6570 Background: 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. 17-AAG, a small molecule analog of geldanamycin, binds specifically and inhibits HSP-90 function causing degradation of its client oncoproteins 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. However, the activity of 17-AAG in non-Hodgkin’s lymphoma (NHL) and Hodgkin’s lymphoma (HL) is not known. Methods: The activity of 17-AAG was determined in 9 lymphoma cell lines (Hodgkin Lymphoma, Anaplastic Large Cell Lymphoma, Mantle Cell Lymphoma). Cell viability was determined by the MTS assay, and apoptosis by Annexin-V binding. Molecular changes were determined by western blot. Results: HSP90 was abunndently expressed in all lymphoma cell lines. 17-AAG induced cell death in all cell lines in a time and dose dependent manner. The antiproliferative activity was due to cell cycle arrest in the G0/G1 phase, or in the G2/M phase which was followed by apoptosis. Apoptosis was triggered by activating the intrinsic caspase pathway (by cleaving caspase 9 and PARP), and was partially reversed by the administration of the pan-caspase inhibitor Z-VAD-FMK. Furthermore, 17-AAG decreased the cellular contents of the antiapoptotic proteins (cFLIP, XIAP, Bcl-2), as well as survival and proliferation signaling molecules (AKT, ERK1/2). Moreover, 17-AAG showed synergistic effect when combined with doxorubicin chemotherapy, the proteasome inhibitor bortezomib and the anti-TRAIL death receptors R1 and R2 monoclonal antibodies (HGS-ETR1 and HGS-ETR2). Conclusions: Based on these favorable activities of 17-AAG, we are conducting a phase-II study of 17-AAG in patients with relapsed HL and NHL. No significant financial relationships to disclose.