Abstract 5662: The development of SCLC specific nanoparticle-mediated p53 gene therapy

Lung cancer is the most common cause of cancer-related deaths worldwide. Small cell lung cancer (SCLC) is a highly malignant and aggressive type of lung cancer with widespread metastases and poor prognosis. SCLC is characterized by chemoresistance and radioresistance with an average survival period of 40%; comparable to commercially available transfection reagents. We initiated efficacy assays by validating whether H446 cells possess mutant p53 and are a suitable target for p53 restoration; p53 status in H446 and H460 cells (WT control) was confirmed by direct sequencing. A plasmid encoding WT p53-GFP under the control of the CMV promoter (CMV-p53-GFP) was used to reconstitute exogenous expression of WT p53. An 8 h incubation with 456:CMV-p53-GFP complex induced WT p53 expression in H446 cells (p53-mutant) but not in H460 cells (p53 WT); leading to a moderate p21 induction, subsequent G1-arrest and anti-proliferative effects. A CMV-p53-GFP plasmid without p53 (CMV-GFP) served as a negative control for induction and activity of exogenous p53. Additionally, 456 and 457 exhibited in vivo tumoral transfection of CMV-LUC DNA after an intratumoral or an intravenous injection. These novel in vitro and in vivo effects by PBAEs in H446 cells suggested a possible therapeutic potential for targeted p53 gene therapy in other SCLC cells and mouse models with primary SCLC xenografts. Ongoing studies include genetic characterization of patient-derived primary SCLC xenografts and assessing systemic PBAE-p53 delivery in these xenografts. In parallel, we plan to employ PBAE-p53 delivery in combination with other target genes or with chemo-/radio-therapy in SCLC cell lines and mouse models. We strongly believe that PBAE-based gene therapy would provide higher efficacy and minimal adverse effects for improved SCLC treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5662. doi:1538-7445.AM2012-5662