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

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 farnesyltransferase but 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 ; Novartis Pharmaceuticals Corporation, East Hanover, NJ) for chronic myelogenous leukemia (CML). Five years ago, the approval of imatinib, and the identification of the proteasome inhibitor bortezomib (Velcade ; 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]. As we enter the 5th or 15th or 25th anniversary of targeted therapies, evidence has confirmed what we all know but often ignore: solid tumors are very complex. A large group of investigators initially reported the sequence analysis of 13,023 “well annotated” human protein-coding genes in 11 breast and 11 colon cancers and then updated the analysis to include 18,191 genes [11, 12]. They reported that, on average, individual tumors accumulated approximately 90 mutant genes and judged 191 of the genes identified (1.4%! ) to be candidate cancer genes (CAN-genes). The average number of mutant CAN-genes was 12 (range, 4–23) for breast cancers and 9 (range, 3–18) for colorectal cancers with a distinct CAN-gene signature found for each cancer. Furthermore, the mutation spectrum was markedly different between breast and colon cancers with all the differences highly significant (p .0001). According to the authors, “the vast majority of these genes were not known to be genetically altered in tumors and are predicted to affect a wide range of cellular functions, including transcription, adhesion and invasion” and they subsequently concluded that “the genomic landscapes of breast and colorectal cancers are composed of a handful of commonly mutated gene ‘mountains’ and a much larger number of gene ‘hills’ that are mutated at low frequency. ” The complexity of solid tumors becomes clearer when one considers that only about one fourth of all genes were sequenced, that regulatory regions were not examined, and that neither epigenetic changes nor post-translational modifications nor the role of micro-RNAs were assessed. Indeed, it appears solid