Development of Chemotherapy with Cell-Cycle Inhibitors for Adult and Pediatric Cancer Therapy

Abstract

Preclinical and clinical development of agents that inhibit cell-cycle progression have brought an understanding of the feasibility of targeting various cell-cycle regulators in patients with cancer. Small molecule inhibitors targeting key proteins that participate in cell-cycle progression including the cyclin-dependent kinases and checkpoint kinases induce cell-cycle arrest and apoptosis in neoplastic cells. Early phase I studies demonstrate targeted inhibitors can be administered safely in adult and pediatric cancer patients, but these agents generally show limited clinical benefits as single agents. In this review, we discuss biological mechanisms that support dual combination strategies of cell-cycle inhibition with chemotherapeutic agents that are anticipated to achieve rationally targeted therapies for cancer patients. The rationale for evaluating these combination strategies is that DNA damage renders tumors highly responsive to irreversible cell-cycle arrest therapy. This approach is predicted to generate less intensive therapies and to maximize the efficacy of individual agents against solid tumors and hematologic malignancies. Cancer Res; 78(2); 320-5. ©2018 AACR.

Figure 1

Therapies that target the cell cycle. Top: The mechanism of action of some cytotoxic chemotherapies (upper green boxes) may be cell cycle independent (e.g. alkylating agents, yellow box) or rely on specific phases in the cell cycle (blue arrows) to induce cell cycle arrest. Bottom: Cell cycle inhibitors target cell cycle modulators (lower green boxes) that act at specific phases to delay cell cycle progression.