Antiangiogenic Agents in Myeloid Malignancies

Abstract

The role of angiogenesis in the development and progression of solid tumors has been well established over the 1980s and 1990s. Through more recent investigations, it has become increasingly clear that neovascularization within the bone marrow of patients with hematologic malignancies is of primary importance in the development and progression of these disorders. Evidence of malignant angiogenesis in myeloid malignancies includes increased microvascularity and vascular density within the bone marrow cavity, elevated serum or urine levels of soluble angiogenic peptides, and cellular over-expression of angiogenic molecules and their cognate receptors. Autocrine and paracrine secretion of angiogenic factors such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and angiogenin contributes not only to medullary vasculogenesis but also to the proliferation of myeloid precursors and alteration of their microenvironment. Pro-angiogenic molecules have been linked to prognosis and implicated in the progression of hematologic malignancies. Therapeutic strategies intended to inhibit angiogenesis in myeloid malignancies have reached maturity over the 1990s. Lenalidomide is the first such antiangiogenic agent to receive Food and Drug Administration (FDA) approval for the treatment of myelodysplastic syndrome (MDS) based on hematologic and cytogenetic responses. Other investigational agents in the treatment of myeloid disorders, such as thalidomide, arsenic trioxide (ATO), and bevacizumab, have shown promise as single agents or in combination with chemotherapy in the treatment of leukemia and MDS. Novel small-molecule tyrosine kinase inhibitors (TKIs) with activity against a spectrum of angiogenic receptors have completed early-phase clinical trials showing modest clinical activity. Further investigation of the contribution of angiogenic molecules to the development and progression of myeloid malignancies before this new class of therapeutics can be further integrated into standard practice.