HuR Targeted Nanotherapy for Lung Cancer

HuR 靶向纳米疗法治疗肺癌

• 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
• 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

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）：肺癌仍然是世界上一个主要的健康问题。尽管治疗策略取得了进步，总5年生存率仅为14％。因此，需要新颖的疗法。 一种有吸引力的治疗方法是确定在肺癌中过表达的分子靶标，并调节几种支持癌症生长和转移的细胞蛋白的表达。通过抑制这种分子靶标对癌细胞中几种蛋白质表达的全局抑制作用将产生抗癌活性。 Hur是胚胎致命异常视力（ELAV）蛋白家族的成员，是一种控制众多蛋白质翻译并在人类癌中过表达的蛋白质。 HUR是一种核总质式穿梭蛋白，该蛋白特异性结合了3'End的富含Au的位点的mRNA，并将mRNA转运到细胞质中以进行蛋白质翻译。除mRNA运输外，HUR还在mRNA稳定和蛋白质翻译中发挥作用。研究表明，mRNA的几种生长因子，细胞周期调节剂和转录 - 调节蛋白具有ARES，并由HUR结合和调节。此外，在被诊断为卵巢，乳腺癌和结肠癌癌症患者中，HUR表达已被证明是较差的预后标记。尽管研究了HUR在癌症中的研究，但尚未研究HUR在肺癌中的作用，尤其是在非小细胞肺癌（NSCLC）中。此外，已经研究了针对HUR进行癌症治疗的很少的治疗研究。在现有文献和我们自己的初步数据的基础上，证明了人类肺癌组织中的HUR过度表达，我们假设HUR是癌症治疗的新型可药物治疗靶标，其抑制作用将下调多种多种癌蛋白，这些癌蛋白在肿瘤进展中起作用，从而在肿瘤进展中发挥作用，从而在肿瘤中造成增强的肿瘤。此外，将HUR靶向疗法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，我们确定了以下特定目的：目标1：在人体肺肿瘤和正常细胞系中，hursirna-tf纳米颗粒（HUR-TFNPS）治疗的细胞和分子表征。 AIM 2：评估HUR-TFNP对肿瘤异种移植小鼠模型中肺转移的功效。 AIM 3：确定HUR-TFNPs处理与小分子抑制剂在体外和体内的功效。 我们研究的结果将导致高级临床前测试和转化为诊所。