Cancer targeted gene therapy of BikDD inhibits orthotopic lung cancer growth and improves long-term survival

Abstract

Lung cancer is a leading cause of cancer death due to the high incidence of metastasis; therefore novel and effective treatments are urgently needed. A current strategy is cancer specific targeted gene therapy. While many identified cancer specific promoters are highly specific, they tend to have low activity compared to the ubiquitous CMV promoter, limiting their application. We developed a targeted gene therapy expression system for lung cancer that is highly specific with strong activity. Our expression vector uses the survivin promoter, highly expressed in many cancers but not normal adult tissues. We enhanced the survivin promoter activity comparable to the CMV promoter in lung cancer cell lines using an established platform technology, while the survivin promoter remained weak in normal cells. In mouse models, the transgene was specifically expressed in the lung tumor tissue, compared with the CMV promoter that was expressed in both normal and tumor tissues. Additionally, the therapeutic gene BikDD, a mutant form of pro-apoptotic Bik, induced cell killing in vitro, and inhibited cell growth and prolonged mouse survival in vivo. Importantly, there was virtually no toxicity when BikDD was expressed with our expression system. Thus, the current report provides a therapeutic efficacy and safe strategy worthy of development in clinical trials treating lung cancer.

Targeted hepatocellular carcinoma proapoptotic BikDD gene therapy

“…Unlike eAFP-VISA-Luc, mice treated with CMV-Luc showed strong signals in the thoracic area (lungs and heart) (Figures 2a and 3a). These findings suggest that after systemic delivery, the CMV-Luc:liposome complexes flowed through the circulatory system, remained mostly in the lungs and heart, and expressed luciferase because of non-specificity of the CMV promoter, and this data is consistent with the previous studies (Xie et al, 2007Sher et al, 2009).…”

“…At the time of initial design, the versatility of the expression system was also taken into consideration so that it can be used in various cancer types by replacing promoter and therapeutic gene accordingly. Thus far, in addition to the pancreatic model mentioned above (Xie et al, 2007), we have also demonstrated success in tumor reduction in both lung (Sher et al, 2009) and ovarian ) cancer preclinical models.…”

Cancer-Targeted BikDD Gene Therapy Elicits Protective Antitumor Immunity against Lung Cancer

“…All the plasmids used in this study were constructed as previously described (5). To test promoter activity, we used dual-luciferase reporter assay (Promega) to normalize transfection efficiency according to the manufacturer's instructions.…”

“…Previously, we showed that a lung cancer-specific promoter, survivin, is highly active in lung cancer cells but not in other cell types, including immortalized normal cell lines (5). Briefly, survivin is a member of the inhibitor of apoptosis gene family that mediates several antiapoptotic functions (6,7), and its expression is associated with disease progression and poor prognosis in many cancer types (8).…”

“…Moreover, survivin has also been implicated in the development of resistance to apoptosisinducing agents (9) and promotion of metastasis (10). We integrated the survivin promoter into the VISA system to selectively enhance the expression of a therapeutic gene, BikDD, a mutant form of the proapoptotic Bcl2 interacting killer (Bik), to generate survivin-VISA-BikDD (SV-BikDD) and showed that systemic treatment with SV-BikDD DNA in liposome complexes controlled tumor growth and significantly prolonged survival in immunocompromised mice with metastatic human lung cancer and produced virtually no toxicity compared with the CMV promoter vector (5).…”