Apoptosis modulators: P53 targeting

Cancer is a disease initiated, driven, and sustained by genomic instability; many pleiotropic and overlapping signaling pathways contribute to oncogenesis and pathologic progression. Despite accumulating multiple genetic, epigenetic, and chromosomal abnormalities, cancer cells can become dependent on a single or a few oncogenic pathways for both maintenance of the malignant phenotype and cell survival; this phenomenon-termed “oncogene addiction”-has been reported in both cultured cell lines and animal models (1). Thus, reversal of only one or a few of these abnormalities can trigger massive apoptosis resulting in inhibition of cancer cell growth. Considerable progress in the treatment of cancer in recent years stems from the development and clinical application of drugs targeted to specific molecular pathways. Examples of these pathway-specific drugs are Gleevec (imatinib mesylate; Novartis Pharmaceutical Corp., East Hannover, New Jersey, U.S.A.) and Tarceva (erlotinib; Genentech, San Francisco, California, U.S.A.), both of which act as selective tyrosine kinase inhibitors. However, clinical success with these pathway-specific agents has been idiosyncratic. Agents that affect not only one, but various, albeit similar, pathways are being developed and have demonstrated improved clinical results. Such is the case of Sorafenib (Nevaxar; Wayne, New Jersey, U.S.A.), which was initially developed as a RAF-RAS kinase-targeted drug. Further studies showed that, in addition to targeting RAF kinase, Sorafenib also inhibits VEGF and PDGF receptor kinases, as well as KIT and FLT-3 kinases, culminating in tumor cell apoptosis and inhibition of angiogenesis. It appears that the combination of Sorafenib's actions on multiple tyrosine kinase pathways induces an enhanced therapeutic response by this drug. Additional drugs which target multiple kinases that have demonstrated clinical promise are sunitinib (Sutent; Pfizer, Inc., New York, New York, U.S.A.), dasatinib (Sprycel; BristolMyers Squibb, New York, New York, U.S.A.), and lapatinib (GlaxoSmithKline, Brentford, London, U.K.). In contrast, agents which have demonstrated specificity against one kinase target do not always show clinical activity; this concept was exemplified by the lack of robust clinical activity of Iressa(gefitinib; Astrazeneca, Mississauga, Ontario, Canada), despite early enthusiasm.