Multiple myeloma (MM) is the second most common hematological malignancy, remains incurable despite novel agents including proteasome inhibitors (bortezomib) and immunomodulatory drugs (thalidomide, lenalidomide). Therefore biologically-based novel treatment strategies are urgently needed to improve MM patient outcome. Deacetylase (DAC) inhibitors are a new class of novel agents with remarkable anti-MM effects in preclinical studies;however, their clinical activities are limited due to unfavorabl toxicities including fatigue, diarrhea, and thrombocytopenia attendant to broad inhibition of DAC isoforms. We here hypothesize that isoform-selective DAC inhibition can avoid these adverse effects while maintaining potent anti-MM cytotoxicity. We have previously shown that DAC6 selective inhibitors (tubacin, ACY-1215) show significant anti-MM activities in combination with bortezomib and demonstrated its mechanism in preclinical studies. Importantly we have rapidly translated ACY-1215 to clinical trials, alone and with bortezomib, which show favorable tolerability and promising clinical activity. In our preliminary studies, DAC3 selective knockdown and a small molecule inhibitor BG45 show significant MM cell growth inhibition in vitro and in vivo murine xenograft model.
In Aim1, we will further validate DAC3 selective knockdown and its functional impact on MM cell growth, survival, and drug resistance, and delineate the transcriptional and molecular signaling mechanisms of observed effects.
In Aim2, we will develop and validate novel DAC3-selective inhibitors, alone and in combination, using our established in vitro systems of MM in the context of bone marrow microenvironment.
In Aim 3, we will validate the anti-MM activity of DAC3-selective inhibitors in vivo, alone or in combination specifically with proteasome inhibitors. These studies will provide the basis for derived clinical trials of DAC3 inhibitor for MM. We have recently translated DAC6 inhibitor ACY-1215 from the bench to the phase I/II clinical trials in only two years, and here will rapidly in an analogous fashion focus on DAC3 biology and potential as a novel clinical target in MM.

Public Health Relevance

Multiple myeloma (MM) is an incurable plasma cell malignancy, and novel therapeutic agents are urgently needed. Non-selective deacetylase (DAC) inhibitors show remarkable anti-myeloma (MM) activity;however, their clinical utility is limited by adverse effects. This project investigates biologic and functional significance of DAC3 in MM, as well as produces and preclinically validates novel selective DAC3 inhibitors for translation to clinical trials to improve patient outcome in MM.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Clinical Oncology Study Section (CONC)
Program Officer
Alley, Michael C
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Dana-Farber Cancer Institute
United States
Zip Code
GullĂ , A; Hideshima, T; Bianchi, G et al. (2018) Protein arginine methyltransferase 5 has prognostic relevance and is a druggable target in multiple myeloma. Leukemia 32:996-1002
Ray, A; Das, D S; Song, Y et al. (2018) Combination of a novel HDAC6 inhibitor ACY-241 and anti-PD-L1 antibody enhances anti-tumor immunity and cytotoxicity in multiple myeloma. Leukemia 32:843-846
Anderson, Kenneth C (2018) Promise of Immune Therapies in Multiple Myeloma. J Oncol Pract 14:411-413
Harada, T; Ohguchi, H; Grondin, Y et al. (2017) HDAC3 regulates DNMT1 expression in multiple myeloma: therapeutic implications. Leukemia 31:2670-2677
Hideshima, Teru; Cottini, Francesca; Nozawa, Yoshihisa et al. (2017) p53-related protein kinase confers poor prognosis and represents a novel therapeutic target in multiple myeloma. Blood 129:1308-1319
Sagawa, Morihiko; Ohguchi, Hiroto; Harada, Takeshi et al. (2017) Ribonucleotide Reductase Catalytic Subunit M1 (RRM1) as a Novel Therapeutic Target in Multiple Myeloma. Clin Cancer Res 23:5225-5237
Ohguchi, H; Harada, T; Sagawa, M et al. (2017) KDM6B modulates MAPK pathway mediating multiple myeloma cell growth and survival. Leukemia 31:2661-2669
Hideshima, Teru; Mazitschek, Ralph; Qi, Jun et al. (2017) HDAC6 inhibitor WT161 downregulates growth factor receptors in breast cancer. Oncotarget 8:80109-80123
Ohguchi, Hiroto; Hideshima, Teru; Bhasin, Manoj K et al. (2016) The KDM3A-KLF2-IRF4 axis maintains myeloma cell survival. Nat Commun 7:10258
GullĂ , Annamaria; Di Martino, Maria Teresa; Gallo Cantafio, Maria Eugenia et al. (2016) A 13 mer LNA-i-miR-221 Inhibitor Restores Drug Sensitivity in Melphalan-Refractory Multiple Myeloma Cells. Clin Cancer Res 22:1222-33

Showing the most recent 10 out of 22 publications