HuR Targeted Nanotherapy for Lung Cancer

描述（由申请人提供）：肺癌仍然是世界上主要的健康问题。尽管治疗策略取得了进展，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鉴定在肺癌中过表达并且调节支持癌症生长和转移的几种细胞蛋白质的表达的分子靶标。通过抑制这种分子靶标，将产生对癌细胞中几种蛋白质表达的全面抑制作用，从而产生抗癌活性。 HuR是胚胎致死性异常视觉（ELAV）蛋白家族的成员，是控制许多蛋白质的翻译并在人类癌症中过表达的一种这样的蛋白质。HuR是一种核质穿梭蛋白，其特异性结合在3 '端具有富含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，HuR在mRNA稳定和蛋白质翻译中起作用。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具有战神并由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。尽管存在研究癌症中HuR的研究，但HuR在肺癌，特别是在非小细胞肺癌（NSCLC）中的作用尚未研究。此外，很少有针对HuR用于癌症治疗的治疗研究被调查。在现有文献和我们自己的初步数据的基础上，证明HuR在人肺癌组织中的过表达，我们假设HuR是一种新的药物治疗癌症的目标，它的抑制将下调多种癌蛋白，在肿瘤进展中发挥作用，从而增强肿瘤杀伤。此外，将HuR靶向治疗与小分子抑制剂组合将产生增强的抗癌活性。 目的1：HuRSiRNA-Tf-纳米颗粒（HuR-TfNPs）在体外对人肺肿瘤和正常细胞系的治疗的细胞和分子表征。目的2：评估HuR-TfNPs对肿瘤异种移植小鼠模型中肺转移的功效。目的3：在体外和体内确定HuR-TfNP与小分子抑制剂组合治疗的功效。 我们的研究结果将导致先进的临床前测试和临床翻译。

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.