Targeted Expression of BikDD Eliminates Breast Cancer with Virtually No Toxicity in Noninvasive Imaging Models

Abstract

Breast cancer is a major public health problem all over the world, and the current treatment strategies are not potent enough for some patients, especially those with triple-negative breast cancer. Therefore, novel and more effective treatments are critically needed. Of the current methods, targeted therapy, which not only retains cancer-specific expression but also limits toxicity, is a new strategy for treating cancers. In this study, we found that the human telomerase reverse transcriptase (hTERT; T) promoter also possesses high target specificity in breast cancer. Moreover, we developed a versatile T-based breast cancer-specific promoter VISA (VP16-Gal4-WPRE integrated systemic amplifier) composite (T-VISA) to target transgene expression in breast tumors, which has stronger activity comparable or higher than that of the cytomegalovirus promoter in cancer cells. Thereafter, targeted expression of BikDD (a mutant form of proapoptotic gene Bik) through the T-VISA platform in breast cancer initiated robust antitumor effects and prolonged survival in multiple xenograft and syngeneic orthotopic mouse models of breast tumors with virtually no toxicity in intact mice. Thus, these findings show that our T-VISA-BikDD nanoparticles effectively and safely eradicate breast cancer in vitro and in vivo and are worthy of development in clinical trials treating breast cancer. Mol Cancer Ther; 11(9); 1915-24. Ó2012 AACR.

Development of PEA-15 using a potent non-viral vector for therapeutic application in breast cancer

“…In addition, our constructed T-VISA vector has been assured to be a robust cancer-specific promoter, and it hold the ability to drive target gene expression highly and specifically in breast cancer cells[6]. Therefore, to enhance the gene expression activity and specificity, we incorporated PEA-15 into our T-VISA system and then evaluated the potential anti-tumor effects of T-VISA-PEA-15 in numerous breast cancer cells (Fig.…”

“…Tissues were collected under patients’ agreement. Stable cell lines MDA-MB-231-Luc expressing firefly luciferase were constructed and maintained as described before[6]. …”

“…Targeted gene therapy is an attractive strategy due to the benefit of cancer-specific expression of therapeutic genes[4; 5]. We previously showed that T-VISA vector containing hTERT promoter and VISA (VP16-GAL4-WPRE integrated systemic amplifier) system could target gene expression specifically in human breast tumor, without severe toxicity in normal tissues[6]. …”

Interrogating Tumor Metabolism and Tumor Microenvironments Using Molecular Positron Emission Tomography Imaging. Theranostic Approaches to Improve Therapeutics

“…Numerous studies have shown indirect imaging of hTERT in mice using luciferase or green fluorescent protein as reporter genes Xie et al, 2012). The sole study that was reported for imaging telomerase expression by PET used human sodium iodide symporter (hNIS), a PET reporter gene that was introduced to the tumors by recombinant adenoviruses (Groot-Wassink et al, 2004).…”

Targeted BikDD Expression Kills Androgen-Dependent and Castration-Resistant Prostate Cancer Cells

“…More recently, the hTERT-promoter-based VISA (also referred to as T-VISA) vector that we developed for ovarian cancer also drives transgene expression in breast cancer (16) with activities higher than or comparable to the CMV promoter. Since the hTERT promoter activity is activated in more than 85% human cancers, including prostate cancer, but absent in normal somatic cells (17), we also tested the T-VISA vector for its activity in prostate cancer and found that T-VISA is active in both CRPC and ADPC.…”