Development of targeted Sindbis Virus Vectors for Potential Application to Breast Cancer Therapy

摘要

The future progress of cancer gene therapy relies on the development of efficient and safe vectors that can deliver therapeutic genes specifically to tumor cells. Using a replication-competent viral vector targeted to tumor cells may be the most efficient way of killing a large number of malignant cells. We intend to develop Sindbis virus (SV), an alphavirus, into a targeted replication-competent viral vector for breast cancer therapy. Since SV kills cells by apoptosis, specific destruction of tumor cells will occur if the virus is targeted to breast cancer cells. To target SV to breast cancer cells, the putative receptor-binding domain(s) of the SV E2 glycoprotein was replaced with the ligand, heregulin, or with an NGR-containing peptide motif that binds to the CD 13 receptor expressed on tumor-associated endothelial cells. A heregulin- containing SV preferentially kills a breast cancer cell line that expresses the appropriate receptors. The replication and spread of the heregulin-containing SV vectors is significantly attenuated. However, SV antigen expression and heregulin-E2 glycoprotein expression was detected in BHK cells transfected with SV RNA containing heregulin sequence. We have isolated an NGR-containing SV clone, TE-NGR, that is replication competent in BHK and SLK cells. We are investigating the ability of TE-NGR to preferentially kill cancer cells.