Signal Transduction Events and the Regulation of Cell Gr

信号转导事件与细胞Gr的调控

• 批准号: 7292025
• 负责人: JANE B TREPEL
• 金额: --
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7292025
• 关键词: Signal; Transduction; Events; Regulation; Cell

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.

该项目旨在通过研究生长、存活和转移调节信号转导事件来开发一种新的癌症治疗方法，从而确定抗癌药物开发的分子靶点。我们的工作分为基础研究和通过我们建立的转化药物开发设施临床前开发科学核心进行的转化研究。我们目前的工作重点是（1）组蛋白脱乙酰酶作为抗癌药物开发的靶点，以及（2）β-连环蛋白调节造血细胞的分子机制以及鉴定β-连环蛋白作为血液恶性肿瘤的靶点。 (1) 我们对抑制激素难治性前列腺癌细胞生长的信号转导途径的基础研究使我们确定组蛋白脱乙酰酶是这种肿瘤的关键靶点。我们研究了信号通路对调节细胞周期蛋白依赖性激酶抑制剂 p21 启动子的组蛋白乙酰酶复合物的影响，p21 是抗癌组蛋白脱乙酰酶抑制剂的重要转录靶点。我们正在对组蛋白脱乙酰酶抑制剂 MS-275 的 I 期试验进行转化科学和药效学研究，该试验正在 NCI 的实体瘤中进行，在约翰·霍普金斯大学的 Sidney Kimmel 综合癌症中心和马里兰大学格林鲍姆癌症中心的血液恶性肿瘤中进行。我们在马里兰大学的一项 II 期研究中研究了丁酸前药三丁酸甘油酯的药效学反应，并且我们正在与 Mayo Clinic 和 Karmanos 癌症研究所的转化肿瘤学家合作，研究新型 HDAC 抑制剂 PXD101 的药效学方法。对于所有这些研究，我们建立了一种免疫细胞化学测定法，并通过图像分析进行定量，并且在过去的一年中，我们开发了一种新型的蛋白质乙酰化多参数流式细胞术测定法。 NCI 已为我们的工作申请了专利，该工作能够在像指尖采血一样少的血液中分析 HDAC 抑制剂的活性，并且可以通过同时检查 7 个参数来观察联合治疗的药效反应。临床前开发科学核心一直与校内研究人员合作开展一系列 I 期和 II 期临床试验。我是 4 项目前正在进行的临床试验的副研究员。对于每项试验，我们与 PI 合作开发新的药效学终点，包括循环上皮肿瘤细胞的分析。今年，我们完成了对循环上皮肿瘤细胞的分析，以进行哌立福辛治疗雄激素非依赖性前列腺癌的壁内 II 期试验。(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转化）的抗癌作用时，我们发现洛伐他汀促凋亡活性敏感性的一个关键决定因素是洛伐他汀的完整性。 β-连环蛋白。这促使我们研究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模型，发现 β-连环蛋白在这些细胞中发挥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。这些数据将β-连环蛋白确定为血液恶性肿瘤抗癌药物开发的新靶点。我们还在研究 β-连环蛋白在成熟外周淋巴细胞中的作用，我们发现 β-连环蛋白对于外周 T 细胞激活至关重要。我们的数据表明，T 细胞激活需要大量 β-连环蛋白信号传导，而未能适当下调 β-连环蛋白信号传导会促进转化。此外，我们描述了人类 PBL 中 β-连环蛋白翻译后调控的途径。