TY - JOUR
T1 - Enhancement of pomalidomide anti-Tumor response with ACY-241, a selective HDAC6 inhibitor
AU - North, Brian J.
AU - Almeciga-Pinto, Ingrid
AU - Tamang, David
AU - Yang, Min
AU - Jones, Simon S.
AU - Quayle, Steven N.
N1 - Publisher Copyright:
© 2017 North et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2017/3
Y1 - 2017/3
N2 - Thalidomide-based Immunomodulatory Drugs (IMiDs®), including lenalidomide and pomalidomide, are effective therapeutics for multiple myeloma. These agents have been approved with, or are under clinical development with, other targeted therapies including proteasome inhibitors, αCD38 monoclonal antibodies, as well as histone deacetylase (HDAC) inhibitors for combination therapy. HDAC inhibitors broadly targeting Class I and IIb HDACs have shown potent preclinical efficacy but have frequently demonstrated an undesirable safety profile in combination therapy approaches in clinical studies. Therefore, development of more selective HDAC inhibitors could provide enhanced efficacy with reduced side effects in combination with IMiDs® for the treatment of B-cell malignancies, including multiple myeloma. Here, the second generation selective HDAC6 inhibitor citarinostat (ACY-241), with a more favorable safety profile than non-selective pan-HDAC inhibitors, is shown to synergize with pomalidomide in in vitro assays through promoting greater apoptosis and cell cycle arrest. Furthermore, utilizing a multiple myeloma in vivo murine xenograft model, combination treatment with pomalidomide and ACY-241 leads to increased tumor growth inhibition. At the molecular level, combination treatment with ACY-241 and pomalidomide leads to greater suppression of the pro-survival factors survivin, Myc, and IRF4. The results presented here demonstrate synergy between pomalidomide and ACY-241 in both in vitro and in vivo preclinical models, providing further impetus for clinical development of ACY-241 for use in combination with IMiDs for patients with multiple myeloma and potentially other B-cell malignancies.
AB - Thalidomide-based Immunomodulatory Drugs (IMiDs®), including lenalidomide and pomalidomide, are effective therapeutics for multiple myeloma. These agents have been approved with, or are under clinical development with, other targeted therapies including proteasome inhibitors, αCD38 monoclonal antibodies, as well as histone deacetylase (HDAC) inhibitors for combination therapy. HDAC inhibitors broadly targeting Class I and IIb HDACs have shown potent preclinical efficacy but have frequently demonstrated an undesirable safety profile in combination therapy approaches in clinical studies. Therefore, development of more selective HDAC inhibitors could provide enhanced efficacy with reduced side effects in combination with IMiDs® for the treatment of B-cell malignancies, including multiple myeloma. Here, the second generation selective HDAC6 inhibitor citarinostat (ACY-241), with a more favorable safety profile than non-selective pan-HDAC inhibitors, is shown to synergize with pomalidomide in in vitro assays through promoting greater apoptosis and cell cycle arrest. Furthermore, utilizing a multiple myeloma in vivo murine xenograft model, combination treatment with pomalidomide and ACY-241 leads to increased tumor growth inhibition. At the molecular level, combination treatment with ACY-241 and pomalidomide leads to greater suppression of the pro-survival factors survivin, Myc, and IRF4. The results presented here demonstrate synergy between pomalidomide and ACY-241 in both in vitro and in vivo preclinical models, providing further impetus for clinical development of ACY-241 for use in combination with IMiDs for patients with multiple myeloma and potentially other B-cell malignancies.
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U2 - 10.1371/journal.pone.0173507
DO - 10.1371/journal.pone.0173507
M3 - Article
C2 - 28264055
AN - SCOPUS:85014630341
VL - 12
JO - PLoS One
JF - PLoS One
SN - 1932-6203
IS - 3
M1 - e0173507
ER -