Elsevier

Seminars in Oncology

Volume 33, Issue 4, August 2006, Pages 407-420
Seminars in Oncology

New Paradigms in Anticancer Therapy: Targeting Multiple Signaling Pathways With Kinase Inhibitors

https://doi.org/10.1053/j.seminoncol.2006.04.005Get rights and content

Signal transduction in cancer cells is a sophisticated process that involves receptor tyrosine kinases (RTKs) that eventually trigger multiple cytoplasmic kinases, which are often serine/threonine kinases. A number of tumor models have identified several key cellular signaling pathways that work independently, in parallel, and/or through interconnections to promote cancer development. Three major signaling pathways that have been identified as playing important roles in cancer include the phosphatidyl inositol-3-kinase (PI3K)/AKT, protein kinase C (PKC) family, and mitogen-activated protein kinase (MAPK)/Ras signaling cascades. In clinical trials, highly selective or specific blocking of only one of the kinases involved in these signaling pathways has been associated with limited or sporadic responses. Improved understanding of the complexity of signal transduction processes and their roles in cancer has suggested that simultaneous inhibition of several key kinases at the level of receptors and/or downstream serine/threonine kinases may help to optimize the overall therapeutic benefit associated with molecularly targeted anticancer agents. Using targeted agents to inhibit multiple signaling pathways has emerged as a new paradigm for anticancer treatment based on preclinical and clinical data showing potent anti-tumor activity of single drugs inhibiting multiple molecular targets or combination therapies involving multiple drugs with selective or narrow target specificity. Preclinical and clinical studies point to molecules on vascular endothelial cells and pericytes as being important targets for anticancer therapies, as well as molecules on or within tumor cells themselves. This suggests that optimal therapeutic approaches to cancer may involve targeting multiple molecules found in both the tumor and supportive tissues. In this review, we will use the most recent preclinical and clinical data to describe this emerging paradigm for anticancer therapy involving targeting multiple signaling pathways with tyrosine or serine/threonine 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

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