# Rational Design of Non-Toxic Multidrug Combinations Demonstrates Durable and Hypoxia-Enhanced Efficacy Against Renal Cell Carcinoma

## TL;DR

Researchers designed non-toxic drug combinations that effectively target kidney cancer, especially under low oxygen conditions, offering a promising new treatment approach.

## Contribution

The study introduces a novel methodology for designing non-toxic multidrug combinations that show enhanced efficacy in hypoxic conditions.

## Key findings

- Optimized drug combinations (ODCs) containing crizotinib, telaglenastat, U-104, and vismodegib showed non-toxic effects in hepatic, renal, and cardiac cellular models.
- Anti-tumor activity of ODCs was significantly enhanced under hypoxic conditions, reaching up to 77% in 2D and 62% in 3D spheroid models.
- Chronic exposure to ODCs led to durable responses in RCC cell lines, suggesting prolonged therapeutic effects.

## 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.