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

Rudolph, Dorothea; Impagnatiello, Maria Antonietta; Blaukopf, Claudia; Sommer, Christoph; Gerlich, Daniel W.; Roth, Mareike; Tontsch-Grunt, Ulrike; Wernitznig, Andreas; Savarese, Fabio; Hofmann, Marco H.; Albrecht, Christoph; Geiselmann, Lena; Reschke, Markus; Garin‐Chesa, Pilar; Zuber, Johannes; Moll, Jürgen; Adolf, Günther R.; Kraut, Norbert

doi:10.1124/jpet.114.221150

Cited by 57 publications

(76 citation statements)

References 31 publications

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“…In contrast to rigosertib, volasertib induces oncogenic AKT and ERK signalling and synergizes with AKT or mTOR inhibition in vitro 212 . Volasertib demonstrated impressive anti-tumour activity in xenograft models of neuroblastoma (as monotherapy) 213 , ALL (as monotherapy and in combination with cytarabine or quizartinib) 213, 214 , breast cancer (in combination with fulvestrant) 215 and rhabdomyosarcoma (with vincristine) 216 . A clinical phase II trial compared volasertib in combination with low-dose cytarabine versus cytarabine alone for older patients with AML (TABLE 3).…”

Section: Targeting Of Other Cell Cycle Proteinsmentioning

confidence: 99%

Cell cycle proteins as promising targets in cancer therapy

2017

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Preface Cancer is characterized by uncontrolled proliferation resulting from aberrant activity of various cell cycle proteins; therefore, cell cycle regulators are considered attractive targets in cancer therapy. Intriguingly, animal models demonstrated that some of these proteins are not essential for proliferation of non-transformed cells and development of most tissues. In contrast, many cancers are uniquely dependent on these proteins and are hence selectively sensitive to their inhibition. After decades of research on the physiological functions of cell cycle proteins and their relevance for cancer, this knowledge recently translated into the first approved cancer therapeutic targeting of a direct regulator of the cell cycle. Here, we review the role of cell cycle proteins in cancer, the rationale for targeting them in cancer treatment and results of clinical trials, as well as future therapeutic potential of various inhibitors. We focus only on proteins that directly regulate cell cycle progression. Cyclin-dependent kinases with transcriptional functions, as well as PARP inhibitors, which are highly successful in targeting BRCA1/BRCA2-mutant tumours, are not covered by this review.

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Section: Targeting Of Other Cell Cycle Proteinsmentioning

confidence: 99%

Cell cycle proteins as promising targets in cancer therapy

2017

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“…Volasertib (BI6727) is another promising PLK1 inhibitor. Several preclinical experiments have demonstrated that BI6727 is highly efficacious in inducing tumor regression [116], [132], [133], [134]. As a result, this agent has recently been awarded the “Breakthrough Therapy Status” by the Food and Drug Administration for its significant benefit in treating acute myeloid leukemia patients [135].…”

Section: Plk1 and Human Cancermentioning

confidence: 99%

PLK1, A Potential Target for Cancer Therapy

Liu

Sun

Wang

2017

Translational Oncology

349

269

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Polo-like kinase 1 (PLK1) plays an important role in the initiation, maintenance, and completion of mitosis. Dysfunction of PLK1 may promote cancerous transformation and drive its progression. PLK1 overexpression has been found in a variety of human cancers and was associated with poor prognoses in cancers. Many studies have showed that inhibition of PLK1 could lead to death of cancer cells by interfering with multiple stages of mitosis. Thus, PLK1 is expected to be a potential target for cancer therapy. In this article, we examined PLK1’s structural characteristics, its regulatory roles in cell mitosis, PLK1 expression, and its association with survival prognoses of cancer patients in a wide variety of cancer types, PLK1 interaction networks, and PLK1 inhibitors under investigation. Finally, we discussed the key issues in the development of PLK1-targeted cancer therapy.

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“…Volasertib has a very low IC50 of 0.87 umol/L and was shown to impede proliferation of acute myeloid leukemia (AML) cell lines (64). Additionally, a study in bladder cancer found that volasertib was a potent inducer of cell death and cell cycle arrest (65).…”

Section: Plk1 As a Drug Targetmentioning

confidence: 99%

Plk1 Inhibitors in Cancer Therapy: From Laboratory to Clinics

Gutteridge

Ndiaye

Liu

et al. 2016

Molecular Cancer Therapeutics

330

272

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Polo-like kinase 1 (Plk1) overexpression has been shown to occur in a wide range of tumors, prompting research and development of Plk1 inhibitors as a means of cancer treatment. This review discusses recent advances in the development of Plk1 inhibitors for cancer management. Plk1 inhibition has been shown to cause mitotic block and apoptosis of cells with higher mitotic index and therefore higher Plk1 expression. The potential of Plk1 inhibitors as cancer therapeutics has been widely investigated. However, a complete understanding of Plk1 biology/mechanism is yet to be fully achieved. Resistance to certain chemotherapeutic drugs has been linked to Plk1 overexpression, and Plk1-mediated mitotic events such as microtubule rearrangement have been found to reduce the efficacy of chemotherapeutic agents. The Plk1 inhibitor, volasertib, has shown considerable promise in clinical studies, having reached phase III trials. However, preclinical success with Plk1 inhibitors has not translated well into clinical success. In our view, combined therapies targeting other relevant pathways together with Plk1 may be vital to combat issues observed with monotherapy, especially resistance. In addition, research should also be directed towards understanding the mechanisms of Plk1 and designing additional next generations of specific, potent Plk1 inhibitors to target cancer.

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

Cited by 57 publications

References 31 publications

Cell cycle proteins as promising targets in cancer therapy

Cell cycle proteins as promising targets in cancer therapy

PLK1, A Potential Target for Cancer Therapy

Plk1 Inhibitors in Cancer Therapy: From Laboratory to Clinics

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