Targeting polo-like kinase 1 in acute myeloid leukemia

Abstract

Acute myeloid leukemiaAcute myeloid leukemia (AML) is an aggressive hematologic malignancy characterized by a clonal maturation arrest at an early myeloid progenitor stage, and the proliferation of primitive myeloblasts. This results in the accumulation of blast cells in the bone marrow leading to severe cytopenias and associated complications. The median age of AML is approximately 70 and the frequency increases dramatically above age 60 (SEER, 2014).The treatment of younger and more fit older patients consists of intensive induction chemotherapy, using cytarabine plus an anthracycline, to achieve a complete remission (CR), followed by several cycles of consolidation chemotherapy. CR rates are in the 70% range in patients under age 60, and 50-55% in those over age 60 [Tallman et al. 2005; Grimwade et al. 2010;Mrozek et al. 2012]. However, the majority of patients will subsequently relapse. Cytogenetics and molecular mutations are important predictors of both CR and relapse with chemotherapy. Adverse risk cytogenetic groups include monosomal and complex karyotypes, as well as 3p26, 17p and 11q23 abnormalities. CR rates with induction chemotherapy in these patients are in the 30-50% range, with 5-year overall survival (OS) of 10% or less [Grimwade et al. 2001[Grimwade et al. , 2010 Gupta et al. 2005; Farag et al. 2006]. Among molecular mutations, fms-like tyrosine kinase internal tandem duplications (FLT3-ITD) are associated with a higher relapse rate and inferior survival [Mrozek et al. 2012;Linch et al. 2014], while nucleophosmin (NPM1) mutations are associated with a superior CR rate and OS [Schnittger et al. 2005;Mrozek et al. 2012]. Allogeneic hematopoietic stem-cell transplantation (HSCT) in CR can reduce the probability of relapse in poor risk patients, but many patients are not candidates for transplant owing to advanced age and comorbidities. Furthermore, the inability to achieve CR may preclude transplant, and success rates with HSCT are lower in poor risk patients [van Gelder et al. 2013]. In older patients, the 5-year OS with intensive chemotherapy is in the 10% range; for older patients with adverse risk karyotypes, there is little survival benefit with such aggressive treatment approaches, due to the low CR rates and brief CR duration [Gupta et al. 2005; Farag et al. 2006;Kantarjian et al. 2006; Grimwade et al. 2010]. For patients with relapsed/refractory AML, results are dismal and have only marginally improved in recent years [Pemmaraju et al. 2015].Targeting polo-like kinase 1 in acute myeloid leukemia Joseph M. Brandwein Abstract: Polo-like kinase 1 (Plk1) plays a number of important roles in the passage of cells through mitosis. It is expressed at high levels in a variety of malignancies, including acute myeloid leukemia (AML). Inhibition of Plk1 results in cell cycle arrest and apoptosis, and has anti-tumor effects in pre-clinical models. A number of Plk1 inhibitors have been developed, some of which have entered clinical trials. Of these, volasertib (BI6727) has been most extensively stud...

Acute myeloid leukemia in children: Current status and future directions

“…Finally, the general consensus in the field is that only limited improvement in outcome will be achieved with intensification of conventional chemotherapy with or without HSCT, highlighting the necessity for the introduction of new drugs based on AML biology. Several candidate drugs are currently in development for adult and pediatric AML: including clofarabine, a new purine nucleoside analog; FLT3 inhibitors; KIT inhibitors; Polo‐like kinase inhibitors; proteasome inhibitors; epigenetic modifiers, such as demethylating agents and histone deacetylase inhibitors; and novel immunotherapies targeting AML antigens such as bi‐specific T‐cell engager (BiTE) antibodies for CD33 and chimeric antigen receptor (CAR), and T‐cell therapy targeting CD33, CD123, and others . The development of novel drugs to treat childhood malignancy, however, remains a major challenge in Japan because under the Japanese universal health‐care system, use of off‐label drugs is prohibited; thus, it is crucial to develop promising agents with the aim of obtaining approval for marketing authorization.…”

Spotlight on Volasertib: Preclinical and Clinical Evaluation of a Promising Plk1 Inhibitor

“…Both the Plk1 mRNA and protein expression levels are tightly controlled in time, with low levels during interphase and high expression in mitosis . Although Plk1 expression levels are low in most normal tissues (including kidney, liver, brain, lung, and pancreas), active proliferating tissues (including placenta, testis and bone marrow) represented higher levels of Plk1 . The first data that linked Plk1 with neoplastic growth were from studies showing increased Plk1 expression in primary cancer tissues .…”

Pharmaceutically inhibiting polo‐like kinase 1 exerts a broad anti‐tumour activity in retinoblastoma cell lines

“…20 Therapy targeting cell cycle regulators with small molecule inhibitors is promising, and a number of small molecule inhibitors have recently entered clinical trials, including the PLK1 inhibitors, BI6727 and GSK461364, which are now under evaluation for treatment of acute myeloid leukaemia and solid tumours, respectively. 13,14,24 Inhibiting PLK1 function by treatment with BI6727 or GSK461364 induced a dose-dependent decrease in cell viability and proliferation in our in vitro models of retinoblastoma. This effect was mediated via cell cycle arrest in G2, apoptosis or both and was dependent on the cellular background.…”

“…PLK1 governs several key processes in cell cycling, including the initiation of entry into mitosis, centrosome maturation and separation, metaphase to anaphase transition, mitotic exit and the onset of cell division . Therapy targeting cell cycle regulators with small molecule inhibitors is promising, and a number of small molecule inhibitors have recently entered clinical trials, including the PLK1 inhibitors, BI6727 and GSK461364, which are now under evaluation for treatment of acute myeloid leukaemia and solid tumours, respectively …”