HuR Targeted Nanotherapy for Lung Cancer

描述(申请人提供)：肺癌仍然是世界上的一个主要健康问题。尽管治疗策略有所进步，但总体5年存活率仅为14%。因此，需要新的治疗方法。一种有吸引力的治疗方法是确定一个在肺癌中过度表达的分子靶点，该靶点调控几种支持癌症生长和转移的细胞蛋白的表达。通过抑制这样的分子靶点，将对癌细胞中几种蛋白质的表达产生全局抑制效应，从而产生抗癌活性。HUR是胚胎致死性视觉异常(ELAV)蛋白家族的一员，是一种控制大量蛋白质翻译的蛋白质，在人类癌症中过表达。HUR是一种核质穿梭蛋白，它与3‘端富含AU(Are)位点的信使核糖核酸结合，将信使核糖核酸转运到细胞质中进行蛋白质翻译。除了信使核糖核酸的运输外，HUR还在信使核糖核酸的稳定和蛋白质的翻译中发挥作用。研究表明，几种生长因子、细胞周期调节因子和转录调节蛋白的mRNA都有ARs，并受Hur结合和调节。此外，在诊断为卵巢癌、乳腺癌和结肠癌的患者中，HUR的表达已被证明是一个不良的预后标志。虽然有研究Hur在癌症中的作用，但Hur在肺癌中的作用，特别是在非小细胞肺癌(NSCLC)中，还没有被研究过。此外，针对HUR用于癌症治疗的治疗研究很少。根据现有文献和我们自己的初步数据证明HUR在人类肺癌组织中过表达，我们假设HUR是一种新的癌症治疗的药物靶点，其抑制将下调多种在肿瘤进展中发挥作用的癌蛋白，从而增强肿瘤杀伤力。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。为了验证我们的假设，我们确定了以下具体目标：目的1：HuRSiRNA-Tf纳米粒(HuRSiRNA-Tf-NPs)体外治疗人肺癌和正常细胞系的细胞和分子特性。目的：评价Hur-TfNPs对荷瘤小鼠肺转移的治疗作用。目的：测定Hur-TfNPs与小分子抑制剂联合治疗的体内外疗效。我们的研究结果将导致先进的临床前测试和临床应用。

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.