Michael Hallek. M.D. University of Cologne (Germany)

NEW DRUGS

Preclinical testing of drug combinations for chronic lymphocytic leukemia (CLL)

Grant Awarded in 2008

Abstract:

Combinations of drugs acting by different mechanisms will be tested on CLL cells freshly isolated from patients. For treatment with drug combinations, the CLL cells will be grown in medium alone or in co-cultures with bone marrow stromal cells, which should mimic the microenvironment of CLL cells. Drug induced changes in cell survival and intracellular signaling will be monitored.

Due to previous work in our laboratory, as a starting compound, we chose the orally available protein tyrosine kinase enzyme inhibitor, dasatinib, which is successfully used for treating leukemias which have a unique BCR-ABL fusion gene. Since dasatinib also targets the activity of Src-family kinases, these enzymes are involved in microenvironment CLL cell interactions and cellular survival functions. We found that dasatinib induces programmed cell death preferentially in patient cells with unfavorable prognostic predictors.

Fludarabine, a key drug in CLL therapy, is the first candidate for combination with dasatinib. The combination of dasatinib and fludarabine increased CLL cell death effects in the laboratory and we will explore these results in a quantitative manner, taking into account patient characteristics.

The next group of combination partners planned for the lab assays are anti-CD20 antibodies, rituximab and GA101, which appear to induce cell death by similar pathways observed with dasatinib. Further agents to be included in the combination schemes are Bcl-2 antagonists and lipopeptides which modify cellular messages. In the long run, the preclinical testing of drug combinations will be extended to a mouse model of CLL.