Expert Sees Need to Leverage New Technologies in Targeting PLK

Published: Friday, Sep 26, 2014
Klaus Strebhardt, PhD

Klaus Strebhardt, PhD

For more than 20 years, Klaus Strebhardt, PhD, has been exploring the polo-like kinase (PLK) pathway, including its role in cancer and Plk1-targeted anticancer therapies. He was a member of the research team that identified the DNA sequence of the human PLK gene in the mid-1990s1 and has participated in a number of studies of Plk1 inhibitors in a variety of cancer types.

In addition to studying specific molecules, Strebhardt has employed new technologies to profile molecular interactions involving the pathway, notably through the use of Kinobeads,2 an innovative method that can measure the binding interactions of more than 300 different kinases simultaneously.3

Strebhardt provided an overview of pending issues in the field in this interview with OncologyLive.

What makes the polo-like kinases attractive targets for cancer therapy?

The inhibition of Plk1 by various experimental strategies resulted in the inhibition of proliferation associated with an induction of apoptosis in a wide variety of cancer cell lines. In vivo findings have demonstrated the efficacy of siRNA knockdown of Plk1, leading to the suppression of tumor growth.

By contrast, siRNA targeting of Plk1 in primary human cells and in adult transgenic animals reduced Plk1 mRNA almost completely but neither inhibited the proliferative activity of cells nor increased apoptosis significantly. This differential sensitivity of benign and malignant tissues toward Plk1 inhibition is one the major reasons for targeting Plk1 in cancer drug development.

What are the most promising PLK-targeted agents currently in development?

The Boehringer Ingelheim compound volasertib, a highly potent and selective inhibitor of polo-like kinases, was recently used in a randomized phase II trial for the treatment of older patients with acute myeloid leukemia (AML) (median age 75 years), who were not considered suitable for intensive induction therapy. In this trial, low-dose cytarabine (LDAC) was compared with or without volasertib. Response rate (complete remission [CR] and CR with incomplete blood count recovery [CRi]) was higher for LDAC plus volasertib versus LDAC (31.0% vs 13.3%; odds ratio, 2.91; P = .052). Responses in the LDAC plus volasertib arm were observed across all genetic groups. Median event-free survival was significantly prolonged by LDAC plus volasertib compared with LDAC (5.6 vs 2.3 months).

These encouraging data have prompted the initiation of a phase III trial of volasertib in AML. The improved pharmacokinetic profile of volasertib might be one reason for the successful development of this Plk inhibitor.

The PLK inhibitor rigosertib recently failed several phase III trials. Why do you think this agent has not been successful?

Although the original article4 by the lab of Dr E.P. Reddy on rigosertib (ON01910.Na) claimed that this non-ATP competitive compound is a potent Plk1 inhibitor, the same lab stated a few years later5 that a direct effect on Plk1 could not be confirmed. In addition, other labs confirmed that ON01910.Na does not inhibit Plk1 directly. Furthermore, the exact mechanism of action of ON01910.Na remains unknown.

What are the most significant hurdles to the successful development of PLK inhibitors?

To address whether inhibitors of mitotic kinases such as Plk1 are more effective at tumor cell–selective killing than microtubule-targeting agents are, we must improve the breadth of understanding and the selectivity of the inhibitors.

A prerequisite of the design of an optimized therapy is our understanding of the kinase selectivity of novel inhibitors. In vitro kinase assays that have been often used for the determination of inhibitor selectivity do not represent an optimal strategy to discover off-target effects in drug development.

Thus, more comprehensive approaches like Kinobead technology are better suited to monitor a broad spectrum of kinases under near-physiological conditions. Learning how to design more generally and what constitutes an optimal treatment will be crucial for developing new cancer therapies. In addition, patient stratification by using appropriate biomarkers will be of utmost importance.

In your opinion, how will we derive the most therapeutic benefit from PLK inhibitors?

Numerous target validation trials in a spectrum of cancer cells in culture and in xenograft models came to the conclusion that Plk1 is an excellent target in many different cancer cell types. However, in both experimental systems, cancer cells proliferate at high speed; that is, they have a higher percentage of cells in mitosis compared with some slow-growing human solid cancers.


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