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Depletion of Mouse Cells from Human Tumor Xenografts Significantly Improves Downstream Analysis of Target Cells
Published on: July 29, 2016
Systematic repurposing screening in xenograft models identifies approved drugs with novel anti-cancer activity
Jeffrey J Roix1, S D Harrison2, Elizabeth A Rainbolt2
1BioMed Valley Discoveries Inc., Kansas City, Missouri, United States of America.
Abstract:
Approved drugs target approximately 400 different mechanisms of action, of which as few as 60 are currently used as anti-cancer therapies. Given that on average it takes 10-15 years for a new cancer therapeutic to be approved, and the recent success of drug repurposing for agents such as thalidomide, we hypothesized that effective, safe cancer treatments may be found by testing approved drugs in new therapeutic settings. Here, we report in-vivo testing of a broad compound collection in cancer xenograft models. Using 182 compounds that target 125 unique target mechanisms, we identified 3 drugs that displayed reproducible activity in combination with the chemotherapeutic temozolomide. Candidate drugs appear effective at dose equivalents that exceed current prescription levels, suggesting that additional pre-clinical efforts will be needed before these drugs can be tested for efficacy in clinical trials. In total, we suggest drug repurposing is a relatively resource-intensive method that can identify approved medicines with a narrow margin of anti-cancer activity.
Insights
Drug repurposing offers a path to new cancer treatments. Researchers identified 3 approved drugs showing promise when combined with temozolomide in preclinical cancer models.
Area of Science:
- Oncology
- Pharmacology
- Drug Discovery
Background:
- Limited number of drug mechanisms currently used in anti-cancer therapies.
- Significant time and cost associated with developing novel cancer therapeutics.
- Successful precedent of drug repurposing, exemplified by thalidomide.
Purpose of the Study:
- To investigate the potential of repurposing approved drugs for novel anti-cancer applications.
- To identify existing medications that can be effectively combined with chemotherapy.
Main Methods:
- In-vivo testing of a diverse compound library (182 compounds, 125 mechanisms) in cancer xenograft models.
- Evaluation of drug combinations, specifically with the chemotherapeutic agent temozolomide.
Main Results:
- Identification of 3 drugs demonstrating reproducible anti-cancer activity in combination therapy.
- Observed efficacy at dose levels potentially exceeding current therapeutic ranges, necessitating further preclinical investigation.
- Drug repurposing identified approved medicines with a narrow therapeutic window for anti-cancer activity.
Conclusions:
- Drug repurposing is a viable, albeit resource-intensive, strategy for discovering new cancer treatments.
- Further preclinical studies are required to validate the identified drug candidates for clinical trials.
- Approved drugs can be repurposed to target cancer, expanding therapeutic options.
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