HuR Targeted Nanotherapy for Lung Cancer

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。尽管治疗策略有所进步，但总体5年生存率仅为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在肺癌中过度表达的分子靶标，并调节支持癌症生长和转移的几种细胞蛋白的表达。通过抑制这样一个分子靶点，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是胚胎致死性异常视力（ELAV）蛋白家族的一员，是一种控制许多蛋白质翻译并在人类癌症中过度表达的蛋白质。HuR是一种核细胞质穿梭蛋白，它特异性地与3'端富含AU （ARE）位点的mRNA结合，并将mRNA转运到细胞质中进行蛋白质翻译。除了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，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AREs，并受HuR的结合和调节。此外，HuR表达已被证明是卵巢癌、乳腺癌和结肠癌患者预后不良的标志。虽然有研究探讨了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的癌症治疗研究很少。根据现有文献和我们自己在人肺癌组织中显示HuR过表达的初步数据，我们假设HuR是一种新的癌症治疗药物靶点，其抑制会下调多种在肿瘤进展中起作用的癌蛋白，从而增强肿瘤杀伤。此外，将hr靶向治疗与小分子抑制剂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：目标1：体外研究hursirna - tf纳米颗粒（huri - tfnps）对人肺肿瘤和正常细胞系治疗的细胞和分子特性。目的2：评价HuR-TfNPs对肿瘤移植小鼠肺转移的影响。目的3：确定hr - 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转化为临床。

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.