Targeted Expression of BikDD Eradicates Pancreatic Tumors in Noninvasive Imaging Models

Abstract

Pancreatic cancer is an aggressive malignancy with morbidity rates almost equal to mortality rates because of the current lack of effective treatment options. Here, we describe a targeted approach to treating pancreatic cancer with effective therapeutic efficacy and safety in noninvasive imaging models. We developed a versatile expression vector "VISA" (VP16-GAL4-WPRE integrated systemic amplifier) and a CCKAR (cholecystokinin type A receptor) gene-based, pancreatic-cancer-specific promoter VISA (CCKAR-VISA) composite to target transgene expression in pancreatic tumors in vivo. Targeted expression of BikDD, a potent proapoptotic gene driven by CCKAR-VISA, exhibited significant antitumor effects on pancreatic cancer and prolonged survival in multiple xenograft and syngeneic orthotopic mouse models of pancreatic tumors with virtually no toxicity.

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.…”

“…The system consists of a cancer-specific promoter and transcriptional amplification module called VISA (VP16-GAL4-WPRE4 Integrated Systemic Amplifier), which allows expression of target gene at a level comparable with or even higher than the cytomegalovirus (CMV) promoter (Xie et al, 2007). When coupled with a potent proapoptotic therapeutic gene, BikDD, under a cancer-specific expression vector and encapsulated in DOTAP:cholesterol (Templeton et al, 1997), a liposome formulation that has been tested in a phase I clinical trial (NCT00059605), the VISA system demonstrated significant reduction of tumor without toxicity in pancreatic cancer model (Xie et al, 2007). On the basis of the encouraging results, relevant toxicity studies to fulfill requirement for approval by the Food and Drug Administration to initiate a Phase I human clinical trial is completed and an investigator-initiated Investigational New Drug is currently under preparation.…”

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

“…However, most of the identified cancerspecific promoters that exhibit a high level of cancer specificity are still much weaker than the nonspecific strong cytomegalovirus (CMV) promoter (3). To overcome this issue, a promoter amplification system called VP16-GAL4-WPRE integrated systemic amplifier (VISA) was developed to amplify the cancer-specific promoter activity, and the activity in some cancer cell lines are even able to reach a level comparable to that of CMV in cancer cells though remaining inactive in normal tissues (4).…”

Advanced Pancreatic Cancer: Flourishing Novel Approaches in the Era of Biological Therapy

“…nab-Paclitaxel and its combination with different agents is now one of the most popular areas of clinical research in APC. Another innovative approach to improve drug delivery using nanotechnology and cancerspecific liposomes [89] is under development.…”