Proliferation is one of the major hallmarks of tumor biology, and has been intensely investigated for the prognosis and chemotherapy sensitivity prediction. Cyclin-dependent kinases (CDKs) play a central role in cell cycle progression. A series of molecular pathological investigations have clearly showed that the regulatory molecules of CDK activity, such as cyclins and CDKIs, are clinically significant prognosis and prediction factors for various cancer species.

Based on the above solid evidences, we hypothesized that CDK-activity assay would serve invaluable information for cancer diagnosis. We then established an original method enabling simultaneous analysis of protein expressions and kinase activities of CDK molecules in a lysate of tumor tissue (Cell Cycle Profiling technology, see reference 1). The technology could serve a specific activity (SA) of CDK molecules, as the activity is compensated by the protein expression. To clarify the clinical significance of the technology, 284 frozen tissues of breast cancer were first analyzed (Osaka study, see reference 2).

In the study, we found that tumors with high CDK1SA and high CDK2SA showed significantly poorer 5-year-relapse-free survival (5-y-RFS) than those with low CDK1SA and low CDK2SA, respectively. Based on the above findings, we defined an equation to calculate the risk score (C2P RS) for recurrence and the cutoff values were determined. The cutoffs were successfully evaluated in another study with frozen breast cancer specimens from 352 Dutch patients (Dutch study, see reference 3).

In this presentation, Dr. Ishihara will introduce the R&D and developmental strategies of Sysmex Corporation and discuss Cell Cycle Profiling technology advances as a new cancer diagnostics system.

References

1. Ishihara, H., et al. (2005) A new cancer diagnostic system based on a CDK profiling technology. Biochim Biophys Acta 1741: 226-233.
2. Kim, SJ., et al. (2008) Determination of the specific activity of CDK1 and CDK2 as a novel prognostic indicator for early breast cancer. Ann Oncol. 19: 68-72.
3. van Nes, JG., et al. (2009) Cyclin-Dependent Kinase 1 and 2 activity as prognostic markers in early breast cancer. Br J Cancer. 100(3):494-500.