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Review
. 2015 Apr 10;4(4):634-664.
doi: 10.3390/jcm4040634. eCollection 2015 Apr.

Rational Combinations of _targeted Agents in AML

Prithviraj Bose  1 , Steven Grant  2
Affiliations
Review

Rational Combinations of _targeted Agents in AML

Prithviraj Bose et al. J Clin Med. .

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.

Keywords: AML; BH3-mimetics; CDK inhibitors; HDAC inhibitors; Mcl-1; apoptosis; checkpoint abrogators; proteasome inhibitors; rational combinations; _targeted therapies.

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Figures

Figure 1
Figure 1
Mechanisms of HDACI lethality. Reproduced, with permission, from [45].
Figure 2
Figure 2
Should be: Mechanisms of potentiation of BH3-mimetic lethality by strategies _targeting Mcl-1. Reproduced, with permission, from [184].
Figure 3
Figure 3
Hypothetical model of interactions between PI3K/AKT/mTOR pathway inhibitors and Bcl-2 antagonists. Reproduced, with permission, from [192].
See this image and copyright information in PMC

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