title: Rational Combinations of Targeted Agents in AML.
abstract: Despite modest improvements in survival over the last several decades, the treatment of AML continues to present a formidable challenge. Most patients are elderly, and these individuals, as well as those with secondary, therapy-related, or relapsed/refractory AML, are particularly difficult to treat, owing to both aggressive disease biology and the high toxicity of current chemotherapeutic regimens. It has become increasingly apparent in recent years that coordinated interruption of cooperative survival signaling pathways in malignant cells is necessary for optimal therapeutic results. The modest efficacy of monotherapy with both cytotoxic and targeted agents in AML testifies to this. As the complex biology of AML continues to be elucidated, many "synthetic lethal" strategies involving rational combinations of targeted agents have been developed. Unfortunately, relatively few of these have been tested clinically, although there is growing interest in this area. In this article, the preclinical and, where available, clinical data on some of the most promising rational combinations of targeted agents in AML are summarized. While new molecules should continue to be combined with conventional genotoxic drugs of proven efficacy, there is perhaps a need to rethink traditional philosophies of clinical trial development and regulatory approval with a focus on mechanism-based, synergistic strategies.
authors.affiliation: Department of Internal Medicine, Virginia Commonwealth University and VCU Massey Cancer Center Center, 1201 E Marshall St, MMEC 11-213, P.O. Box 980070, Richmond, VA 23298, USA.
authors.forename: Prithviraj
authors.initials: P
authors.lastname: Bose
authors.affiliation: Departments of Internal Medicine, Microbiology and Immunology, Biochemistry and Molecular Biology, Human and Molecular Genetics and the Institute for Molecular Medicine, Virginia Commonwealth University and VCU Massey Cancer Center, 401 College St, P.O. Box 980035, Richmond, VA 23298, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Grant
keywords: AML; BH3-mimetics; CDK inhibitors; HDAC inhibitors; Mcl-1; apoptosis; checkpoint abrogators; proteasome inhibitors; rational combinations; targeted therapies