Previous studies from this and other laboratories have established that histone deacetylase inhibitors (HDACIs) and proteasome inhibitors such as bortezomib interact synergistically to induce apoptosis in malignant human hematopoietic cells. In chronic lymphocytic leukemia (CLL) cells, postulated mechanisms of synergism have focused on bortezomib-mediated blockade of HDACI-induced RelA acetylation and activation of the canonical and alternative NF-:B pathways, resulting in down regulation of NF-:B-dependent survival proteins (e.g., Bcl-xL and XIAP). Very recently, we have observed that when co-administered in vitro at extremely low concentrations (i.e. 3-5 nM each), the Class I HDACI romidepsin (depsipeptide;FK228) interacts with bortezomib to induce very pronounced apoptosis in fresh primary CLL cells as well as .CLL cell lines. Furthermore, these events are associated with prevention of romidepsin-induced activation of the classical and alternative NF-:B pathways, down regulation of the NF-:B dependent proteins Bcl-xL and XIAP, and induction of the pro-apoptotic protein Bim. We now propose to begin testing the in vivo implications of these preclinical findings by conducting a Phase I trial.
The specific aims of this proposal are: First, to determine the maximum tolerated dose (MTD) for the combination of bortezomib and romidepsin administered weekly x 3 every 4 weeks in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL);to determine the safety and describe the toxicities of the combination;and to document activity of the combination observed in the course of the dose finding study. Second, to demonstrate adequate techniques for the assessment of pharmacodynamic responses of CLL cells to the combination with respect to effects on activation of the canonical and alternative NF-:B pathways (nuclear RelA and p52 as a marker of p100 processing), expression of the NF-:B-dependent proteins XIAP and Bcl-xL, and expression of the pro-apoptotic protein Bim;and to document pharmacodynamic responses observed in the course of the dose finding study.
Studies from our laboratory have shown a potent interaction between the histone deacetylase inhibitor romidepsin and the proteosome inhibitor in inducing cell death in primary chronic lymphocytic leukemia (CLL) cells. The purpose of this study is to determine the maximum tolerated dose (MTD) for the combination administered weekly x 3 every 4 weeks in patients with chronic lymphocytic leukemia/small cell lymphocytic lymphoma (CLL/SLL), to determine the safety and describe the toxicities of the combination, and to document activity of the combination observed in the course of the dose finding study. Further, the purpose is to demonstrate adequate techniques for the assessment of pharmacodynamic responses of CLL cells to the combination with respect to effects on activation of the canonical and alternative NF-:B pathways, expression of selected NF-:B-dependent proteins, and expression of pro-apoptotic protein Bim, and to document pharmacodynamic responses observed in the course of the dose finding study. This will position us to perform future trials that will determine the effectiveness of this novel drug combination in patients with CLL or SLL and address the validity of our preclinical pharmacodynamic observations.
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