title: Novel combination treatments targeting chronic myeloid leukemia stem cells.
abstract: Chronic myeloid leukemia (CML) is currently considered incurable in most patients. Stem cell transplantation, an accepted curative option for which extensive experience has been gained, is limited by high morbidity and mortality rates, particularly in older patients. Tyrosine kinase inhibitors targeting BCR-ABL are widely used and induce remission in a high proportion of patients, but resistance and incomplete response to these agents portends eventual relapse and disease progression. Although BCR-ABL inhibitors eradicate most CML cells, they are largely ineffective against the reservoir of quiescent leukemic stem cells (LSCs). Thus a strong medical need exists for therapies that effectively eradicate LSCs and is currently a focus of extensive research. To date, evidence obtained from in vitro studies, animal models, and clinical CML specimens suggests that an effective approach may be to partner existing BCR-ABL inhibitors with compounds targeting key stem cell molecular effectors, including Wnt/β-catenin, hedgehog pathway components, histone deacetylase (HDAC), transforming growth factor-β (TGF-β), Janus kinase 2, promyelocytic leukemia protein, and arachidonate 5-lipoxygenase (ALOX5). Novel combinations may sensitize LSCs to BCR-ABL inhibitors, thereby overcoming resistance and creating the possibility of improving disease outcome beyond the current standard of care.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Indiana University, Indianapolis, IN 46202, USA.
authors.forename: Tareq
authors.initials: T
authors.lastname: Al Baghdadi
authors.forename: Rafat
authors.initials: R
authors.lastname: Abonour
authors.forename: H Scott
authors.initials: HS
authors.lastname: Boswell
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use*; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism; D058990:Molecular Targeted Therapy; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D016044:Fusion Proteins, bcr-abl