Mathematical modeling predicts pathways to successful implementation of combination TRAIL-producing oncolytic virus and PAC-1 to treat granulosa cell tumors of the ovary

Abstract

ABSTRACT The development of new cancer therapies requires multiple rounds of validation from in vitro and in vivo experiments before they can be considered for clinical trials. Mathematical models assist in this preclinical phase by combining experimental data with human parameters to provide guidance about potential therapeutic regimens to bring forward into trials. However, granulosa cell tumors of the ovary lack a relevant mouse model, complexifying preclinical drug development for this rare tumor. To bridge this gap, we established a mathematical model as a framework to explore the potential of using a tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-producing oncolytic vaccinia virus in combination with the chemotherapeutic agent first procaspase activating compound (PAC-1). We have previously shown that TRAIL and PAC-1 act synergistically on granulosa tumor cells. In line with our previous results, our current model predicts that, although it is unable to stop the tumor from growing in its current form, combination oral PAC-1 with oncolytic virus (OV) provides the best result compared to monotherapies. Encouragingly, our results suggest that increases to the OV infection rate can lead to the success of this combination therapy within a year. The model developed here can continue to be improved as more data become available, allowing for regimen-tailoring via virtual clinical trials, ultimately shepherding effective regimens into trials.