title: Acute myeloid leukemia in the vascular niche.
abstract: The greatest challenge in treating acute myeloid leukemia (AML) is refractory disease. With approximately 60-80% of AML patients dying of relapsed disease, there is an urgent need to define and target mechanisms of drug resistance. Unfortunately, targeting cell-intrinsic resistance has failed to improve clinical outcomes in AML. Emerging data show that cell-extrinsic factors in the bone marrow microenvironment protect and support AML cells. The vascular niche, in particular, regulates AML cell survival and cell cycling by both paracrine secretion and adhesive contact with endothelial cells. Moreover, AML cells can functionally integrate within vascular endothelia, undergo quiescence, and resist cytotoxic chemotherapy. Together, these findings support the notion of blood vessels as sanctuary sites for AML. Therefore, vascular targeting agents may serve to remit AML. Several early phase clinical trials have tested anti-angiogenic agents, leukemia mobilizing agents, and vascular disrupting agents in AML patients. In general, these agents can be safely administered to AML patients and cardiovascular side effects were reported. Response rates to vascular targeting agents in AML have been modest; however, a majority of vascular targeting trials in AML are monotherapy in design and indiscriminate in patient recruitment. When considering the chemosensitizing effects of targeting the microenvironment, there is a strong rationale to build upon these early phase clinical trials and initiate phase IB/II trials of combination therapy where vascular targeting agents are positioned as priming agents for cytotoxic chemotherapy.
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL, USA. Electronic address: christopher.cogle@medicine.ufl.edu.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Cogle
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Raphael C
authors.initials: RC
authors.lastname: Bosse
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Takae
authors.initials: T
authors.lastname: Brewer
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Yazan
authors.initials: Y
authors.lastname: Migdady
authors.affiliation: Health research institute, Research Center of Thalassemia & Hemoglobinopathy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
authors.forename: Reza
authors.initials: R
authors.lastname: Shirzad
authors.affiliation: Department of Pediatric Oncology/Hematology, University Medical Center Groningen, University of Groningen, The Netherlands.
authors.forename: Kim Rosalie
authors.initials: KR
authors.lastname: Kampen
authors.affiliation: Health research institute, Research Center of Thalassemia & Hemoglobinopathy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
authors.forename: Najmaldin
authors.initials: N
authors.lastname: Saki
mesh_terms: D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D000818:Animals; D001853:Bone Marrow / Q000098:blood supply*; D019008:Drug Resistance, Neoplasm; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D019899:Paracrine Communication / Q000187:drug effects; D012008:Recurrence; D015398:Signal Transduction / Q000187:drug effects; D059016:Tumor Microenvironment
chemical_list: D020533:Angiogenesis Inhibitors
keywords: Angiogenesis; Bone marrow; Clinical trials; Leukemia; Vascular targeting agents; Vasculogenesis