Exploring Myxoma virus oncolytic virotherapy in combination with carboplatin for the treatment of epithelial ovarian cancer
Epithelial ovarian cancer (EOC) is the most lethal of the gynaecologic malignancies as 75% of cases are diagnosed after extensive metastasis. EOC metastasis involves shedding of cancer cells from the primary tumor directly into the peritoneal cavity where EOC cells form multicellular aggregates or spheroids that implant in and invade the peritoneal mesothelium to initiate secondary tumors. EOC spheroids undergo dormancy in suspension to promote survival and in turn demonstrate resistance to standard chemotherapeutics such as carboplatin. In an in vitro model of EOC metastasis, we have recently demonstrated that Myxoma virus (MYXV) effectively kills adherent EOC cells and reduces spheroid reattachment. In order for MYXV to advance toward clinical use as a first-line therapy for ovarian cancer, its compatibility with current chemotherapeutics must be assessed. We propose that combination treatment using MYXV and carboplatin will decrease the viability of EOC spheroids. Herein, we show that carboplatin does not impede MYXV replication or oncolytic potential in EOC cells in monolayer or spheroid culture. Administration of different sequential regimens of carboplatin and virus does not enhance sensitivity to oncolysis of EOC cell lines in monolayer culture. Furthermore, co-treatment of MYXV and carboplatin did not consistently induce oncolysis in spheroids generated from EOC cell lines or patient ascites. However, upon reattachment, spheroids treated with various combination regimens revealed additive cytopathic effects. Remarkably, we also encountered a patient sample which responded to MYXV only in the presence of carboplatin suggesting that chemotherapy-sensitive primary EOC spheroid cells are possibly eliminated by MYXV-mediated oncolysis during co-treatment. We hope to include more patient sample analyses that allow for strong pre-clinical evaluation of this combination treatment.