Rational Design of Non-Toxic Multidrug Combinations Demonstrates Durable and Hypoxia-Enhanced Efficacy Against Renal
Valentin Mieville1,2,3, Jakub Gubala1,2,3, Mathis Fiault1,2,3
1School of Pharmaceutical Sciences, Faculty of Science, University of Geneva, 1211 Geneva, Switzerland.
Abstract:
Background/Objectives: Despite recent therapeutic advances, the clinical management of renal cell carcinoma (RCC) remains suboptimal. Current treatments are hindered by limited efficacy, the emergence of acquired drug resistance, suboptimal tolerability, and a lack of tumor-specific targeting. While development of novel agents remains an important avenue, it is often constrained by high costs, long development time, and low success rates. As an alternative approach, drug combinations of approved agents offer a promising strategy. Methods: Using our proprietary drug combination methodology, we identified multidrug combinations in RCC cells representing the clear cell (786O) and sarcomatoid chromophobe (UOK276) histological subtypes of RCC. Results: From an initial panel of 10 drugs, either approved or undergoing clinical trial, the optimized drug combinations (ODCs) contained crizotinib, telaglenastat, U-104, and vismodegib at clinical and subtherapeutic doses. The ODCs were non-toxic in advanced hepatic, renal, and cardiac cellular models. Importantly, their anti-tumor activity, already notable in normoxic (21% O2) conditions (approx. 50%) was markedly enhanced in tumor-relevant hypoxia (1.5% O2), reaching up to 77% in 2D and 62% in 3D spheroid 786O models. Moreover, chronic exposure of 786O and UOK276 cells led to durable responses, suggesting a prolonged effect in responders. Conclusions: Our findings demonstrate the potential of optimized, non-toxic drug combinations as a highly selective and effective strategy for accelerating the development of precision RCC treatment.
Insights
Optimized drug combinations (ODCs) show promise for renal cell carcinoma (RCC) treatment. These non-toxic combinations are effective, especially in hypoxic conditions, offering a faster path to precision medicine for RCC patients.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Renal cell carcinoma (RCC) management is suboptimal due to limited treatment efficacy, drug resistance, and poor targeting.
- Novel drug development for RCC is costly, time-consuming, and has low success rates.
- Drug combinations of approved agents present a viable alternative strategy.
Purpose of the Study:
- To identify optimized multidrug combinations (ODCs) for renal cell carcinoma (RCC).
- To evaluate the efficacy and safety of these ODCs in RCC cell lines.
- To assess the impact of hypoxia on ODC anti-tumor activity.
Main Methods:
- Utilized a proprietary drug combination methodology to screen potential ODCs in RCC cell subtypes (786O and UOK276).
- Evaluated combinations of approved or investigational drugs, including crizotinib, telaglenastat, U-104, and vismodegib.
- Assessed ODC toxicity in hepatic, renal, and cardiac cellular models and anti-tumor activity under normoxic and hypoxic conditions.
Main Results:
- Identified ODCs containing crizotinib, telaglenastat, U-104, and vismodegib at clinical and subtherapeutic doses.
- ODCs demonstrated non-toxicity in advanced hepatic, renal, and cardiac cellular models.
- Anti-tumor activity was significantly enhanced under hypoxia (up to 77% in 2D and 62% in 3D spheroid models) compared to normoxia (approx. 50%).
- Chronic exposure led to durable responses in RCC cells, suggesting prolonged efficacy.
Conclusions:
- Optimized, non-toxic drug combinations offer a highly selective and effective strategy for RCC treatment.
- This approach can accelerate the development of precision medicine for renal cell carcinoma.
- The enhanced efficacy under hypoxia highlights the importance of targeting tumor microenvironment conditions.
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