PROJECT 2: Molecular Inhibition of Apoptosis Inhibitors B-cell chronic lymphocytic leukemia [B-CLL] arises primarily because of failures in apoptosis mechanisms. Aberrant over-expression of anti-apoptotic Bcl-2 family proteins contributes greatly to the long lifespan of CLL cells, and also thwarts attempts to eradicate these leukemic cells by chemotherapy. The human genome contains six genes encoding anti-apoptotic Bcl-2 family proteins (Bcl-2, BCI-XL, Mcl-1, Bfl-1, Bcl-W, Bcl-B), several of which are often highly expressed in CLLs. Expression of Mcl-1 or Bfl-1 accounts for resistance to chemical antagonists of Bcl-2, such as ABT263 analogs. Moreover, expression of these pro survival proteins increases in CLL cells thriving in microenvironmental niches. We hypothesize that redundancy caused by multiple anti-apoptotic Bcl-2 family members is a critical barrier to effective treatment of CLL. We propose to test this hypothesis through 3 complementary approaches. First. ABT263 and other small molecule Bcl-2 antagonists currently in clinical development bind a regulatory site on Bcl-2, mimicking endogenous antagonists that contain the BH3 domain. We have generated novel BH3 mimicking compounds with broad-spectrum inhibitory activity against all anti-apoptotic Bcl-2 family proteins. These compounds will be tested for preclinical activity against primary human CLL cells in culture and against murine CLL cells in transgenic mouse models. Second, we have identified a non-BH3 regulator of Bcl-2 in the Nur77/TR3 protein, an orphan nuclear receptor that binds to Bcl-2, Bfl-1, and Bcl-B, converting these proteins from antito pro-apoptotic. Using Nur77/TR3, we have discovered a novel non-BH3 regulatory site on Bcl-2 family proteins that will be targeted with small molecules as an alternative approach to Bcl-2 antagonism. Third. expression of many anti-apoptotic Bcl-2 family proteins (including Mel-1, BCI-XL, and Bfl-1) is upregulated when CLL cells are influenced by microenvironment. Hence, agents from Aims 1 and 2 will be evaluated for activity against CLL cells using in vitro culture models of microenvironment interactions. Altogether, our goal is to extend preclinical studies of novel Bcl-2 family antagonists towards the ultimate goal of bringing these concepts and new agents into the clinic via the CLL Research Consortium (CRC).
CLL is the most common type of leukemia in the Western world, remaining incurable with currently available therapies. In this project, we propose to generate novel pro-apoptotic drugs and to elucidate synergistic drug combinations, creating novel strategies for the improved treatment of CLL.
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