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Published on: March 28, 2021
Rapid screening of novel agents for combination therapy in sarcomas
Christopher L Cubitt1, Jiliana Menth, Jana Dawson
1Chemical Biology and Molecular Medicine, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA ; Translational Research Lab, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA.
Abstract:
For patients with sarcoma, metastatic disease remains very difficult to cure, and outcomes remain less than optimal. Treatment options have not largely changed, although some promising gains have been made with single agents in specific subtypes with the use of targeted agents. Here, we developed a system to investigate synergy of combinations of targeted and cytotoxic agents in a panel of sarcoma cell lines. Agents were investigated alone and in combination with varying dose ratios. Dose-response curves were analyzed for synergy using methods derived from Chou and Talalay (1984). A promising combination, dasatinib and triciribine, was explored in a murine model using the A673 cell line, and tumors were evaluated by MRI and histology for therapy effect. We found that histone deacetylase inhibitors were synergistic with etoposide, dasatinib, and Akt inhibitors across cell lines. Sorafenib and topotecan demonstrated a mixed response. Our systematic drug screening method allowed us to screen a large number of combinations of sarcoma agents. This method can be easily modified to accommodate other cell line models, and confirmatory assays, such as animal experiments, can provide excellent preclinical data to inform clinical trials for these rare malignancies.
Insights
Researchers developed a drug screening system to find synergistic combinations for sarcoma treatment. Histone deacetylase inhibitors showed promise when combined with other agents, offering new therapeutic strategies for metastatic sarcoma.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Metastatic sarcoma remains challenging to treat, with limited curative options.
- Current treatment strategies for sarcoma have seen minimal advancement, despite the emergence of targeted agents for specific subtypes.
- Optimizing therapeutic outcomes for sarcoma patients necessitates novel treatment approaches.
Purpose of the Study:
- To develop and implement a systematic drug screening system for evaluating synergistic combinations of targeted and cytotoxic agents in sarcoma.
- To identify effective drug combinations that can overcome treatment resistance in various sarcoma subtypes.
- To provide preclinical data to guide the development of clinical trials for rare sarcoma malignancies.
Main Methods:
- A panel of sarcoma cell lines was utilized to screen combinations of targeted and cytotoxic agents.
- Dose-response curves were analyzed for synergy using established Chou and Talalay methods.
- A promising combination (dasatinib and triciribine) was further evaluated in a murine sarcoma model (A673 cell line).
Main Results:
- Histone deacetylase inhibitors demonstrated synergistic effects when combined with etoposide, dasatinib, and Akt inhibitors across multiple sarcoma cell lines.
- The combination of dasatinib and triciribine showed therapeutic effects in a murine model, confirmed by MRI and histological analysis.
- Sorafenib and topotecan exhibited a mixed response in the drug screening assays.
Conclusions:
- The developed systematic drug screening method is effective for identifying synergistic drug combinations for sarcoma.
- Histone deacetylase inhibitors represent a promising class of agents for combination therapy in sarcoma.
- Preclinical data from this systematic approach, including animal experiments, can inform future clinical trials for sarcoma patients.
