B-CLL models for testing BH3-mimetic compounds

Chronic lymphocytic leukaemia (CLL) is the commonest form of leukaemia in adults, and is a clinically heterogeneous disease. For younger patients, and those with aggressive disease, treatment is often unsatisfactory, particularly following relapse after modern chemo-immunotherapy. An underlying defect in CLL cells is resistance to programmed cell death (apoptosis) due to the overexpression of Bcl-2. Apoptosis normally operates to remove damaged and unwanted cells, thereby preventing the development of diseases such as leukaemia. Because of the apoptotic defect, CLL cells are typically long-lived and over time develop resistance to chemotherapy. Bcl-2 is therefore an attractive target for novel therapies which aim to directly trigger apoptosis in CLL. Recently, a new class of anti-cancer agents has been developed that directly target the Bcl-2 pro-survival proteins. These BH3 mimetic compounds are designed to mimic the natural antagonists of Bcl-2, the BH3-only proteins. By mimicking their physiological antagonists, BH3 mimetics bind and directly antagonize the action of pro-survival Bcl-2 proteins. Compounds in this class have shown single agent activity in refractory or relapsed lymphoid malignancies. However, pre-clinical and early phase clinical studies suggest that they only eliminate a proportion of the leukaemic cells in some patients. The main objective of this research proposal is to develop and validate clinically relevant models of CLL for the in vitro and in vivo pre-clinical assessment of a range of BH3 mimetic compounds in order to understand the basis of treatment outcomes. The goals of this project are to generate models that most closely approximate the human disease and then to validate and optimize therapeutic regimens incorporating newly available BH3-mimetic compounds.