Abstract C032: A novel integrin-targeted therapeutic agent for ovarian cancer

Abstract

Abstract No present therapy effectively impacts overall survival of advanced ovarian cancer (OC). The current standard-of-care includes surgical debulking followed by combination intravenous (IV) or intraperitoneal (IP) chemotherapy. Although there is increasing interest in IP chemotherapy, side effects from cytotoxic agents result in a significant percentage of women discontinuing treatment. We propose to examine the efficacy of IP administration of a novel non-cytotoxic, non-immunogenic, anti-invasive peptide called vicrostatin (Mol. Wt. 7,146). We investigated the clinical translational potential of this disintegrin, which was conceived, produced and developed in our laboratory. Vicrostatin is produced recombinantly using a bacterial system in amounts sufficient for clinical trials. It has high binding affinity for a number of RGD (Arg-Gly-Asp)-integrins, including αvβ3, αvβ5, α5β1 and αIIbβ3. Vicrostatin disruption of the actin cytoskeleton, which occurs exclusively in motile cells (cancer and angiogenic endothelial cells), accounts for its mechanism of action. We showed lack of toxicity following vicrostatin introduction into rodents. We used several different experimental animal models to demonstrate the efficacy of vicrostatin in ovarian cancer. We compared saline and Oxiplex formulations for IP delivery of vicrostatin in mouse models. Oxiplex, a hydrogel composed of polyethylene oxide and carboxymethyl cellulose, stabilized by CaCl2, is impregnated with vicrostatin; incorporation of vicrostatin at 2-10 mg/ml results in its sustained release for 10-12 days. We eventually settled on a 5 mg/week (250mg/kg) dose per mouse and compared efficacies of Oxiplex versus saline in animals harboring IP xenografts (10 animals per group) of SKOV3GFP/LUC spheroids (2x106 cell equivalents); the spheroids were allowed to implant for 4 days before treatment with weekly IP injections of either 5 mg of vicrostatin in 1 ml saline, 5mg of vicrostatin in 1 ml of Oxiplex, or 1 ml of Oxiplex alone (control). After one-month animals in Oxiplex alone group showed extensive and widespread cancer cell dissemination based on bioluminescent imaging and findings at autopsy. Vicrostatin-saline and vicrostatin-Oxiplex treatments resulted in dramatically less or, in some animals, no grossly visible tumor foci and in ~95-98% reduction in bioluminescent signals. These results were reproduced in three independent experiments and suggest that both delivery modalities are similarly effective. An advantage of the Oxiplex formulation is its ability to prevent post-surgical adhesions, a frequent complication of gynecological surgery. We are presently using RNAseq technologies to investigate changes in expression of genes involved in intracellular pathways suspected to represent predictive biomarkers of ovarian cancer response to vicrostatin therapy in xenografts of SKOV3 ovarian cancer cells. The results will enhance our understanding of pathways targeted by vicrostatin and provide biomarkers of clinical responsiveness in future clinical trials. Citation Format: Franics S Markland, Steve Swenson, Radu Minea, Louis Dubeau. A novel integrin-targeted therapeutic agent for ovarian cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C032. doi:10.1158/1535-7163.TARG-19-C032