The clinical applications of heat shock protein inhibitors in cancer - present and future.
The potential clinical applications of the prototype first-in-class Hsp90 inhibitor 17AAG and other emerging Hsp90 drugs are very exciting. Rigorously planned and executed clinical trials, incorporating measurement of appropriate biomarkers and pharmocodynamic endpoints are critical for selecting the optimal dose and schedule. A detailed understanding of the molecular mode of action of Hsp90 inhibitors alongside the elucidation of the molecular pathology of individual cancers will help us to identify tumour types and individual patients that will benefit most from treatment. Careful in vitro and in vivo experiments are needed to choose the most potentially advantageous combination studies. It is important to construct a pharmacologic audit trail linking molecular biomarkers and pharmacokinetic and pharmacodynamic parameters to tumour response endpoints. Phase I clinical studies with 17AAG have shown that the drug can be given at does that are well tolerated and that also achieve active pharmacokinetic exposures and elicit molecular signatures of gene and protein expression that are indicative of Hsp90 inhibition. Furthermore, examples of disease stabilisation have been documented, consistent with the generally cytostatic responses that are seen in animal models. Selecting tumour types for Phase II clinical trials must involve balancing 1) our knowledge of molecular response determinants, such as the expression of and dependence upon key client proteins and 2) more pragmatic evidence of antitumour activity in the relevant preclinical models. Examples of likely disease targets include chronic myeloid leukaemia, melanoma, breast, ovarian, brain, thyroid, colorectal and prostate cancer.
Banerji
Udai
U
Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK. paul.workman@icr.ac.uk
Judson
Ian
I
Workman
Paul
P
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016227:Benzoquinones; D016503:Drug Delivery Systems; D004359:Drug Therapy, Combination; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D047029:Lactams, Macrocyclic; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D017828:Rifabutin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
D000970:Antineoplastic Agents; D016227:Benzoquinones; D006360:Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D017828:Rifabutin; C112765:tanespimycin