Effects of a novel proteasome inhibitor, UR238 on the tumor immune microenvironment and growth in epithelial ovarian cancer

Abstract

High-grade serous ovarian cancer (HGSOC) is a deadly gynecologic malignancy, often diagnosed at an advanced stage and most patients will experience recurrence and resistance to platinum-based chemotherapy. While there are few targeted therapies available for HGSOC, there are no effective immunotherapies available to treat this disease. The ubiquitin-proteasome system (UPS) maintains cellular protein homeostasis by degrading misfolded or damaged proteins. In epithelial ovarian cancer (EOC) elevated expression of proteasome subunit PSMB4 correlates with epithelial ovarian cancer growth and poor prognosis. A proteasome inhibitor has yet to be approved for EOC treatment despite evidence of activity in phase-1/2 clinical trials. Limitations of past generation proteosome inhibitors include sub-optimal solid tumor/tissue penetration due to boronic acid functionality, and poor solubility. Here, we show that a novel proteasome inhibitor, UR238, suppresses viability of several EOC cell lines and reduces tumor burden in both murine xenograft and rat syngeneic models. In a rat EOC model, UR238 treatment reduced tumor burden, shifted the predominantly suppressive immune microenvironment to an inflammatory phenotype with reduced suppressive macrophages, and decreased PD-L1 expression on myeloid cells. Additionally, in a mouse model, UR238 also induced robust immune changes in HGSOC bearing mice without a corresponding reduction in tumor burden. Our data highlights the promise of UR238 for the treatment of ovarian cancers as a single-agent or in combination with immunotherapies, where modulating the immune composition of these tumors will be important in improving outcomes for ovarian cancer patients.