(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：
8591012
负责人：
Gabriel Lopez-Berestein
金额：
$ 20.88万
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/8591012
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（由申请人提供）：Znf304通过siRNA致死性筛查在卵巢癌中的作用和治疗潜力，我们最近发现卵巢癌存活需要一种新型的转录因子Znf304基因。更重要的是，我们发现当我们分析癌症基因组图集（TCGA）卵巢癌患者数据库时，ZnF304基因的表达与卵巢癌患者的预后不良显着相关，并且卵巢癌患者的总生存期显着相关（OS）（n = 500）。我们还发现，Znf304蛋白在包括紫杉醇和顺铂耐药克隆（包括紫杉醇和顺铂及其表达）的所有5种不同的卵巢癌细胞中都高度过表达，无法检测到正常的卵巢上皮。 siRNA对ZnF304的体外沉默显着抑制了细胞的增殖和卵巢癌细胞的侵袭，这表明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标。我们假设ZnF304表达参与了疾病进展，通过驱动关键细胞蛋白的表达，从而促进卵巢癌细胞中促进细胞增殖，存活和侵袭/转移。我们还假设，由于其临床意义和调节关键细胞蛋白和信号通路的调节，ZnF304是卵巢癌中潜在的新分子靶标。因此对此进行治疗沉默通过系统施用的siRNA纳米疗法的基因将有效抑制肿瘤的生长并增强标准化学疗法在人体转移性卵巢癌原位模型中的功效。在特定目标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AIM 2中，我们将通过在卵巢癌模型中将其系统地靶向卵巢癌模型中的ZnF304的治疗潜力，并将其作为卵巢癌模型中的分子靶标验证。为此，我们将生成常规和AXL特异性硫型硫糖剂偶联的纳米脂质体载体，该纳米型体载体掺入Znf304 siRNA将siRNA向量靶向卵巢肿瘤，并提供双重抗肿瘤效应策略，作为AXL激酶，这是与基于基于患者生存的较短患者生存的分子靶标的，在我们的初步数据上。了解Znf304在卵巢癌生物学，预后不良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提供基础。