Project title: Combination of a novel TRAIL-expressing oncolytic virus with a caspase-3 activator for treatment of granulosa cell tumours
Viruses such as vaccinia virus have a natural ability to grow in many different types of cells, resulting in cell death. We have modified vaccinia virus so that it is no longer able to infect and grow in normal non-dividing cells, but retains robust replication in tumours. We propose that the anti-tumour activity of this virus could be improved by combining it with a complementary strategy that induces “programmed” cell death in tumour cells. We have shown that programmed cell death can be activated in GCT cells by a protein called TRAIL together with a drug called PAC1 that sensitizes tumour cells to TRAIL. TRAIL and PAC1 killed patient-derived GCT cultures in the laboratory, but importantly, these two agents were not harmful to normal cells. Here we will test whether our modified virus can be used to deliver TRAIL protein to GCT cells, and together with sensitization by PAC1, will be sufficient to eradicate GCT tumours grown in mouse models for this type of ovarian cancer, without harming normal cells. If this treatment is shown to be effective, this strategy could be further developed for the treatment of women with primary or recurrent GCT, and may produce fewer side effects with a more durable anti-tumour response than therapies that are currently available.
This project fits squarely within the mandate for funding from the Granulosa Cell Tumor (GCT) Research Foundation. The project is focused entirely on the development of novel treatments for granulosa cell tumors, an uncommon form of ovarian cancer. We have previously used the adult GCT cell line, KGN, for our in vitro studies. Here, we will use a new immune competent mouse model for GCT that accurately simulates the human disease. We will continue to develop this model to aid in assessing our proposed treatment, as well as future treatments for GCT recurrence.