The pupose of this study was to evaluate the activity of
ON 01910.Na, a mitotic inhibitor, in in vitro and in vivo models of
pancreatic cancer and to discover
biomarkers predictive of efficacy. Successive in vitro and in vivo models were used; these included cell line-derived and patient-derived
tumors from our PancXenoBank, a live collection of freshly generated
pancreatic cancer xenografts.
ON 01910.Na showed equivalent activity to
gemcitabine against
pancreatic cancer cell lines in vitro. The activity of the agent correlated with suppression of phospho-CDC25C and
cyclin B1. These markers were optimized for a fine-needle aspirate ex vivo rapid assay.
Cyclin B1 mRNA evaluation yielded the most optimal combination of accuracy and reproducibility. Next, nine patient-derived
tumors from the PancXenoBank were profiled using the assay developed in cell lines and treated with
ON01910.Na for 28 days. Two cases were cataloged as potential responders and seven as resistants. There was a correlation between the ex vivo assay and sensitivity to the tested agent, as the two cases prospectively identified as sensitive met prespecified criteria for response. Of the seven
tumors of predictive resistant, only one was found to be sensitive to
ON 01910.Na. In addition, there was a good correlation between
cyclin B1 downregulation ex vivo and changes in
cyclin B1 protein post-treatment. The novel mitotic inhibitor,
ON 01910.Na, showed activity in preclinical model of
pancreatic cancer. A rapid assay was rationally developed that not only identified cases sensitive to
ON 01910.Na, but also anticipated the pharmacodynamic events occurring after in vivo exposure.