Oncotarget

Research Papers:

Targeting PIM kinase as a therapeutic strategy in human hepatoblastoma

Laura L. Stafman, Smitha Mruthyunjayappa, Alicia M. Waters, Evan F. Garner, Jamie M. Aye, Jerry E. Stewart, Karina J. Yoon, Kimberly Whelan, Elizabeth Mroczek-Musulman and Elizabeth A. Beierle _

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Oncotarget. 2018; 9:22665-22679. https://doi.org/10.18632/oncotarget.25205

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Abstract

Laura L. Stafman1, Smitha Mruthyunjayappa2, Alicia M. Waters1, Evan F. Garner1, Jamie M. Aye3, Jerry E. Stewart1, Karina J. Yoon4, Kimberly Whelan3, Elizabeth Mroczek-Musulman2 and Elizabeth A. Beierle1

1Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA

2Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA

3Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA

4Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL, USA

Correspondence to:

Elizabeth A. Beierle, email: elizabeth.beierle@childrensal.org

Keywords: hepatoblastoma; PIM kinase; AZD1208; HuH6

Received: January 29, 2018     Accepted: April 04, 2018     Published: April 27, 2018

ABSTRACT

Increasing incidence coupled with poor prognosis and treatments that are virtually unchanged over the past 20 years have made the need for the development of novel therapeutics for hepatoblastoma imperative. PIM kinases have been implicated as drivers of tumorigenesis in multiple cancers, including hepatocellular carcinoma. We hypothesized that PIM kinases, specifically PIM3, would play a role in hepatoblastoma tumorigenesis and that PIM kinase inhibition would affect hepatoblastoma in vitro and in vivo. Parameters including cell survival, proliferation, motility, and apoptosis were assessed in human hepatoblastoma cells following PIM3 knockdown with siRNA or treatment with the PIM inhibitor AZD1208. An in vivo model of human hepatoblastoma was utilized to study the effects of PIM inhibition alone and in combination with cisplatin. PIM kinases were found to be present in the human hepatoblastoma cell line, HuH6, and in a human hepatoblastoma patient-derived xenograft, COA67. PIM3 knockdown or inhibition with AZD1208 decreased cell survival, attachment independent growth, and motility. Additionally, inhibition of tumor growth was observed in a hepatoblastoma xenograft model in mice treated with AZD1208. Combination therapy with AZD1208 and cisplatin resulted in a significant increase in animal survival when compared to either treatment alone. The current studies showed that PIM kinase inhibition decreased human hepatoblastoma tumorigenicity both in vitro and in vivo, implying that PIM inhibitors may be useful as a novel therapeutic for children with hepatoblastoma.


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