Commentary: Novel therapies for cancer: why dirty might be better.

摘要

Among targeted therapies for solid tumors, it can be argued that the most effective therapy to date was conceived nearly 25 years ago and only recently approved. Aromatase inhibitors, the brainchild of Angela Brodie, were finally approved for the treatment of breast cancer in 2004 as a result of, in large part, the perseverance of Dr. Brodie, Dr. Charles Coombes, and a dedicated group of clinical investigators at the Royal Marsden Hospital in London [1-3]. It was around the same time 25 years ago that farnesyl transferase inhibitors were first described, and while the final chapter on this story has yet to be written, the early promise of this targeted therapy has been largely followed by a series of disappointments as it became apparent that not only farnesyltransferasebut also geranylgeranyltransferase I could generate biologically active Ras [4-6]. Then, about 15 years ago, Brian Druker, together with Nicholas B. Lydon and other investigators at Ciba-Geigy, began the process of identifying a compound that would inhibit the breakpoint cluster region-Abelson(Bcr-Abl) protein and that ultimately would lead to the approval of imatinib mesylate (Gleevec~R; NovartisPharmaceuticals Corporation, East Hanover, NJ) for chronic myelogenous leukemia (CML). Five years ago, the approval of imatinib, and the identification of the proteasomeinhibitor bortezomib (Velcade~R; Millennium Pharmaceuticals, Inc., Cambridge, MA) as an agent with activity in multiple myeloma, created an enthusiastic frenzy for new targeted therapies that has yet to abate [7-10].