Gene transfer to carcinoma of the breast with fiber-modified adenoviral vectors in a tissue slice model system

Abstract

Successful adenoviral (Ad) vector-mediated strategies for breast cancer gene therapy and virotherapy have heretofore been hindered by low transduction efficiency. This has recently been understood to result from a relative paucity of expression of the primary adenovirus receptor, coxsackie-adenovirus-receptor (CAR), on primary tumor cells. To further investigate this issue, we evaluated the expression of CAR on breast cancer cell lines as well as primary breast cancer cells. With the exception of one patient sample, CAR expression was notably higher in the tumor cells from patients compared to CAR expression in the tumor cell lines. Furthermore, we explored CAR-independent targeting strategies to breast cancer tissue by exploring a panel of infectivity-enhanced Ad vectors, which contain CAR-independent targeting motifs for their utility in breast cancer gene therapy and virotherapy. These targeting motifs included Ad 3 knob (Ad5/3), canine Ad serotype 2 knob (Ad5CAV-2), RGD (Ad5.RGD), polylysine (Ad5.pK7), or both RGD and polylysine (Ad5.RGD.pK7), and were tested using the breast cancer tissue slice model, which is the most stringent substrate system available. Of all the tested tropism modified Ad vectors, Ad5/3 exhibited the highest transductional efficiency in breast cancer. These preclinical results suggest that Ad5/3 is the most useful modification to achieve higher clinical efficacy of breast cancer gene therapy and virotherapy.

Proteasome inhibitor MG-132 modifies coxsackie and adenovirus receptor expression in colon cancer cell line lovo

“…17,18 Low level of CAR in tumor cells has been regarded as one of the reasons for poor efficacy of adenovirus based gene therapy. [19][20][21][22][23][24] By now, the decreased expression of CAR in tumor tissue was observed in prostate, 25 bladder, 12,20 thyroid, 26 gastrointestinal malignancies (esophageal, pancreatic, colorectal and liver cancer), 27 head and neck carcinomas. 23 The gene expression could be regulated by transcriptional and posttranscriptional mechanism, including DNA methylation, histone acetylation of chromatin structure and the protein degradation via ubiquitin-proteasome pathway.…”

Herpes Simplex Virus Type 1 Preferentially Targets Human Colon Carcinoma: Role of Extracellular Matrix

“…Such a system may serve as a means to study viral tropism in the context of a three-dimensional tissue structure (8,14). Organ cultures derived from normal liver tissue and from ovarian and breast carcinomas have also been applied to the study of gene transfer by viral vectors (21,41,46,47). The organ culture method described here is unique because it allows direct comparison of viral infection of tumor tissue versus the corresponding normal tissue (22).…”

Antitumor Activity of an Oncolytic Adenoviral-CD40 Ligand (CD154) Transgene Construct in Human Breast Cancer Cells

“…Adenoviruses have been used as delivery platforms to deliver cytotoxic agents to cancers of the head and neck, multiple myeloma, ovarian, prostate, and breast (5). Breast cancer primary tumors express high levels of the Coxsackie virus and adenovirus receptor, the primary cell surface receptor for adenovirus attachment during the viral infection process (6). Coxsackie virus and adenovirus receptor expression has been shown to increase with tumor grade (7), supporting the strategy of adenoviral-based gene transfer for experimental therapy of human breast cancer.…”