Heat shock protein (HSP)-90 is an intracellular protein that chaperons several client oncoproteins important for the neoplastic process, making it a promising molecular target for cancer therapy. HSP-90 maintains the conformation, stability, and function of several critical client oncoproteins involved in regulating cell survival, proliferation, and apoptosis. Several cancer types, including lymphoma cells, have been shown to express high levels of HSP-90 compared with normal tissue. 17-AAG, a small molecule analog of geldanamycin, binds specifically and inhibits HSP-90 function, causing degradation of its client oncoproteins such as AKT, mutant p53, cyclin D1, Raf and other client proteins that are involved in cell signaling, survival, and proliferation. 17-AAG has demonstrated anti proliferative activity against several solid tumor and leukemia cells in preclinical models, and phase-l studies have demonstrated its safety in patients with cancer. However, the activity of 17-AAG in non-Hodgkin's lymphoma (NHL) and Hodgkin lymphoma (HL) is not known. We and others have recently demonstrated that HSP-90 is abundantly expressed in lymphoma cells. Furthermore, our preliminary data demonstrated that 17-AAG can induce apoptosis in several NHL and HL cell lines in a dose and time-dependent manner. At the molecular level, our preliminary data demonstrated that 17-AAG decreased lymphoma cellular contents of critical survival and cell cycle proteins including AKT, ERK, and cyclin D1; and activated the intrinsic caspase pathway. These favorable in vitro anti-tumor activities were observed in mantle cell lymphoma (MCL), anaplastic large cell lymphoma (ALCL) and HL cell lines. With this background, we initiated a phase-lI study of 17-AAG in patients with relapsed lymphoma. The purpose of this proposal is to evaluate the efficacy and safety of 17-AAG in the treatment of patients with relapsed and refractory NHL and classical HL.
In Aim 1, we propose to examine the activity of 17-AAG in a multi-center, CTEP-sponsored phase-ll clinical trial in patients with relapsed and refractory MCL, ALCL, and classical HL.
In Aim 2, we propose to evaluate the biologic effect of 17-AAG on selected molecular targets in primary lymphoma cells obtained from patients treated with 17-AAG.
In Aim 3 we will correlate the biologic effects of 17-AAG and clinical response in patients with relapsed MCL, ALCL, and HL. ? ? ?
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