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

• Applicants: Professor Dr. Christoph Klein, since 10/2012; Privatdozent Dr. Carsten Rudolph, until 10/2012
• Co-Applicant: Professor Abraham Hochberg, Ph.D.
• Subject Area: Pediatric and Adolescent Medicine
• Term: from 2010 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 164587406

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.

• DFG Programme: Research Grants
• International Connection: Israel