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

摘要

The purpose of the proposed research is to develop a propagation- competent (PC) aiphavirus vector that is targeted specifically to receptors expressed on breast cancer cells or to receptors expressed on tumor-associated vasculature. This type of targeted vector would provide a very efficient means of specifically killing a large number of malignant cells. Two Sindbis virus (SV) vectors containing the epidermal-like growth factor domain of heregulin in place of a portion of its receptor-binding domains, were impaired in their ability to assemble and bud from transfected cells. However, transfection of cells with the heregulin-containing SV RNAs resulted in preferential killing of breast cancer cells. Using a sequence encoding a 13 amino acid NUR-containing peptide ligand, we were able to produce a replication-competent SV. This recombinant virus did not preferentially replicate and kill cells expressing the target CD 13 receptor. Breast cancer tumors were produced in nude mice using MDA-MB-23 1 cells. Difficulties with production of PC heregulin containing virus and with production of sufficient quantities of viral RNA precluded performance of properly controlled animal studies. Future studies will focus on identifying other ligands, permissive sites of replacement versus insertion in the SV genome, and further development of the animal models.