Development of cancer gene therapy has been hampered by the fact that there are no effective cancer-specific expression vectors available, which is critical for improving therapeutic efficacy and reducing toxicity in clinics. To overcome this problem, we recently developed a safe and effective strategy fro targeting a potent pro-apoptotic gene (BikDD) to the pancreatic tumors (Xie et al. Cancer Cell, 2007), lung cancer (Sher et al. Oncogene, 2009) and ovarian cancer (Xie et al. Molecular Cancer Therapeutics, 2009). A VISA system (VP16-Gal4-WPRE integrated systemic amplifier) was engineered by using the two-step transcriptional amplification (TSTA) system and the posttranscriptional regulatory element of the woodchuck hepatitis virus (WPRE). The VISA system can boost the activity of cancer-specific promoters by an average of 600-800-folds compared to their basal levels. C-VISA (CCKAR-VISA) nanoparticles transcriptionally targets transgene expression effectively to pancreatic tumors in vivo. C-VISA-BikDD nanoparticles was shown to be highly effective in reducing tumor burden and increasing animal survival rate in orthotopic pancreatic cancer models which is moving into clinical trials at University of Texas M.D. Anderson Cancer Center, USA. In the current study, we identified hTERT(human telomerase reverse transcriptase), survivin, β-cateinin, claudin-4, and FASN (fatty acid synthase) promoters as breast cancer-selective promoters, and amplified their activity to hundreds of folds greater by the “VISA” system(called x-VISA) without loss of their specificity. Very importantly, the x-VISA promoters were also robust in the primary cultured breast cancer cells, with 42.5 %-65% of the CMV promoter, while retaining stringent pancreatic cancer specificity. x-VISA was also shown to target expression of firefly luciferase to MDA-MB-468 xenografts in an orthotopic mouse model, confirmed by noninvasive imaging with an Xenogen IVIS™ imaging system and measuring with a luminometer. The cancer-specific index was 35-60 for x-VISA-Luc and 0.01 for CMV-Luc in vivo. We further demonstrated significant antitumor activity of targeted BikDD expression driven by nanoparticles of the hTERT-VISA-BikDD vectors in Her-2-negative and-positive and triple-negative breast cancer cell lines in vitro, and in multiple breast cancer models of living imaging by the Xenogen IVIS imaging system with limited toxicity. In addition, treatment with hTERT-VISA-BikDD nanoparticles plus lapatinib or produces evident combinational therapeutic efficacy, which is likely due to the ability of lapatinib to promote apoptosis of Her-2-overexpressing breast cancer cells. Thus, our newly developed hTERT-VISA-BikDD nanoparticles are an innovative strategy for targeted antitumor effects of Her-2-negative, Her-2-positive and triple-negative breast cancer.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-05-01.