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.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
1R01CA178264-01A1
Application #
8757662
Study Section
Clinical Oncology Study Section (CONC)
Program Officer
Alley, Michael C
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02215
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Tai, Yu-Tzu; Acharya, Chirag; An, Gang et al. (2016) APRIL and BCMA promote human multiple myeloma growth and immunosuppression in the bone marrow microenvironment. Blood 127:3225-36
Hideshima, Teru; Qi, Jun; Paranal, Ronald M et al. (2016) Discovery of selective small-molecule HDAC6 inhibitor for overcoming proteasome inhibitor resistance in multiple myeloma. Proc Natl Acad Sci U S A 113:13162-13167
Ohguchi, Hiroto; Hideshima, Teru; Bhasin, Manoj K et al. (2016) The KDM3A-KLF2-IRF4 axis maintains myeloma cell survival. Nat Commun 7:10258
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Bae, J; Prabhala, R; Voskertchian, A et al. (2015) A multiepitope of XBP1, CD138 and CS1 peptides induces myeloma-specific cytotoxic T lymphocytes in T cells of smoldering myeloma patients. Leukemia 29:218-29
Hideshima, T; Mazitschek, R; Santo, L et al. (2014) Induction of differential apoptotic pathways in multiple myeloma cells by class-selective histone deacetylase inhibitors. Leukemia 28:457-60

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