A Novel 3D High‐Throughput Phenotypic Drug Screening Pipeline to Identify Drugs with Repurposing Potential for the Treatment of Ovarian Cancer

Ovarian cancer's high recurrence and therapy resistance demand new strategies. A high-throughput drug screening pipeline using 3D spheroids, which showed poor concordance with 2D models, identified rapamycin as a promising candidate. In combination with cisplatin, rapamycin demonstrated significant in vitro and in vivo efficacy, highlighting the potential of drug repurposing in ovarian cancer treatment.t.

Abstract

Ovarian cancer (OC) poses a significant clinical challenge due to its high recurrence rates and resistance to standard therapies, particularly in advanced stages where recurrence is common, and treatment is predominantly palliative. Personalized treatments, while effective in other cancers, remain underutilized in OC due to a lack of reliable biomarkers predicting clinical outcomes. Accordingly, precision medicine approaches are limited, with PARP inhibitors showing efficacy only in specific genetic contexts. Drug repurposing offers a promising, rapidly translatable strategy by leveraging existing pharmacological data to identify new treatments for OC. Patient-derived polyclonal spheroids, isolated from ascites fluid closely mimic the clinical behavior of OC, providing a valuable model for drug testing. Using these spheroids, a high-throughput drug screening pipeline capable of evaluating both cytotoxicity and anti-migratory properties of a diverse drug library, including FDA-approved, investigational, and newly approved compounds is developed. The findings highlight the importance of 3D culture systems, revealing a poor correlation between drug efficacy in traditional 2D models and more clinically relevant 3D spheroids. This approach has expedited the identification of promising candidates, such as rapamycin, which demonstrated limited activity as a monotherapy but synergized effectively with standard treatments like cisplatin and paclitaxel in vitro. In combination with platinum-based therapy, Rapamycin led to significant in vitro cytotoxicity and a marked reduction in tumor burden in a syngeneic in vivo model. This proof-of-concept study underscores the potential of drug repurposing to rapidly advance new treatments into clinical trials for OC, offering renewed hope for patients with advanced disease.