| Reference | 1. PLoS One. 2017 Mar 6;12(3):e0173507. doi: 10.1371/journal.pone.0173507.
eCollection 2017.
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Enhancement of pomalidomide anti-tumor response with ACY-241, a selective HDAC6
inhibitor.
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North BJ(1), Almeciga-Pinto I(1), Tamang D(1), Yang M(1), Jones SS(1), Quayle
SN(1).
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Author information: <br>
(1)Acetylon Pharmaceuticals, Boston, Massachusetts, United States of America.
<br>
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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2. Oncotarget. 2017 Jan 10;8(2):2694-2707. doi: 10.18632/oncotarget.13738.
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Selective HDAC inhibition by ACY-241 enhances the activity of paclitaxel in solid
tumor models.
<br><br>
Huang P(1), Almeciga-Pinto I(1), Jarpe M(1), van Duzer JH(1), Mazitschek R(2),
Yang M(1), Jones SS(1), Quayle SN(1).
<br>
Author information: <br>
(1)Acetylon Pharmaceuticals, Inc., Boston, MA 02210, USA.
(2)Center for Systems Biology, Massachusetts General Hospital, Harvard Medical
School, Boston, MA, USA.
<br><br>
ACY-241 is a novel, orally available and selective histone deacetylase (HDAC) 6
inhibitor in Phase 1b clinical development in multiple myeloma (NCT 02400242).
Like the structurally related drug ACY-1215 (ricolinostat), ACY-241 has the
potential for a substantially reduced side effect profile versus current
nonselective HDAC inhibitor drug candidates due to reduced potency against Class
I HDACs while retaining the potential for anticancer effectiveness. We now show
that combination treatment of xenograft models with paclitaxel and either
ricolinostat or ACY-241 significantly suppresses solid tumor growth. In cell
lines from multiple solid tumor lineages, combination treatment with ACY-241 and
paclitaxel enhanced inhibition of proliferation and increased cell death relative
to either single agent alone. Combination treatment with ACY-241 and paclitaxel
also resulted in more frequent occurrence of mitotic cells with abnormal
multipolar spindles and aberrant mitoses, consistent with the observed increase
of aneuploid cells. At the molecular level, multipolar mitotic spindle formation
was observed to be NuMA-dependent and γ-tubulin independent, suggesting that
treatment-induced multipolar spindle formation does not depend on centrosomal
amplification. The significantly enhanced efficacy of ACY-241 plus paclitaxel
observed here, in addition to the anticipated superior safety profile of a
selective HDAC6 inhibitor versus pan-HDAC inhibitors, provides a strong rationale
for clinical development of this combination in patients with advanced solid
tumors.
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