Systematic repurposing screening in xenograft models identifies approved drugs with novel anti-cancer activity

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...

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Published in:PloS one 2014-08, Vol.9 (8), p.e101708
Main Authors: Roix, Jeffrey J, Harrison, S D, Rainbolt, Elizabeth A, Meshaw, Kathryn R, McMurry, Avery S, Cheung, Peter, Saha, Saurabh
Format: Article
Language:English
Subjects:
Animals
Anticancer properties
Antineoplastic Agents - isolation & purification
Antineoplastic Agents - therapeutic use
Benzimidazoles - therapeutic use
Biology and Life Sciences
Cancer
Cancer therapies
Cell Line, Tumor
Chemotherapy
Clinical trials
Dacarbazine - analogs & derivatives
Dacarbazine - therapeutic use
Drug Approval
Drug development
Drug dosages
Drug Repositioning - methods
Drugs
Etidronic Acid - analogs & derivatives
Etidronic Acid - therapeutic use
Experiments
Female
High-Throughput Screening Assays - methods
Humans
Male
Medical research
Medical screening
Medicine and Health Sciences
Mice
Mice, Inbred C57BL
Mice, Nude
Mice, Transgenic
Neoplasms - drug therapy
Prescription drugs
Risedronate Sodium
Studies
Survival analysis
Target recognition
Temozolomide
Tetrazoles - therapeutic use
Thalidomide
Xenograft Model Antitumor Assays
Xenografts
Xenotransplantation
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cited_by cdi_FETCH-LOGICAL-c526t-6b6afc1d8b12f678eced2924f11ec0b12805f50a750a7b5c1bd33086bf34d4343
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creator Roix, Jeffrey J
Harrison, S D
Rainbolt, Elizabeth A
Meshaw, Kathryn R
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Cheung, Peter
Saha, Saurabh
description 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.
doi_str_mv 10.1371/journal.pone.0101708
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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. 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subjects Animals
Anticancer properties
Antineoplastic Agents - isolation & purification
Antineoplastic Agents - therapeutic use
Benzimidazoles - therapeutic use
Biology and Life Sciences
Cancer
Cancer therapies
Cell Line, Tumor
Chemotherapy
Clinical trials
Dacarbazine - analogs & derivatives
Dacarbazine - therapeutic use
Drug Approval
Drug development
Drug dosages
Drug Repositioning - methods
Drugs
Etidronic Acid - analogs & derivatives
Etidronic Acid - therapeutic use
Experiments
Female
High-Throughput Screening Assays - methods
Humans
Male
Medical research
Medical screening
Medicine and Health Sciences
Mice
Mice, Inbred C57BL
Mice, Nude
Mice, Transgenic
Neoplasms - drug therapy
Prescription drugs
Risedronate Sodium
Studies
Survival analysis
Target recognition
Temozolomide
Tetrazoles - therapeutic use
Thalidomide
Xenograft Model Antitumor Assays
Xenografts
Xenotransplantation
title Systematic repurposing screening in xenograft models identifies approved drugs with novel anti-cancer activity
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