B-cell chronic lymphocytic leukemia [B-CLL] is a human neoplastic disorder characterized by the progressive accumulation of quiescent B lymphocyte. We have hypothesized that B CLL arises primarily because of failures in the normal mechanisms of cell turnover through programmed cell death, rather than as a result of alterations in cell cycle regulation, and that anomalies in the expression and function of apoptosis-regulatory proteins are the critical obstacle to the successful treatment of this malignancy. The overall goal of the biochemistry component of the B-CLL Research Consortium [CRC] is to define the fundamental abnormalities of apoptosis regulation in B-CLL, and to devise targeted treatments that address the basic problems. During the previous funding period, our experiments have demonstrated that several pro-apoptotic proteins [including Bax, BH3-only proteins such as Bim, caspases] are abundantly expressed in B-CLL but are maintained in an inactive state by the concomitant high-level expression of specific anti-apoptotic proteins [including Bcl-2, Mcl-1, lAPs, FLIP]. Accordingly, the specific hypothesis to be tested in this renewal application is that chemical agents that release pro-apoptotic proteins from inhibitory complexes will trigger apoptosis of B-CLL cells, or render these malignant cells more susceptible to cytotoxic therapy or immunotherapy. Working in collaboration with members of the CRC and other scientists, we have identified several new agents that can overcome in vitro some of the apoptosis defects in B-CLL. These prototype compounds have been demonstrated to block Bcl-2 interaction with BH3 proteins, to reverse IAP inhibition of caspases, or to release the BH3-only protein Bim from microtubules. The focus of the planned experiments in the CRC grant renewal is to continue our preclinical analysis of these prototype therapeutics, testing their efficacy against cultured CLL B-cells, improving our understanding of their mechanisms of action, and optimizing approaches for employing these agents, in hope of rapidly bringing these concepts and the new agents into the clinic.
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