title: Systematic repurposing screening in xenograft models identifies approved drugs with novel anti-cancer activity.
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.
authors.affiliation: BioMed Valley Discoveries Inc., Kansas City, Missouri, United States of America.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Roix
authors.affiliation: Charles River Discovery Research Services, Morrisville, North Carolina, United States of America.
authors.forename: S D
authors.initials: SD
authors.lastname: Harrison
authors.affiliation: Charles River Discovery Research Services, Morrisville, North Carolina, United States of America.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Rainbolt
authors.affiliation: Charles River Discovery Research Services, Morrisville, North Carolina, United States of America.
authors.forename: Kathryn R
authors.initials: KR
authors.lastname: Meshaw
authors.affiliation: Charles River Discovery Research Services, Morrisville, North Carolina, United States of America.
authors.forename: Avery S
authors.initials: AS
authors.lastname: McMurry
authors.affiliation: BioMed Valley Discoveries Inc., Kansas City, Missouri, United States of America.
authors.forename: Peter
authors.initials: P
authors.lastname: Cheung
authors.affiliation: BioMed Valley Discoveries Inc., Kansas City, Missouri, United States of America.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Saha
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000302:isolation & purification* / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000627:therapeutic use; D001713:Biphenyl Compounds; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000627:therapeutic use; D017277:Drug Approval; D058492:Drug Repositioning / Q000379:methods*; D012968:Etidronic Acid / Q000031:analogs & derivatives / Q000627:therapeutic use; D005260:Female; D057166:High-Throughput Screening Assays / Q000379:methods; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008822:Mice, Transgenic; D009369:Neoplasms / Q000188:drug therapy*; D000068296:Risedronic Acid; D000077204:Temozolomide; D013777:Tetrazoles / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D013777:Tetrazoles; D003606:Dacarbazine; D000068296:Risedronic Acid; D012968:Etidronic Acid; C081643:candesartan; D000077204:Temozolomide
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