疗方法。本工作目前集中于（1）作为抗癌药物开发靶点的组蛋白脱乙酰酶，和（2）通过β-连环蛋白调节造血细胞的分子机制和鉴定β-连环蛋白作为血液恶性肿瘤的靶点。 (1)我们的信号转导途径，可以抑制肿瘤难治性前列腺癌细胞的生长的基础研究，使我们确定组蛋白脱乙酰酶作为一个关键的目标，在这种肿瘤。我们对这个项目采取双管齐下的办法。首先，我们正在进行基础研究的信号通路的影响组蛋白乙酰化酶复合物调节的启动子的细胞周期蛋白依赖性激酶抑制剂p21，这是一个重要的转录靶点的抗癌组蛋白去乙酰化酶抑制剂。第二，我们正在对一种新的组蛋白去乙酰化酶抑制剂MS-275的I期试验进行所有的转化科学和药效学研究，该试验正在NCI的实体瘤和马里兰州大学癌症中心的血液恶性肿瘤中进行。(2)在研究洛伐他汀（一种在NCI进行I期临床试验的药物，作为我们研究的直接翻译）的抗癌作用时，我们发现对洛伐他汀促凋亡活性敏感性的关键决定因素是β-连环蛋白的完整性。这使我们研究β-连环蛋白在细胞凋亡中的作用。我们使用血液恶性肿瘤作为我们的模型，发现β-连环蛋白在这些细胞中起着意想不到的重要作用。我们的数据表明，β-连环蛋白调节白血病细胞的存活，增殖和粘附特性。这些数据确定β-连环蛋白作为一个新的目标，抗癌药物开发的血液恶性肿瘤。我们也在研究β-连环蛋白在成熟外周淋巴细胞中的作用，并有证据表明β-连环蛋白在外周T细胞活化中至关重要。我们的数据表明，假设β-连环蛋白信号的爆发是T细胞活化所必需的，并且未能适当下调β-连环蛋白信号正在转化。

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.