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Cytotoxic Efficacy of Photodynamic Therapy in Osteosarcoma Cells In Vitro
Published on: March 18, 2014
Identification of Synergistic, Clinically Achievable, Combination Therapies for Osteosarcoma
Diana Yu1,2, Elliot Kahen1,2, Christopher L Cubitt2
1Sunshine Lab, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612 Florida USA.
Abstract:
Systemic therapy has improved osteosarcoma event-free and overall survival, but 30-50% of patients originally diagnosed will have progressive or recurrent disease, which is difficult to cure. Osteosarcoma has a complex karyotype, with loss of p53 in the vast majority of cases and an absence of recurrent, targetable pathways. In this study, we explored 54 agents that are clinically approved for other oncologic indications, agents in active clinical development, and others with promising preclinical data in osteosarcoma at clinically achievable concentrations in 5 osteosarcoma cell lines. We found significant single-agent activity of multiple agents and tested 10 drugs in all permutations of two-drug combinations to define synergistic combinations by Chou and Talalay analysis. We then evaluated order of addition to choose the combinations that may be best to translate to the clinic. We conclude that the repurposing of chemotherapeutics in osteosarcoma by using an in vitro system may define novel drug combinations with significant in vivo activity. In particular, combinations of proteasome inhibitors with histone deacetylase inhibitors and ixabepilone and MK1775 demonstrated excellent activity in our assays.
Insights
This study explored repurposing drugs for osteosarcoma treatment. Combinations of proteasome inhibitors with histone deacetylase inhibitors, ixabepilone, and MK1775 showed significant activity against this difficult-to-treat cancer.
Area of Science:
- Oncology
- Pharmacology
- Cancer Biology
Background:
- Systemic therapy has improved outcomes for osteosarcoma patients, yet a significant percentage experience progressive or recurrent disease.
- Osteosarcoma is characterized by a complex karyotype, frequent p53 loss, and a lack of recurrent, targetable pathways, complicating treatment.
- Effective therapeutic strategies for recurrent or refractory osteosarcoma remain a critical unmet need.
Purpose of the Study:
- To identify novel drug combinations for osteosarcoma by repurposing existing and investigational agents.
- To evaluate the efficacy of single agents and drug combinations in osteosarcoma cell lines.
- To determine synergistic drug combinations and optimal sequences for potential clinical translation.
Main Methods:
- Screened 54 clinically approved or investigational agents against 5 osteosarcoma cell lines at achievable concentrations.
- Assessed single-agent activity and performed Chou and Talalay analysis for synergistic effects in two-drug combinations.
- Evaluated the order of drug addition to identify optimal combination strategies for clinical application.
Main Results:
- Identified significant single-agent activity for multiple tested agents in osteosarcoma cell lines.
- Discovered synergistic activity in various two-drug combinations, with specific emphasis on proteasome inhibitors and histone deacetylase inhibitors.
- Ixabepilone and MK1775 combinations demonstrated particularly strong efficacy in in vitro assays.
Conclusions:
- Drug repurposing in osteosarcoma using in vitro systems can identify novel, effective drug combinations.
- Combinations of proteasome inhibitors with histone deacetylase inhibitors, ixabepilone, and MK1775 represent promising therapeutic strategies for osteosarcoma.
- These findings support further investigation of these drug combinations for in vivo efficacy and potential clinical translation in osteosarcoma.
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