New Paradigms in Anticancer Therapy: Targeting Multiple Signaling Pathways With Kinase Inhibitors
Section snippets
Paradigm Shifts in Anticancer Therapy
Pharmacologic therapy of cancer continues to evolve as more is learned about the cellular and molecular biology of individual cancers and additional agents are developed based on this knowledge. A brief history of anticancer pharmacotherapies illuminates some of the changes that have occurred up this point. It also creates a picture of the current environment and points to possible future trends that may lead to further improvements in cancer therapy.
Targeting Multiple Signaling Pathways
As illustrated in Table 1, most molecularly targeted anticancer therapies currently approved for use in patients with solid tumors are likely to target a single molecule. Imatinib—which selectively binds KIT, PDGFR, and BCR-ABL—is the sole exception. For a variety of reasons discussed below, the future of anticancer therapy may largely lie with individual agents that target multiple molecules important for particular cancer types (“multitargeted agents”), imatinib being an early-generation
Investigational Agents Targeting Serine/Threonine Kinases or Multiple Tyrosine Kinases
A large number of investigational drugs have been designed to target key molecules involving in cancer processes. Some of these target RTKs, and others target downstream effectors in signaling pathways (Table 2). Here we will take a closer look at some agents of interest, including everolimus (RAD-001) and other mTOR inhibitors designed to disrupt signaling via the PI3K pathway; PKC412 (N-benzoyl-staurosporine) and the role of PKC activity in cancer development; and SU11248 and other
Conclusions
Increased understanding of the mechanisms underlying cancer suggests that an integrated approach to cancer therapy involves inhibition of multiple signaling pathways. Targeting multiple RTKs with a single agent, as exemplified by SU11248 and sorafenib, shows great promise as an anticancer strategy. Early results suggest that targeting intracellular serine/threonine kinases at the convergence of multiple signaling pathways with agents such as RAD001 and PKC412 may also be a useful anticancer
Acknowledgment
The authors would like to thank Michael Coco and Wendy Sacks who provided writing services on behalf of Pfizer Inc. Michael Coco is a freelance medical writer and Wendy Sacks a scientific director with Thomson ACUMED.
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S.F. and E.R are consultants for Pfizer Inc. S.D. is employed by Pfizer Inc