Targeting ZAP-70 Tyrosine Kinase in Chronic Lymphocytic Leukemia
Januario Castro, M.D.
University of California- San Diego
Abstract:
This proposal will study signaling pathways and protein-protein interaction of the zeta associated protein kinase of 70 kDa (ZAP-70) in chronic lymphocytic leukemia (CLL), with the goal to develop innovative treatments for patients with high-risk disease.
Leukemia cells of patients with aggressive CLL aberrantly express ZAP-70. We have found that leukemia cells that express ZAP-70 undergo stronger cellular activation and signaling through survival pathways than ZAP-70 negative CLL cells. This observation suggests that aberrant expression of ZAP-70 provides a growth factor stimulus to CLL cells that may drive disease progression.
Recently, we found that very low concentrations of 17-allyl-amino-demethoxy geldanamycin (17-AAG), an inhibitor of heat shock protein 90 (Hsp90), can selectively decrease the expression of ZAP-70 and induce cell death in CLL cells but not in normal T cells (1). These findings suggest that ZAP-70 is an Hsp90 client protein that can be targeted by Hsp90 antagonists.
The specific aims of our proposal are the following:
Examine whether the presence of active Hsp90 is a prognostic factor in CLL B cells either independently or in association with other prognostic factors.
Examine the molecular and biochemical basis that determine the status of “conditional” Hsp90 client protein of ZAP-70 expressed in CLL-B cells but not in normal T cells.
Characterize the process of ZAP-70 associated survival in CLL-B cells and the mechanisms involved in CLL B cell death after Hsp90 inhibition alone or in combination with other agents such as Fludarabine and Rituximab.
Develop a phase I/II clinical trial in patients with CLL using a novel lipid formulation of 17-AAG and assess in vivo:
safety and toxicity profile
pharmacokinetic, pharmacodynamic and biomarker parameters