Exploiting cell cycle pathways in cancer therapy: New (and old) targets and potential strategies

There is a now a large body of evidence supporting the notion that cancer cells have vastly altered cell cycle networks that serve to maintain their high rate of proliferation. Consequently, targeting these pathways pharmacologically has been long studied, but only recently have some promising compounds progressed into the clinic. In this chapter, we review cell cycle function in both normal cells and describe how cancer cells deregulate this fundamental process. Next we describe in detail the development of different classes of CDK inhibitors and review the failures and successes so far, and provide insight into some future directions for research and clinical trials in order to exploit the ever-expanding molecular characterization of tumors with the drugs available and in the pipelines. In addition, we present a short overview of using differential cell cycle characteristics of normal and tumor cells as a way of protecting normal cells from cytotoxic chemotherapies. Finally we describe other potential targets such as regulating p27, inhibiting PIM and MELK kinases as well as some of the mitotic kinases.