HuR Targeted Nanotherapy for Lung Cancer

HuR 靶向纳米疗法治疗肺癌

基本信息

批准号：
8440451
负责人：
Rajagopal Ramesh
金额：
$ 40.24万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES 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：
2013-01-01 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8440451
关键词：
Address Animal Model Binding Binding Proteins Breast Cancer Biology Cell Cycle Cell Line Cell Survival Clinic Colon Cytoplasm Data Diagnosis Drug Formulations Embryo Genetic Transcription Goals Growth Growth Factor Health Human In Transferrin In Vitro Lead Literature Lung Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of ovary Messenger RNA Molecular Molecular Target Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Normal Cell Oncogene Proteins Outcome Pathology Patients Play Preclinical Testing Prognostic Marker Protein Family Proteins Research Personnel Role Signal Transduction Site Survival Rate Testing Therapeutic Therapeutic Studies Tissues Transferrin Receptor Translating Translations Transportation Vision anticancer activity base cancer cell cancer therapy improved in vivo inhibitor/antagonist innovation killings member mouse model nanoparticle nanotherapy neoplastic cell novel overexpression pre-clinical preclinical study public health relevance research clinical testing small molecule treatment strategy tumor tumor progression tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): Lung cancer remains a major health problem in the world. Despite advances in treatment strategies the overall 5-year survival rate is only 14%. Therefore, novel therapies are needed. One attractive therapeutic approach is to identify a molecular target that is overexpressed in lung cancer and which regulates the expression of several cellular proteins that support cancer growth and metastasis. By inhibiting such a molecular target a global inhibitory effect on the expression of several proteins in a cancer cell will be produced resulting in anticancer activity. HuR, a member of the embryonic lethal abnormal vision (ELAV) protein family, is one such protein that controls the translation of numerous proteins and overexpressed in human cancers. HuR is a nucleo-cytoplasmic shuttling protein that specifically binds to mRNA that has AU rich (ARE) sites at the 3'end and transports the mRNA to the cytoplasm for protein translation. In addition to mRNA transportation, HuR plays a role in mRNA stabilization and protein translation. Studies have shown mRNA's of several growth factors, cell-cycle regulators, and transcription- regulating proteins have AREs and are bound and regulated by HuR. Additionally, HuR expression has been demonstrated to be a poor prognostic marker in patients diagnosed with cancer of the ovary, breast and colon. Although studies investigating HuR in cancer exist, the role of HuR in lung cancer, especially in non-small cell lung cancer (NSCLC), has not been investigated. In addition, very few therapeutic studies targeting HuR for cancer therapy have been investigated. On the basis of the existing literature and our own preliminary data demonstrating HuR overexpression in human lung cancer tissues we hypothesize that HuR is a novel druggable target for cancer therapy and its inhibition will downregulate multiple oncoproteins that play a role in tumor progression resulting in enhanced tumor killing. Additionally, combining HuR-targeted therapy with small molecule inhibitors will produce enhanced anticancer activity. To test our hypothesis we have identified the following specific aims: Aim 1: Cellular and molecular characterization of HuRSiRNA-Tf-nanoparticles (HuR-TfNPs) treatment on human lung tumor and normal cell lines in vitro. Aim 2: Evaluate the efficacy of HuR-TfNPs on lung metastasis in a tumor xenograft mouse model. Aim 3: Determine the efficacy of HuR-TfNPs treatment in combination with small molecule inhibitors in vitro and in vivo. The outcome of our studies will result in advanced preclinical testing and translation to the clinic.

描述（由申请人提供）：肺癌仍然是世界上的一个主要健康问题。尽管治疗策略取得了进步，但总体 5 年生存率仅为 14%。因此，需要新的疗法。一种有吸引力的治疗方法是确定在肺癌中过度表达的分子靶标，该分子靶标调节支持癌症生长和转移的几种细胞蛋白的表达。通过抑制这样的分子靶标，将对癌细胞中几种蛋白质的表达产生全局抑制作用，从而产生抗癌活性。 HuR 是胚胎致死性视力异常 (ELAV) 蛋白家族的成员之一，它是控制多种蛋白翻译并在人类癌症中过度表达的蛋白之一。 HuR 是一种核质穿梭蛋白，可特异性结合 3' 端富含 AU (ARE) 位点的 mRNA，并将 mRNA 转运至细胞质进行蛋白质翻译。除了 mRNA 运输之外，HuR 在 mRNA 稳定和蛋白质翻译中也发挥着作用。研究表明，多种生长因子、细胞周期调节因子和转录调节蛋白的 mRNA 均具有 ARE，并受 HuR 结合和调节。此外，HuR 表达已被证明是诊断患有卵巢癌、乳腺癌和结肠癌的患者的不良预后标志物。尽管存在研究 HuR 在癌症中的作用，但 HuR 在肺癌，特别是非小细胞肺癌 (NSCLC) 中的作用尚未得到研究。此外，针对 HuR 进行癌症治疗的治疗研究很少。根据现有文献和我们自己证明人类肺癌组织中 HuR 过度表达的初步数据，我们假设 HuR 是癌症治疗的新型药物靶标，其抑制将下调多种在肿瘤进展中发挥作用的癌蛋白，从而导致肿瘤增强杀戮。此外，将 HuR 靶向治疗与小分子抑制剂相结合将产生增强的抗癌活性。为了检验我们的假设，我们确定了以下具体目标：目标 1：HuRSiRNA-Tf-纳米颗粒 (HuR-TfNP) 体外治疗人肺肿瘤和正常细胞系的细胞和分子特征。目标 2：评估 HuR-TfNP 对肿瘤异种移植小鼠模型中肺转移的功效。目标 3：确定 HuR-TfNPs 与小分子抑制剂联合治疗的体外和体内疗效。我们的研究结果将导致先进的临床前测试并转化为临床。