Microenvironmental influence on pre-clinical activity of polo-like kinase inhibition in multiple myeloma: implications for clinical translation.

Douglas W McMillin
Jake Delmore
Joseph Negri
Melissa Ooi
Steffen Klippel
Chandrasekhar V Miduturu
Nathanael S Gray
Paul G Richardson
Kenneth C Anderson
Andrew L Kung
Constantine S Mitsiades

Open link

DOI

10.1371/journal.pone.0020226

Publisher

Public Library of Science (PLoS)

Journal

issn:1932-6203

Abstract

Polo-like kinases (PLKs) play an important role in cell cycle progression, checkpoint control and mitosis. The high mitotic index and chromosomal instability of advanced cancers suggest that PLK inhibitors may be an attractive therapeutic option for presently incurable advanced neoplasias with systemic involvement, such as multiple myeloma (MM). We studied the PLK 1, 2, 3 inhibitor BI 2536 and observed potent (IC50<40 nM) and rapid (commitment to cell death <24 hrs) in vitro activity against MM cells in isolation, as well as in vivo activity against a traditional subcutaneous xenograft mouse model. Tumor cells in MM patients, however, don't exist in isolation, but reside in and interact with the bone microenvironment. Therefore conventional...