Oncotarget

Research Papers:

Selective HDAC inhibition by ACY-241 enhances the activity of paclitaxel in solid tumor models

Pengyu Huang, Ingrid Almeciga-Pinto, Matthew Jarpe, John H. van Duzer, Ralph Mazitschek, Min Yang, Simon S. Jones _ and Steven N. Quayle

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Oncotarget. 2017; 8:2694-2707. https://doi.org/10.18632/oncotarget.13738

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Abstract

Pengyu Huang1,*, Ingrid Almeciga-Pinto1,*, Matthew Jarpe1, John H. van Duzer1, Ralph Mazitschek2, Min Yang1, Simon S. Jones1, Steven N. Quayle1

1Acetylon Pharmaceuticals, Inc., Boston, MA 02210, USA

2Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

*These authors contributed equally to this work

Correspondence to:

Simon S. Jones, email: [email protected]

Keywords: HDAC, paclitaxel, solid tumors, mitotic spindle

Received: August 26, 2016     Accepted: November 24, 2016     Published: December 01, 2016

ABSTRACT

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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