Wednesday, April 2, 2025
4/2/2025
Repurposing Auranofin As a Novel Notch Pathway Inhibitor for Combinational Ovarian Cancer Therapy - Ovarian cancer is the deadliest gynecologic cancer, with ~20,000 new cases predicted for 2023. Although first-line treatment with a platinum compound and taxane yields a response rate of more than 80% in advanced ovarian cancer, the median time of progression-free survival is only 18 months. Retreatment can be performed after relapse, but chemoresistance becomes a major issue. Therefore, new options for the treatment of both primary and relapsed ovarian cancer are urgently needed. The Notch signaling pathway regulates cell proliferation and differentiation. Aberrant Notch activation plays roles in the initiation, progression, and chemoresistance of a variety of cancer types. Data from The Cancer Genome Atlas reveal that Notch-pathway aberrations associate with 22% of high-grade serous ovarian cancer, and Notch pathway disruption can sensitize ovarian tumor cells to platinum-based therapy. Accordingly, drugs that inhibit Notch signaling will be of great value for treatment of Notch-associated ovarian cancers. To date, the utility of Notch-pathway inhibitors is limited by dose-dependent and off-target toxicities. Most Notch inhibition strategies have focused on the level Notch receptor activation. We hypothesized that modulating the interaction of RBPJ, the sole Notch transcriptional effector, with its gene targets would provide a means to intervene in all Notch-associated cancers, regardless of the mechanisms of aberrant pathway activation. We discovered that the FDA-approved drug auranofin is a potent Notch pathway inhibitor. Moreover, we found that auranofin interacts synergistically with cisplatin, preferentially reducing the viability of high Notch-expressing ovarian cancer cells. In this proposed study, we will use different preclinical models to test the utility of auranofin and cisplatin cotreatment for targeted ovarian cancer therapy. We will use a collection of ovarian cancer cell lines to examine how levels of the different Notch receptors and ligands impact the auranofin response. We will also use patient-derived tumor organoids (PDO) and patient- derived xenograft (PDX) mouse models to examine auranofin and cisplatin synergy in 3-D culture and the peritoneal environment. We will also study how auranofin impacts cancer stem-cell expansion and cancer relapse. The impact of these studies, if successful, will be significant, as our proposal has the potential to repurpose an FDA-approved agent for immediate deployment in targeted therapy of both primary and relapsed ovarian cancers that are Notch-dependent.
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