Januario E. Castro, M.D. University of California, San Diego

THERAPY/ PROGNOSTIC

Targeting ZAP-70 Tyrosine Kinase in Chronic Lymphocytic Leukemia

Grant awarded in 2005

Abstract:

This proposal will study signaling pathways and 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. The abnormal expression of ZAP-70 provides a potential growth factor stimulus to CLL cells that may drive disease progression.

The specific aims of our proposal are the following:

1. Examine whether the presence of a protein (active Hsp90) is a prognostic factor in CLL-B cells either independently or in association with other factors.
2. Examine the molecular and biochemical basis that determines protein expression in CLL-B cells but not in normal T-cells.
3. 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.
4. Develop a phase I/II clinical trial in patients with CLL using a novel lipid formulation of 17-AAG and assess: 1) safety and toxicity profile, 2) pharmacokinetic, pharmacodynamic and biomarker parameters, and 3) evaluate response to treatment.