Evaluating Baculovirus as a Vector for Human Prostate Cancer Gene Therapy

Abstract

Gene therapy represents an attractive strategy for the non-invasive treatment of prostate cancer, where current clinical interventions show limited efficacy. Here, we evaluate the use of the insect virus, baculovirus (BV), as a novel vector for human prostate cancer gene therapy. Since prostate tumours represent a heterogeneous environment, a therapeutic approach that achieves long-term regression must be capable of targeting multiple transformed cell populations. Furthermore, discrimination in the targeting of malignant compared to non-malignant cells would have value in minimising side effects. We employed a number of prostate cancer models to analyse the potential for BV to achieve these goals. In vitro, both traditional prostate cell lines as well as primary epithelial or stromal cells derived from patient prostate biopsies, in two- or three-dimensional cultures, were used. We also evaluated BV in vivo in murine prostate cancer xenograft models. BV was capable of preferentially transducing invasive malignant prostate cancer cell lines compared to early stage cancers and non-malignant samples, a restriction that was not a function of nuclear import. Of more clinical relevance, primary patient-derived prostate cancer cells were also efficiently transduced by BV, with robust rates observed in epithelial cells of basal phenotype, which expressed BV-encoded transgenes faster than epithelial cells of a more differentiated, luminal phenotype. Maximum transduction capacity was observed in stromal cells. BV was able to penetrate through three-dimensional structures, including in vitro spheroids and in vivo orthotopic xenografts. BV vectors containing a nitroreductase transgene in a gene-directed enzyme pro-drug therapy approach were capable of efficiently killing malignant prostate targets following administration of the pro-drug, CB1954. Thus, BV is capable of transducing a large proportion of prostate cell types within a heterogeneous 3-D prostate tumour, can facilitate cell death using a pro-drug approach, and shows promise as a vector for the treatment of prostate cancer.

PACE4 regulates apoptosis in human prostate cancer cells via endoplasmic reticulum stress and mitochondrial signaling pathways

“…In recent years, gene therapy has become a hot topic in the study of a different diseases. 37 , 38 Previous study has also indicated that silencing of the PACE4 gene could trigger the apoptosis of other cancer cells, such as, PCa, ovarian cancer, breast cancer, etc. 39 – 41 However, the specific mechanism of the PACE4 regulation has not been elucidated.…”

Antitumor Effects of a Recombinant Baculovirus Displaying Anti-HER2 Scfv Expressing Apoptin in HER2 Positive SK-BR-3 Breast Cancer Cells

“…Gene therapy has become an attractive strategy for the cancer treatment in recent years, with the use of . Whereas baculoviruses has demonstrating several potential advantages over other vectors in this field [30]. For the first time, Hofmann and colleagues demonstrated that the baculovirus has the ability as a vector to deliver sustainable foreign genes expression in human hepatocytes in 1995 [31].…”

Baculovirus-Derived Vectors for Immunization and Therapeutic Applications

“…A reflection of this is the increasing number of peerreviewed publications that use recombinant baculoviruses over other viral vectors. For example, Swift et al (2013) used a baculovirus with a prodrug approach to mediate cell-death of prostate cancer cells with success, even observing the good capacity of cell-layer penetration compared to other viral vectors. In the last few years, gene silencing by RNA interference has become more relevant for gene regulation.…”