Antiangiogenic strategies for the treatment of haematological malignancies

Angiogenesis plays a key role in the pathogenesis of haematological malignancies such as acute myeloid leukaemia (AML), multiple myeloma (MM) and lymphoma (NHL). The evidence supporting this theory includes the finding of increased bone marrow microvessel density and increased levels of plasma and urinary pro-angiogenic cytokines in patients with these malignancies as well as encouraging results from preclinical and clinical studies using antiangiogenic therapies. A significant limiting factor in most of these studies has been the short half-life of most antiangiogenic compounds which has necessitated the use of cumbersome administration protocols resulting in poor compliance and an inability to administer the drug long enough to result in its desired therapeutic effect. The aim of this thesis therefore is to investigate the therapeutic effects of stable antiangiogenic expression in xenograft models of AML, NHL and MM. We investigated the antitumour effects of stably blocking the vascular endothelial growth factor (VEGF) pathway, the matrix metalloproteinase pathway and the use of interferons, a family of cytokines with significant antitumour activity resulting not only from their antiangiogenic properties but also from their anti-proliferative, anti-apoptotic and immunomodulatory effects. Murine models of AML, NHL and MM were developed by engrafting a number of well characterized tumour cell lines – HL-60, Raji and KMS12-BM respectively into β2mnull NOD/SCID immunodeficient mice, resulting in a tumour phenotype resembling the human disease. Blockade of the VEGF pathway was achieved by stably expressing the soluble form of the VEGF receptor (sFlk-1) using adeno associated viral vectors or by using an antibody directed against VEGF but neither strategy resulted in antitumour activity in AML or NHL xenograft models. We were however able to show that stable expression of tissue inhibitor of metalloproteinase-3 (TIMP-3) resulted in significant antitumor activity against MM cells in vivo. Finally we were able to demonstrate for the first time that Interferon-β has profound antileukaemic activity in the setting of a xenograft model and that even low level expression when stable can significantly inhibit primary AML engraftment in vivo