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A Novel 3D High-Throughput Phenotypic Drug Screening Pipeline to Identify Drugs with Repurposing Potential for the
Nazanin Karimnia1,2, Amy L Wilson1,2, Brittany R Doran1,2
1Hudson Institute of Medical Research, 27-31 Wright St, Clayton, VIC, 3168, Australia.
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.
Insights
Drug repurposing using patient-derived ovarian cancer spheroids identified rapamycin as a promising combination therapy. This approach accelerates the discovery of new ovarian cancer treatments, offering hope for advanced disease.
Area of Science:
- Oncology
- Drug Discovery
- Biomedical Engineering
Background:
- Ovarian cancer (OC) presents a significant clinical challenge with high recurrence and resistance to therapies, limiting personalized medicine due to a lack of predictive biomarkers.
- Current precision medicine in OC is restricted, with treatments like PARP inhibitors effective only in specific genetic subsets.
- Drug repurposing offers a viable strategy to accelerate the identification of novel OC treatments by utilizing existing drug data.
Purpose of the Study:
- To develop and validate a high-throughput drug screening pipeline using patient-derived ovarian cancer spheroids for identifying novel therapeutic strategies.
- To evaluate the efficacy of drug repurposing for ovarian cancer, focusing on identifying compounds that can overcome treatment resistance.
- To assess the correlation between drug efficacy in 2D versus 3D spheroid models and identify synergistic drug combinations.
Main Methods:
- Established patient-derived polyclonal spheroids from ovarian cancer ascites fluid to model the disease's clinical behavior.
- Developed a high-throughput screening pipeline to assess drug cytotoxicity and anti-migratory effects on 3D spheroids.
- Evaluated a diverse drug library, including FDA-approved and investigational agents, and tested promising candidates in combination with standard therapies in vitro and in vivo.
Main Results:
- Demonstrated a poor correlation between drug efficacy in traditional 2D cell cultures and clinically relevant 3D spheroid models.
- Identified rapamycin as a potential therapeutic agent, showing limited efficacy alone but significant synergy with cisplatin and paclitaxel in vitro.
- Rapamycin combined with platinum-based therapy resulted in substantial in vitro cytotoxicity and reduced tumor burden in a syngeneic in vivo model.
Conclusions:
- Patient-derived 3D spheroid models are crucial for accurate drug screening in ovarian cancer, outperforming traditional 2D methods.
- Drug repurposing, exemplified by rapamycin's synergistic effects, presents a rapid and translatable strategy for advancing ovarian cancer treatments.
- This approach holds promise for accelerating the clinical translation of new therapies for patients with advanced ovarian cancer.
