Ketorolac and Related NSAIDs for Targeting Rho-family GTPases in Ovarian Cancer

项目总结

PROJECT SUMMARY Cheminformatics identification of R-ketorolac as a novel pharmacologic entity with Rho-family GTPase inhibitory activity for ovarian cancer motivates a two-tiered validation strategy. Preclinical and ex vivo testing will evaluate repurposed new use of the FDA approved, clinically used [R,S]-ketorolac for ovarian cancer and R-ketorolac for an Investigational New Drug filing. Rho family GTPases (Rac, Rho and Cdc42) collectively control cell proliferation, adhesion and migration and are of interest as functional therapeutic targets in numerous epithelial cancers. A virtual drug screen of -carboxylate containing drugs first predicted the R- enantiomer of the approved drug [R,S]-ketorolac as a high value, clinically relevant GTPase inhibitor. Prior to our work, the S-enantiomer was considered the sole active component in the racemic drug formulations, with selective activity against cyclooxygenases (COX) for mitigating inflammation and acute pain. GTPase activity measurements demonstrate that R-ketorolac is an allosteric inhibitor of guanine nucleotide binding, while the S-enantiomer of ketorolac shows little to no activity against GTPases. In cell-based assays, R-ketorolac blocks Rac1 and Cdc42 activation, actin remodeling and downstream cell adhesion, migration and invasion of human ovarian cancer cell lines. Human efficacy is supported by both our retrospective study demonstrating significant survival benefit and our prospective Phase 0 trial. [R,S]-ketorolac administration, has favorable pharmacokinetic distribution, reduces GTPase activities, and inhibits behaviors associated with invasion and metastasis in patient tumor cells. Based on our comprehensive published data, we hypothesize that repurposing [R,S]-ketorolac and development of R-ketorolac as an Investigational New Drug will minimize ovarian cancer relapse by inhibiting Rac1 and Cdc42 dependent tumor metastasis, and reducing protection in specialized niches to increase vulnerability to chemotherapy. A series of three aims will validate 1) the benefit of ketorolac in reducing tumor relapse using an animal xenograft model of tumor recurrence, 2) the impact of ketorolac on minimizing tumor cell-niche interactions through ex vivo organotypic and bioreactor cultures, and 3) ketorolac/ovarian cancer as a predicted therapeutic/ indication pair. These studies will inform `Go vs. No Go' decision-making for Phase 2a clinical trial implementation of [R,S] ketorolac and R-ketorolac alone in ovarian cancer patients. An additional outcome of the studies will be to enhance readiness to submit an FDA Investigational New Drug filing for R-ketorolac as a new therapy for ovarian cancer to overcome the toxicities and limitations associated with racemic drug.