Rational Combinations of Targeted Agents in AML
Abstract
:1. Introduction
2. Combinations Involving Epigenetic Therapies
2.1. DNMTIs + HDACIs
2.2. Other DNMTI-Based Combinations
2.3. BET Inhibitor-Based Combinations
3. HDACI-Based Combinations Involving Non-Epigenetic Therapies (Table 1)
3.1. HDACIs + Proteasome Inhibitors
3.2. HDACIs + CDK Inhibitors
3.3. HDACIs + TKIs
3.4. HDACIs + G2/M Checkpoint Abrogators
3.5. Other HDACI-Based Rational Combinations in AML
4. Priming Apoptosis
Partner Agent Class | Mechanism(s) of Synergy | Clinical Trials, if any | Reference(s) |
---|---|---|---|
Proteasome inhibitors (PIs), e.g., bortezomib, carfilzomib, ixazomib, oprozomib, marizomib | NF-κB inhibition by PIs (activated by HDACIs); inhibition by HDACIs of aggresome formation and of Hsp90→increased proteotoxic stress, multiple other actions | NCT01075425; closed to accrual; phase I; enrolled primarily relapsed/refractory patients with AML; one CR, one prolonged SD (see text) | [48,49] |
Cyclin-dependent kinase inhibitors (CDKIs), e.g., flavopiridol (alvocidib), roscovitine (seliciclib), dinaciclib, palbociclib | Down-regulation of XIAP and Mcl-1 by cyclin T/CDK9 inhibitors via transcriptional repression; blockade by CDKIs of HDACI-induced up-regulation of p21 | NCT00278330; completed; phase I; enrolled primarily relapsed/refractory patients with AML; no objective responses; 50% achieved SD | [62,63,64,65,66,67] |
Multi-kinase inhibitors (that inhibit aurora kinases and critical signaling molecules in AML, e.g., FLT3, JAK2), e.g., MK-0457, KW-2449, AT9283 | Down-regulation of Hsp90 “client” proteins by HDACIs, e.g., FLT3, c-Raf, Akt, JAK2, disruption of mitotic spindle checkpoints and induction of mitotic “slippage” | [77,79,81] | |
Checkpoint abrogators, e.g., MK-8776 (Chk1 inhibitor), AZD-1775 (Wee1 inhibitor) | Induction of DNA damage and inhibition of DNA repair by HDACIs; down-regulation of ATR, Chk1 and Wee1 by HDACIs via Hsp90 inhibition | Phase I clinical trial of Wee1 inhibitor AZD-1775 and belinostat in patients with relapsed/refractory or poor-prognosis AML in development | [115,128] |
Polo-like kinase inhibitors, e.g., BI2536, volasertib | Potentiation of DNA damage and disruption of the DNA damage response by HDACIs | [136] | |
Protein neddylation inhibitors (MLN4924) | Inhibition of NF-κB (activated by HDACIs) by MLN4924, ROS generation and induction of DNA damage by MLN4924 as well as by HDACIs, opposing effects on autophagy | Manuscript in preparation | |
BH3-mimetics, e.g., obatoclax, navitoclax, venetoclax | Up-regulation of Bim by HDACIs, which is released from Bcl-2 and Bcl-xL by ABT-737, activation of cytotoxic autophagy (obatoclax) | [189,190] | |
PI3K/Akt/mTOR pathway inhibitors, e.g., LY294002, buparlisib, idelalisib, duvelisib (PI3K inhibitors), perifosine (Akt inhibitor), BEZ235 (PI3K/mTOR inhibitor) | Bcl-2 and Bid cleavage, down-regulation of Mcl-1 and XIAP, MAPK/ERK inactivation, JNK activation, ROS generation, blockade of HDACI-mediated induction of p21 | [160,161] |
5. Other Rational Combinations
6. Conclusions
Author Contributions
Conflicts of Interest
Acknowledgements
References
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Bose, P.; Grant, S. Rational Combinations of Targeted Agents in AML. J. Clin. Med. 2015, 4, 634-664. https://doi.org/10.3390/jcm4040634
Bose P, Grant S. Rational Combinations of Targeted Agents in AML. Journal of Clinical Medicine. 2015; 4(4):634-664. https://doi.org/10.3390/jcm4040634
Chicago/Turabian StyleBose, Prithviraj, and Steven Grant. 2015. "Rational Combinations of Targeted Agents in AML" Journal of Clinical Medicine 4, no. 4: 634-664. https://doi.org/10.3390/jcm4040634