Changes in Susceptibility to Oncolytic Vesicular Stomatitis Virus during Progression of Prostate Cancer

Amajor challenge to oncolytic virus therapy is that individual cancers vary in their sensitivity to oncolytic viruses, even when these cancers arise from the same tissue type. Variability in response may arise due to differences in the initial genetic lesions leading to cancer development. Alternatively, susceptibility to viral oncolysis may change during cancer progression. These hy-potheses were tested using cells from a transgenic mouse model of prostate cancer infected with vesicular stomatitis virus (VSV). Primary cultures frommurine cancers derived from prostate-specific Pten deletion contained a mixture of cells that were suscep-tible and resistant to VSV. Castration-resistant cancers contained a higher percentage of susceptible cells than cancers from non-castrated mice. These results indicate both susceptible and resistant cells can evolve within the same tumor. The role of Pten de-letion was further investigated using clonal populations of murine prostate epithelial (MPE) progenitor cells and tumor-derived Pten/ cells. Deletion of Pten in MPE progenitor cells using a lentivirus vector resulted in cells that responded poorly to inter-feron and were susceptible to VSV infection. In contrast, tumor-derived Pten/ cells expressed higher levels of the antiviral transcription factor STAT1, activated STAT1 in response to VSV, and were resistant to VSV infection. These results suggest that early in tumor development following Pten deletion, cells are primarily sensitive to VSV, but subsequent evolution in tumors leads to development of cells that are resistant to VSV infection. Further evolution in castration-resistant tumors leads to tumors in which cells are primarily sensitive to VSV