Discovery and development of the Polo-like kinase inhibitor volasertib in cancer therapy

Abstract

Owing to their integral involvement in cell cycle regulation, the Polo-like kinase (Plk) family, particularly Plk1, has emerged as an attractive therapeutic target in oncology. In recent years, several Plk1 inhibitors have been developed, with some agents showing encouraging results in early-phase clinical trials. This review focuses on volasertib (BI 6727; an investigational agent), a potent and selective Plk inhibitor. Volasertib has shown promising activity in various cancer cell lines and xenograft models of human cancer. Trials performed to date suggest that volasertib has clinical efficacy in a range of malignancies, with the most promising results seen in patients with acute myeloid leukemia (AML). Encouragingly, recent phase II data have demonstrated that volasertib combined with low-dose cytarabine (LDAC) was associated with higher response rates and improved event-free survival than LDAC alone in patients with previously untreated AML. Based on these observations, and its presumably manageable safety profile, volasertib is currently in phase III development as a potential treatment for patients with AML who are ineligible for intensive remission induction therapy. Given that many patients with AML are of an older age and frail, this constitutes an area of major unmet need. In this review, we discuss the biologic rationale for Plk1 inhibitors in cancer, the clinical development of volasertib to date in solid tumors and AML, and the future identification of biomarkers that might predict response to volasertib and help determine the role of this agent in the clinic.

Efficacy and Mechanism of Action of Volasertib, a Potent and Selective Inhibitor of Polo-Like Kinases, in Preclinical Models of Acute Myeloid Leukemia

“…Consistent with its biologic role, Plk1 is highly expressed in proliferating cells and therefore appears to be overexpressed in a broad spectrum of cancers, with high expression levels being correlated with poor prognosis in several cancer types (Takai et al, 2005). Taken together, these observations highlight Plk1 as an attractive molecular target for cancer therapy (Strebhardt and Ullrich, 2006;Christoph and Schuler, 2011;Gjertsen and Schoffski, 2015 ).…”

Identification of synthetic lethality of PLK1 inhibition and microtubule-destabilizing drugs

“…At present, PLK1 inhibitors are under evaluation in early clinical trials in a variety of cancers. 26 As the PLK1 inhibitor BI 6727 is currently tested as monotherapy in a phase I clinical trial in childhood cancer (www.clinicaltrials.gov), and because VCR is used as standard therapy of RMS, it is feasible that this combination can be translated into clinical application in pediatric oncology. The significance of developing PLK1 inhibitor-based combinations is underlined by a recent study of the Pediatric Preclinical Testing Program showing only modest single-agent antitumor activity of BI 6727 against the pediatric solid tumor xenograft panel.…”

Cervical Cancer Growth Is Regulated by a c-ABL–PLK1 Signaling Axis

“…The active form promotes entry into the mitotic phase. PLK1 is highly expressed in multiple cancer, including colon and lung cancers, which oncogenic properties are believed to be due to its role in driving cell-cycle progression (24,25). PLK1 is also being studied as a target for cancer therapy (26).…”