Novel strategies for personalized treatment of lung cancer using H19 gene regulatory sequences combined with targeted nucleic acid delivery

无论是发病率还是死亡率，肺癌都是最常见的癌症。尽管有各种治疗方案，但预后仍然很差。这一令人沮丧的最先进水平表明，新的治疗策略是必要的，以满足这一未得到满足的医疗需求。H19基因产生一种非编码的RNA，是在人类中发现的第一个父系印记的癌胎儿RNA。虽然它在胚胎和胎儿的整个发育过程中都有表达，但在出生后不久和成年后不久就会关闭，并在包括肺癌在内的许多恶性肿瘤中重新表达，有时是通过丢失印记。在这个方案中，我们将评估H19启动子(H19-DTA)控制下的白喉毒素(DTA)α链表达的治疗潜力，以选择性地通过抑制蛋白质合成来对肺癌细胞造成损伤。此外，通过RNA干扰抑制H19基因的活性将抑制肺癌的进展。在第三种策略中，将研究含有内源性microRNAs靶序列的DTA-mRNA的传递，这些序列不在肺癌细胞中表达，用于肺癌治疗。完善的气雾剂输送方案将进一步优化，并与纳米颗粒工程相结合，以进一步提高核酸输送用于肺癌治疗的特异性和效力。

Lung cancer is the most common cancer in terms of both incidence and mortality. Despite various therapeutic schemes, prognosis is still poor. This frustrating state-of-the–art demonstrates that novel therapeutic strategies are necessary to address this unmet medical need. The H19 gene produces a noncoding RNA and was the first paternally imprinted oncofetal RNA to be discovered in human. While it is expressed throughout development of the embryo and the fetus, it is shut down shortly after birth and during adult life, and re-expressed, sometimes via loss of imprinting, in a wide number of malignancies, including lung cancer. In this proposal we will evaluate the therapeutic potential of Diphtheria toxin (DTA) alpha chain expression under control of H19 promoter (H19-DTA) to selectively inflict the damage on lung cancer cells by inhibition of protein synthesis. Besides, lung cancer progression will be inhibited by inhibition of H19 gene activity using RNA interference. In a third strategy, delivery of DTA-mRNA comprising target sequences of endogenous microRNAs, not expressed in the lung cancer cells, will be investigated for lung cancer treatment. Well-established aerosol delivery protocols will be further optimized and combined with nanoparticle engineering to further increase the specificity and potency of nucleic acid delivery for lung cancer treatment.