Targeting proapoptotic PKCdelta signaling in hepatocellular carcinoma

靶向肝细胞癌中的促凋亡 PKCdelta 信号传导

基本信息

批准号：
7744031
负责人：
CHING-SHIH CHEN
金额：
$ 19.8万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-01-01 至 2011-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7744031
关键词：
Address Apoptosis Biological Assay Biological Markers Cancer Etiology Cause of Death Cell Line Cell Survival Cells Cessation of life Clinical Management Data Defect Development Disease Drug effect disorder Environment Evaluation Exhibits Fostering Functional disorder Genetic Glutathione S-Transferase Goals Growth Hepatitis C Hepatocyte Human Immunosuppression Immunosuppressive Agents Incidence Induction of Apoptosis Investigation Laboratories Lead Libraries Life Link Malignant Epithelial Cell Malignant Neoplasms Modeling Molecular Abnormality Molecular Target Neoplasm Metastasis Oral Outcome Parents Patient Selection Patients Pharmaceutical Chemistry Pharmaceutical Preparations Predisposition Prevalence Primary carcinoma of the liver cells Protein Kinase C Reactive Oxygen Species Research Resistance Resources Signal Transduction Site Subcutaneous Tissue System Systemic Therapy Therapeutic Therapeutic Agents United States Validation Western Blotting Xenograft Model Xenograft procedure base cancer therapy citrate carrier clinically relevant disorder control improved in vivo intrahepatic neoplastic cell new therapeutic target novel novel strategies novel therapeutics public health relevance response scaffold small molecule stem tumor tumor growth tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): Hepatocellular carcinoma (HCC) is a leading cause of death worldwide, and is rapidly increasing in prevalence in the United States. Current systemic therapies for the large proportion of HCC patients with advanced, nonresectable disease have been largely unsuccessful; thus, a clear need exists to develop effective, life- prolonging therapeutic strategies for this disease. The PI's laboratory has devoted vital resources to developing novel oral, small-molecule agents that target the molecular and cellular defects in HCC cells that make the clinical management of this disease so challenging. In this project, we focus on the mechanistic investigation and structural optimization of a novel class of protein kinase C (PKC)d-targeted agents by using FTY720, an immunosuppressive agent, as a scaffold. This study stems from our mechanistic finding that FTY720 triggers apoptosis in HCC cells by facilitating the activation of ROS-PKCd signaling. The following aims constitute the foci of this investigation: (1) to conduct structural optimization of FTY720 and mechanistic validation of optimal derivatives; and (2) to assess the in vivo effect of structurally optimized (S)-FTY2 derivatives on suppressing HCC xenograft growth. In Aim 1, lead optimization of FTY720 is directed at separating the immunosuppressive activity of FTY720 from its effects on ROS-PKCd signaling. (S)-FTY2, which represents a lead compound in this regard, will then be structurally optimized using a bioassay-guided, two-tiered strategy involving cell survival assays and Western blotting to screen against a (S)-FTY2-based compound library to generate potent PKCd-targeted agents. In Aim 2, the in vivo efficacies of optimal derivatives in suppressing the growth of HCC tumors will be examined in both orthotopic and ectopic xenograft tumor models. We expect the proposed studies to yield data in support of our hypothesis that targeting ROS- PKCd signaling by small-molecule agents represents a therapeutically relevant approach to treat HCC, and ultimately lead to new approaches that will improve the treatment of HCC and increase the survival of HCC patients. PUBLIC HEALTH RELEVANCE:Hepatocellular carcinoma (HCC) is a leading cause of death worldwide, and is rapidly increasing in prevalence in the United States. Our overall research goal is to develop novel therapeutic agents that target the molecular and cellular defects in HCC cells that make the clinical management of this disease so challenging. We expect that this project will ultimately yield new drugs that will improve the treatment of HCC and increase the survival of HCC patients.

描述（由申请人提供）：肝细胞癌（HCC）是全球死亡的主要原因，在美国的患病率正在迅速提高。目前针对患有晚期，不可切除疾病的HCC患者的当前全身疗法在很大程度上没有成功。因此，存在明确的需求，以制定有效的，寿命延长的治疗策略。 PI的实验室致力于开发新型的口服小型分子药物，该药物针对HCC细胞中的分子和细胞缺陷，使该疾病的临床管理变得如此具有挑战性。在这个项目中，我们专注于一种新型蛋白激酶C（PKC）D靶向剂的机械研究和结构优化，使用免疫抑制剂FTY720作为脚手架。这项研究源于我们的机械性发现，即FTY720通过促进ROS-PKCD信号的激活来触发HCC细胞中的凋亡。以下目的构成了本研究的重点：（1）进行FTY720的结构优化和最佳衍生物的机械验证；（2）评估结构优化（S）-FTY2衍生物对抑制HCC异种移植生长的体内影响。在AIM 1中，FTY720的铅优化旨在将FTY720的免疫抑制活性与对ROS-PKCD信号的影响分开。（S）-FTY2代表这方面的铅化合物，然后将使用生物测定引导的两层策略在结构上进行优化，该策略涉及细胞存活分析和蛋白质印迹，以针对基于A的基于A（S）-FTY2的化合物库产生有效的PKCD靶向药物。在AIM 2中，将在原位和异位异种移植肿瘤模型中检查最佳衍生物抑制HCC肿瘤生长的体内效率。我们期望拟议的研究能够产生数据，以支持我们的假设，即小分子剂靶向ROS-PKCD信号传导代表一种治疗HCC的治疗方法，并最终导致新方法可以改善HCC治疗并增加HCC患者的存活。公共卫生相关性：肝细胞癌（HCC）是全球死亡的主要原因，在美国的患病率正在迅速提高。我们的总体研究目标是开发针对HCC细胞中分子和细胞缺陷的新型治疗剂，使该疾病的临床管理变得如此挑战。我们预计该项目最终将产生新药物，以改善HCC的治疗并增加HCC患者的存活率。