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

PLoS One. 2014 Aug 5;9(8):e101708. doi: 10.1371/journal.pone.0101708. eCollection 2014.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Validation Study

MeSH terms

  • Animals
  • Antineoplastic Agents / isolation & purification*
  • Antineoplastic Agents / therapeutic use*
  • Benzimidazoles / therapeutic use
  • Cell Line, Tumor
  • Dacarbazine / analogs & derivatives
  • Dacarbazine / therapeutic use
  • Drug Approval*
  • Drug Repositioning / methods*
  • Etidronic Acid / analogs & derivatives
  • Etidronic Acid / therapeutic use
  • Female
  • High-Throughput Screening Assays / methods
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Nude
  • Mice, Transgenic
  • Neoplasms / drug therapy*
  • Risedronic Acid
  • Temozolomide
  • Tetrazoles / therapeutic use
  • Xenograft Model Antitumor Assays*

Substances

  • Antineoplastic Agents
  • Benzimidazoles
  • Tetrazoles
  • Dacarbazine
  • Risedronic Acid
  • Etidronic Acid
  • candesartan
  • Temozolomide

Grant support

All studies were sponsored and funded by BioMed Valley Discoveries, Inc. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.