Abstract A41: ROR1 is associated with ovarian cancer progression and chemoresistance

Abstract

Abstract Background: New targets for ovarian cancer treatment are critically needed. The Wnt receptors ROR1 and ROR2 are overexpressed in all subtypes of ovarian cancer and appear to play a role in both the tumor and surrounding microenvironment (1). In vitro studies support the approach of targeting these receptors together to inhibit ovarian cancer migration and invasion (2, 3). Aim: To investigate the role of ROR1 and ROR2 in ovarian cancer progression, survival and chemoresistance, to determine their feasibility as therapeutic targets. Methods: Analysis of RNA-Seq data from publicly available ovarian cancer datasets was performed to determine associations with overall survival and platinum resistance. ROR1 IHC using a recently released monoclonal antibody (4A5, BD Bioscience) was performed on a cohort of ovarian cancer patients. ROR1 and/or ROR2 were silenced in a unique preclinical organotypic model of platinum-resistant ovarian cancer metastasis. Results: There is a significant increase (p=0.01) in ROR1 expression in both primary resistant and acquired resistant (p=0.03) high-grade serous ovarian cancer (HGSOC). ROR2 expression is not significantly associated with chemoresistance. High ROR1 (P=0.002, HR 1.93) or high ROR2 (P=0.004, HR 1.9) expression is associated with a significantly shorter overall survival (OS) in the Tothill cohort (4). Patients expressing both high ROR1 and high ROR2 have the shortest OS (P=0.0003, HR 2.38). ROR1 protein expression was detected in 97% of HGSOC patients via IHC, with 59% of HGSOC expressing “high ROR1” (IHC score 2 or 3). Overall, patients with higher-grade tumors expressed significantly higher ROR1 levels (P=0.001) than patients with low-grade tumors. Silencing ROR1 and ROR2 in combination inhibits adhesion and invasion of platinum resistant ovarian cancer in a 3D organotypic coculture model. Conclusion: Our data support targeting both ROR1 and ROR2 as a new approach to treating ovarian cancer. The development of a number of monoclonal antibodies targeting ROR1 and ROR2 that are currently in phase 1 trials for other tumor types makes this clinically feasible in the future. These data also suggest that this may be most effective in the context of HGSOC with platinum resistance.