Preclinical evaluation of TRAIL combined with PAC-1 to control granulosa cell tumour

Abstract

Granulosa cell tumour (GCT) is a malignant sex-cord stromal cell form of ovarian cancer that constitutes ~5% of ovarian neoplasms. Current chemotherapy regimens are not effective enough in controlling recurrent GCT, and as a result ~80% of women who relapse will die of disease. Procaspase-activating compound 1 (PAC-1) is a small-molecule activator of procaspase-3 that has shown efficacy in treating several cancers either alone or in combination with other agents. Here we investigated the effectiveness of PAC-1 in treating GCT in vitro, and the amount of synergy displayed by combining PAC-1 with selected apoptosis-inducing agents. We found that while tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) was only marginally toxic to GCT, combining it with PAC-1, even at low doses, was strongly synergistic in killing an established GCT cell line. The combination was also toxic to patient samples of primary and recurrent GCT cells. Based on those results we sought to overcome known limitations in the clinical effectiveness of TRAIL through generation of a novel recombinant oncolytic vaccinia virus that secretes human TRAIL (VACVTRAIL). Infection and replication by our virus was efficient, it generated significant levels of TRAIL, and it displayed strong cytotoxicity in GCT model cell line KGN. Our attempt to develop a xenograft mouse model using KGN cells for in vivo testing of PAC-1 and VACVTRAIL was unsuccessful. While we did see small lesions in mice injected with KGN cells expressing Runx3, the extended time required for development of tumours and their small size currently limits the model’s utility as a test platform. Never the less, we propose that the novel combination of this TRAIL-expressing oncolytic virus and caspase-activator PAC-1 has potential as a GCT treatment, and warrants further investigation in models of GCT that are under development.