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Drug Repurposing to Identify a Synergistic High-Order Drug Combination to Treat Sunitinib-Resistant Renal Cell
Magdalena Rausch1,2,3, Adriano Rutz1,2, Pierre-Marie Allard1,2
1School of Pharmaceutical Sciences, University of Geneva, CMU-Rue Michel-Servet 1, CH-1211 Geneva, Switzerland.
Abstract:
Repurposed drugs have been evaluated for the management of clear cell renal cell carcinoma (ccRCC), but only a few have influenced the overall survival of patients with advanced disease. To combine repurposed non-oncology with oncological drugs, we applied our validated phenotypic method, which consisted of a reduced experimental part and data modeling. A synergistic optimized multidrug combination (ODC) was identified to significantly reduce the energy levels in cancer remaining inactive in non-cancerous cells. The ODC consisted of Rapta-C, erlotinib, metformin and parthenolide and low doses. Molecular and functional analysis of ODC revealed a loss of adhesiveness and induction of apoptosis. Gene-expression network analysis displayed significant alterations in the cellular metabolism, confirmed by LC-MS based metabolomic analysis, highlighting significant changes in the lipid classes. We used heterotypic in vitro 3D co-cultures and ex vivo organoids to validate the activity of the ODC, maintaining an efficacy of over 70%. Our results show that repurposed drugs can be combined to target cancer cells selectively with prominent activity. The strong impact on cell adherence and metabolism indicates a favorable mechanism of action of the ODC to treat ccRCC.
Insights
Repurposed drugs, including Rapta-C, erlotinib, metformin, and parthenolide, form an optimized multidrug combination (ODC) that selectively targets clear cell renal cell carcinoma (ccRCC) by reducing cancer cell energy and inducing apoptosis.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Clear cell renal cell carcinoma (ccRCC) management has limited options for advanced disease.
- Repurposed drugs show potential but require optimized combination strategies.
Purpose of the Study:
- To develop a synergistic optimized multidrug combination (ODC) of repurposed drugs for ccRCC.
- To evaluate the efficacy and mechanism of action of the ODC in ccRCC treatment.
Main Methods:
- Validated phenotypic screening with data modeling to identify synergistic drug combinations.
- Molecular and functional analyses including gene-expression and LC-MS metabolomics.
- In vitro 3D co-cultures and ex vivo organoid validation.
Main Results:
- An ODC comprising Rapta-C, erlotinib, metformin, and parthenolide at low doses was identified.
- The ODC selectively reduced cancer cell energy levels, induced apoptosis, and decreased cell adhesion.
- Metabolomic analysis revealed significant alterations in lipid metabolism within cancer cells.
- The ODC demonstrated over 70% efficacy in validated in vitro and ex vivo models.
Conclusions:
- Repurposed drugs can be effectively combined to create a potent ODC for ccRCC.
- The ODC exhibits selective targeting of cancer cells through metabolic disruption and apoptosis induction.
- The ODC shows promise as a novel therapeutic strategy for advanced ccRCC.
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