Mechanism-Based Pharmacologic Intervention

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PROJECT SUMMARY (See instructions): While development of new therapeutic approaches have contributed to the increase in the complete remission rate for CLL patients, relapses and resistance to re-treatment remain a significant problem. Nevertheless, changes that occur in the biology of CLL upon relapse from front-line therapies provide clues to resistance mechanisms that prevent prolonged complete responses. Our overall strategy is to employ three novel approaches that are each directed at an aspect of the pathophysiology of CLL and the mechanisms associated with resistance. First, a deletion at 11q22-23, the site of the ATM gene, occurs in half of relapsed/refractory patients. Mutation of the residual allele (-50%) inactivates homologous recombinafion (HR) repair of double strand breaks. Because Sapacitabine causes one-ended double strand breaks, cells that lack ATM are selectively sensitized. We will develop assays to identify patients who's CLL lacks ATM function, and initiate a clinical trial of Sapacitabine therapy to test the hypothesis that their disease will be selecfively sensitized. Second, studies in model systems demonstrate that loss of p53 function is a resistance mechanism to cytotoxic therapy. Neariy half of relapsed refractory patients lack p53 funcfion. We postulate that expression of the epigenetically silenced p73 will serve in place of p53 to activate expression of pro-apoptotic proteins. This will be validated in model systems and tested in a clinical trial. Third, a novel mechanism by which the microenvironment sustains CLL cells and increases resistance to chemotherapy appears to act by providing precursors for glutathione. This sustains CLL by neutralizing the destructive action of reactive oxygen species that are innately over-expressed by CLL. By using a small molecule to reduce glutathione we will test this hypothesis to sensitize CLL cells in vitro and in vivo. These investigations will provide mechanism-based rationales for development of combination therapies.