Kinetic Biomarker for CLL Prognosis

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DESCRIPTION (provided by applicant) PHASE I The need for reliable biomarkers in cancer is clear, for areas including prognosis, stratification, therapeutic monitoring and drug discovery and approval. The fundamental disorder in cancer is altered cell kinetics (cell proliferation and/or death). The ideal biomarker for cancer would therefore measure these cellular kinetic events directly. Chronic lymphocytic leukemia (CLL) is an excellent clinical cancer model for applying a kinetic biomarker, by virtue of its accessibility (being a liquid tumor) and its relatively well-established kinetic basis (as a paradigm of malignancy involving inhibition of the normal apoptotic process). Until recently, no method for measuring cell kinetics had been available, however, that was technically reliable and applicable in humans. The laboratory of Dr M. Hellerstein at the University of California recently developed, patented, and has extensively used in human research a direct kinetic biomarker of cell proliferation and death. The technique is based on stable (non-radioactive) isotope incorporation (e.g. heavy water, 2/H20) into cellular DNA followed by mass spectrometric analysis and is exclusively licensed to KineMed, Inc. (a company formed to commercialize kinetic measurements in medical diagnostics and drug development). The objective of this Phase I applications to make technical advances toward the application of this patented kinetic biomarker (KineMarker TM) in CLL. Encouraging pilot data has been generated in B-CLL. Here, purity, lower limits on tissue sampling, timing and duration of heavy water dosing, evaluation of a potentially ultrasensitive mass spectrometric instrument, and other technical aspects of the test will be established for B-CLL. The specific aims are, (1) to confirm the purity of CD19+/CD5+ cells isolated by a simplified protocol from the blood of B-CLL patients; (2) to assess the adequacy of a 10 ml blood draw in B-CLL patients; (3) to compare results from short 2H20 labeling protocols to longer protocols in B- CLL patients; (4) to evaluate the potentially ultrasensitive gas chromatography/pyrrolysis-isotope ratio/mass spectrometric instrument for measuring cell kinetics in B-CLL patients; and (5) to establish the organizational structure for a large-scale clinical study of the KineMarker Tm as a predictive test in B-CLL, in phase II of this project. Measurable milestones for entry into Phase II are defined. In summary, this project will attempt to lay the foundation for applying stable isotope/mass spectrometric techniques to the measurement of cell proliferation in the hematologic cancer CLL in humans; for subsequent use as a predictive test of CLL disease progression.