BT-06 * PLK1 AS A POTENTIAL THERAPEUTIC TARGET FOR DIPG

Abstract

Diffuse intrinsic pontine gliomas (DIPGs) are highly aggressive, universally fatal, childhood tumors that arise in the brainstem. DIPGs have no effective treatment, and their location and diffuse nature render them inoperable. Radiation therapy remains the standard of care for this devastating disease. Polo-like kinase 1 (PLK1) regulates critical steps in mitotic progression and has been shown to be highly expressed in many human cancers. We examined the expression of PLK1 mRNA in DIPG tumor samples through microarray analysis and found it to be upregulated versus normal pons. This finding highlighted PLK1 as a potential small-molecule target. Recent studies have shown that inhibition of PLK1 leads to a decrease in cell proliferation and radiosensitization in other forms of pediatric brain tumors. Treatment of DIPG cell lines with BI 6727, a new generation, highly selective inhibitor of PLK1, resulted in decreased cell proliferation and a marked increase in cellular apoptosis. Cell cycle analysis of treated cells showed a significant arrest in G2/M phase and a substantial increase in sub-G0/G1 cell population, a finding that correlates with the expected mechanism of action of BI 6727. Treatment also resulted in an increased γH2AX expression, indicating BI 6727 can induce DNA damage. Together, these findings suggest that targeting PLK1 with small-molecule inhibitors, in combination with radiation therapy, will hold a novel strategy in the treatment of DIPG that warrants further investigation.