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.
Highlights
Despite significant progress in recent years in unraveling the genetic basis of acute myeloid leukemia (AML) [1], resulting in improvements in our ability to prognosticate and predict outcomes with certain therapies [2], it remains a devastating disease
histone deacetylase inhibitor (HDACI) disrupt mitotic spindle checkpoints in neoplastic cells [70] and induce “mitotic slippage” [71]. These findings have provided the rationale for multiple preclinical studies that have demonstrated the synergism between HDACIs and
The number of rational combinations of targeted agents that are possible in AML and may be effective, at least in theory, is virtually limitless
Summary
Despite significant progress in recent years in unraveling the genetic basis of AML [1], resulting in improvements in our ability to prognosticate and predict outcomes with certain therapies [2], it remains a devastating disease. The anthracyclinecytarabine backbone, first introduced over 40 years ago [4], remains the cornerstone of initial therapy for most patients, and the only truly targeted agent to receive http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4470160/?report=printable regulatory approval, gemtuzumab ozogamycin, has been voluntarily withdrawn from the market by the manufacturer [5,6]. The concept of rationally combining targeted agents to defeat the redundancy of survival pathways in neoplastic cells has rapidly been gaining ground in a variety of tumor types [17].
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