Hsp90: a novel target for cancer therapy.
Hsp90 is a molecular chaperone required for the stress-survival response, protein refolding, and the conformational maturation of a variety of signaling proteins. Natural products that bind selectively to Hsp90 and inhibit its function have been used to determine its biologic role. Experiments with these drugs have shown that Hsp90 is required for maintaining the malignant phenotype of cancer cells. Studies in vivo show that Hsp90 inhibitors have antitumor activity when given alone and in combination with cytotoxics. The basis for the therapeutic index (selective toxicity to cancer cells) of Hsp90 inhibitors is complex and may have to do with induction of degradation of mutant oncoproteins and other proteins necessary for their proliferation and survival as well as to an enhanced requirement of these cells for Hsp90 stress-survival functions. Based on these data, 17-AAG, an ansamycin antibiotic inhibitor of Hsp90, is being tested extensively in clinical trials in patients with advanced cancer. These trials demonstrate that the biologic function of Hsp90 can be inhibited in patients and antitumor activity has been noted in patients with breast cancer, multiple myeloma and other cancers. These data and the physicochemical properties of 17-AAG that limit its use as a drug, have led to broad efforts to develop improved and novel Hsp90 inhibitors. This article will review the preclinical data which supports the testing of Hsp90 inhibitors as cancer drugs and update the reader on the current status of the ongoing clinical trials of Hsp90 inhibitors.
Solit
David B
DB
Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA. solitd@mskcc.org
Rosen
Neal
N
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D003131:Combined Modality Therapy; D015195:Drug Design; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins