Drugs that target a single signaling pathway that drives tumor development and/or progression have been developed successfully to treat a few forms of cancer. However, in many cases drugs designed using this approach have not worked. Dario Altieri and colleagues, at the University of Massachusetts Medical School, Worcester, have now addressed this issue by using a combinatorial approach to drug design.
The research is published Feb. 23, 2009, in the Journal of Clinical Investigation.
The authors developed small molecules, which they termed Gamitrinibs, that target Hsp90, a protein that controls the folding of proteins in multiple signaling networks that drive tumor development and progression. In addition to targeting a protein that controls multiple signaling pathways, the authors designed the drugs to target one specific cellular compartment in which Hsp90 is active in tumor cells, mitochondria. Importantly, treatment with these drugs effectively induced tumor cell death in mice transplanted with human tumor cell lines.
The authors therefore conclude that combinatorial drug design, whereby inhibitors of signaling networks are targeted to specific cellular compartments, may prove a more effective strategy for developing anticancer drugs than targeting single signaling pathways.
In an accompanying commentary, Nesrin Özören and colleagues, at Bogaziçi University, Turkey, highlight the novelty and clinical potential of this approach.
- Kang et al. Combinatorial drug design targeting multiple cancer signaling networks controlled by mitochondrial Hsp90. Journal of Clinical Investigation, 2009; DOI: 10.1172/JCI37613
- Çiǧdem Atay, Serkan Uǧurlu, Nesrin Özören. Shock the heat shock network. J. Clin. Invest., 2009; DOI: 10.1172/JCI38681
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