Lung cancer is the main cause of death from cancer with 5-year survival across all stages at 15-20%. About 80% of these tumors are from non–small-cell histological type (NSCLC), including adenocarcinomas, squamous cell, and large cell carcinomas. Surgery is generally accepted as the best treatment option for NSCLC. Unfortunately, only 1/3 of patients with NSCLC are candidates for curative resection. The remaining patients have more advanced stages: multifocal or bulky N2, unresectable IIIB, or metastatic disease. Patients with non-surgical stage III disease are treated with chemo-radiotherapy. The remainder, representing the majority of cases, is treated with chemotherapy or supportive care depending on age, and performance status. Lung cancer remains fatal even with only localized disease at presentation (Stage IA 5 year survival 80%). A 2008 meta-analysis, performed to take into account the new therapeutic regimens, demonstrated a benefit of chemotherapy for advanced NSCLC, improving survival by 9% at 12 months, increasing survival rate to 29% versus 20%. The benefit seen due to the changes in the lung cancer population and drug the regimens used, remained very small. The limited impact of currently available treatments for inoperable NSCLC and the trend towards fewer or no improvement over time should prompt searches for new therapeutic strategies. We discovered a ligand/receptor complex implicated in all steps of cancer progression. Neurotensin (NTS), a 13 amino acid peptide, and its high affinity receptor, NTSR1 lead to cell proliferation, survival, mobility, and invasiveness in specific cancer cell types and facilitates tumor growth and metastasis process. NTSR1 expression level is associated with poor prognosis in patients with ductal breast cancer and head and neck squamous cell carcinomas, and in stage I primary lung adenocarcinoma. NTS-polyplex is a non-viral gene transfer system using NTSR1 endocytosis to facilitate the entrance of the polyplex molecule carrying a plasmid expression vector, into the cell. It was developed to evaluate gene transfer to neuronal cells and neuroblastoma tumors. We demonstrated that intravenous injection of the NTS-polyplex reached and transfected neuroblastoma tumor cells. NTS-polyplex transfection is therefore more efficient in the tumor cells than in healthy cells of organs known to express the NTSR1. The transfection of the thymidine kinase (HSVTK) suicide gene followed by ganciclovir (GCV) treatment decreased the size and weight of neuroblastoma tumors by 30% to 50% and increased apoptosis when compared to controls. These conclusive results call for further development of this approach for lung cancer therapy. In this project, we propose to clarify the contribution of NTS/NTSR1 complex in lung tumor progression, and to identify the NSCLC patients eligible for cancer gene therapy using NTS-polyplex. The evaluation of NTSR1 expression status will be developed on stage IIIB and IV NSCLC patients included in therapeutic protocols. We propose to develop experimental tumors expressing or not NTSR1 and/or NTS to evaluate a possible gene therapy on advanced lung tumor and their metastasis. The Mexican industrial partner, Psicofarma, will be responsible for developing the products for human therapy. The scientific strengths of this project lie with the combination of basic and translational research (French partners), the continued collaboration in experimental research (between the French and Mexican laboratories), and the future biotechnology development (Psicofarma).