Cancer is a disease characterized by genetic instability. Although identification of novel therapeutic agents via molecular targeting offers the promise of great specificity coupled with reduced systemic toxicity, specific inhibition of individual proteins or signaling pathways faces the potential peril of being subverted by the inherent genetic plasticity of cancer cells. Cancer cells are very adept at adapting to noxious environments. Thus, hormone-dependent tumors eventually become hormone-independent, either by receptor mutation or via activation of alternative pathways leading to receptor stimulation. Similarly, cancer cells exposed to initially fatal levels of chemotherapy eventually activate multiple and overlapping signaling pathways to protect themselves from further harm, while tumors deprived of oxygen upregulate a multifaceted transcriptional response that allows them to cope successfully with the hypoxic state.

If one assumes that cancer cells are always under moderate to severe stress of one type or another, an approach to this apparent dilemma might be to target the basic machinery that allows cancer cells to adapt so successfully to stress. Cells respond to stress by increasing synthesis of a number of molecular chaperones (also known as heat shock proteins, or Hsps, because they were first observed in cells exposed to elevated temperature). These housekeeping proteins, as their name implies, assist general protein folding and prevent nonfunctional side reactions such as the nonspecific aggregation of misfolded or unfolded proteins. However, within the last decade, one chaperone in particular, heat shock protein 90 (Hsp90), has emerged as being of prime importance to the survival of cancer cells. Hsp90 is constitutively expressed at 2-to 10-fold higher levels in tumor cells compared to their normal counterparts, suggesting that it may be critically important for tumor cell growth and/or survival. A small molecule inhibitor of Hsp90, the benzoquinone ansamycin 17-allylamino-17-desmethoxygeldanamycin (17-AAG), has shown antitumor activity in several human xenograft models, including colon, breast, and prostate cancer (Basso et al., 2002; Kelland et al., 1999; Solit et al., 2002). The drug is currently completing multi-institution phase I clinical trials, and phase II trials are being planned. Other Hsp90 inhibitors are also at various stages of development. For a detailed review of Hsp90 inhibitor drug development, including a discussion of pharmacodynamic endpoints, see the recent review by Maloney and Workman (2002). Why has this molecular target garnered so much recent interest?