Recent Advances of Cell-Cycle Inhibitor Therapies for Pediatric Cancer

Abstract

This review describes the pivotal roles of cell-cycle and checkpoint regulators and discusses development of specific cell-cycle inhibitors for therapeutic use for pediatric cancer. The mechanism of action as well as the safety and tolerability of drugs in pediatric patients, including compounds that target CDK4/CDK6 (palbociclib, ribociclib, and abemaciclib), aurora kinases (AT9283 and MLN8237), Wee1 kinase (MK-1775), KSP (ispinesib), and tubulin (taxanes, vinca alkaloids), are presented. The design of mechanism-based combinations that exploit the cross-talk of signals activated by cell-cycle arrest, as well as pediatric-focused drug development, are critical for the advancement of drugs for rare childhood diseases. Cancer Res; 77(23); 6489-98. ©2017 AACR.

Figure 1. Cell cycle inhibitors evaluated in clinical trials against pediatric cancer

A schematic representation of mammalian cell division and inhibitors that target regulatory proteins at various phases of the cell cycle. Mitogenic signals trigger increases in the expression of D-type cyclins and the formation of complexes with CDK4 and CDK6, to initiate the cell cycle (G1) in which the cell prepares for DNA synthesis. Cells transition through S-phase where DNA synthesis occurs, the G2-gap phase and M-phase, where cell division occurs. Yellow stars depict three cell cycle checkpoints: G1/S (the DNA replication checkpoint); G2/M (the DNA damage checkpoint) and SAC (the spindle assembly checkpoint. Regulatory proteins are colored grey. Blunt red arrows illustrate direct inhibition strategies with targeted drugs. Dotted red lines illustrate indirect inhibition strategies.