(PQD3) The role and therapeutic potential of ZNF304 in Ovarian Cancer

(PQD3) ZNF304 在卵巢癌中的作用和治疗潜力

基本信息

批准号：
8733641
负责人：
Gabriel Lopez-Berestein
金额：
$ 16.88万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-12 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8733641
关键词：
Automobile Driving Cancer Biology Cancer Model Cancer Patient Cell Proliferation Cells Cisplatin Code Data Databases Disease Disease Progression Epithelium Foundations Gene Silencing Genes Goals Growth Human Human Genome In Vitro Knowledge Malignant Neoplasms Malignant neoplasm of ovary Mediating Modeling Molecular Molecular Target Neoplasm Metastasis Ovarian PTK2 gene Paclitaxel Patients Pharmaceutical Preparations Phosphotransferases Play Proteins Regulation Resistance Role Signal Pathway Small Interfering RNA The Cancer Genome Atlas Therapeutic Work Zinc Fingers base cancer cell clinically significant nanoliposome nanotherapeutic new therapeutic target novel outcome forecast ovarian neoplasm overexpression public health relevance screening therapeutic target transcription factor tumor tumor growth tumor progression vector

项目摘要

DESCRIPTION (provided by applicant): The role and therapeutic potential of ZNF304 in Ovarian Cancer Through siRNA lethality screening, we recently discovered that ZNF304 gene, a novel transcription factor, is required for ovarian cancer survival. More importantly, we found that expression of ZNF304 gene is significantly associated with poor prognosis and markedly shorter overall survival (OS) of ovarian cancer patients when we analyzed The Cancer Genome Atlas (TCGA) ovarian cancer patient database (n=500). We also found that ZNF304 protein is highly overexpressed in all 5 different ovarian cancer cells including paclitaxel and cisplatin resistant clones and its expression was not detectable normal ovarian epithelium. In vitro silencing of ZNF304 by siRNA significantly inhibited cell proliferation and invasion of ovarian cancer cells, suggesting that ZNF304 may be an important gene driving ovarian cancer progression and transformation thus may be an potential therapeutic target in ovarian cancer. We hypothesize that ZNF304 expression is involved in disease progression by driving expression of critical cellular proteins that promote cell proliferation, survival and invasion/ metastasis in ovarian cancer cells. We also hypothesize that that ZNF304 is potential novel molecular target in ovarian cancer due to its clinical significance and multiple effects in regulation of critical cellular proteins and signaling pathways. Thus therapeutic silencing of this gene by systemically administered siRNA nanotherapeutics will effectively inhibit tumor growth and enhance efficacy of standard chemo therapies in human metastatic ovarian cancers orthotopic models. In specific aim 1, we will determine the role and molecular mechanism of ZNF304-induced proliferation, invasion and ovarian cancer cells. In aim 2, we will determine therapeutic potential of ZNF304 and validate it as a molecular target in ovarian cancer models by therapeutically targeting it systemically administered tumor-targeting siRNA nanotherapeutics in ovarian cancer models. For this purpose we will generate regular and AXL-specific thioaptamer-conjugated nanoliposomal vectors incorporating ZNF304 siRNA to target siRNA vectors to ovarian tumors and also provide dual anti-tumor effect strategy as AXL kinase, which is a molecular target associated with shorter patient survival based on our preliminary data. Understanding the role of ZNF304 in ovarian cancer biology, poor prognosis and therapeutic potential would provide foundation for focusing further on this gene and developing clinically applicable therapeutic approaches.

描述（申请人提供）：ZNF304在卵巢癌中的作用和治疗潜力通过siRNA致死率筛选，我们最近发现ZNF304基因是一种新型转录因子，是卵巢癌生存所必需的。更重要的是，当我们分析癌症基因组图谱（TCGA）卵巢癌患者数据库（n=500）时，我们发现ZNF304基因的表达与卵巢癌患者的不良预后和显着缩短的总生存期（OS）显着相关。我们还发现ZNF304蛋白在所有5种不同的卵巢癌细胞中高度过表达，包括紫杉醇和顺铂耐药克隆，并且其表达在正常卵巢上皮中检测不到。体外siRNA沉默ZNF304可显着抑制卵巢癌细胞的增殖和侵袭，提示ZNF304可能是驱动卵巢癌进展和转化的重要基因，因此可能是卵巢癌的潜在治疗靶点。我们假设 ZNF304 表达通过驱动促进卵巢癌细胞增殖、存活和侵袭/转移的关键细胞蛋白的表达而参与疾病进展。我们还假设 ZNF304 是卵巢癌潜在的新分子靶点，因为它具有临床意义以及在调节关键细胞蛋白和信号通路方面的多种作用。因此治疗性沉默这种通过系统地施用siRNA纳米疗法来治疗基因将有效抑制肿瘤生长并增强人类转移性卵巢癌原位模型中标准化疗的疗效。在具体目标1中，我们将确定ZNF304诱导的增殖、侵袭和卵巢癌细胞的作用和分子机制。在目标 2 中，我们将确定 ZNF304 的治疗潜力，并通过在卵巢癌模型中系统性施用肿瘤靶向 siRNA 纳米治疗药物来验证其作为卵巢癌模型中的分子靶点。为此，我们将生成包含 ZNF304 siRNA 的常规和 AXL 特异性硫适配体缀合的纳米脂质体载体，以将 siRNA 载体靶向卵巢肿瘤，并提供作为 AXL 激酶的双重抗肿瘤效应策略，AXL 激酶是与较短患者生存相关的分子靶点根据我们的初步数据。了解 ZNF304 在卵巢癌生物学、不良预后和治疗潜力中的作用将为进一步关注该基因并开发临床适用的治疗方法奠定基础。