Functional and biologic significance of deacetylase3 inhibition in myeloma

描述（由申请方提供）：多发性骨髓瘤（MM）是第二常见的血液系统恶性肿瘤，尽管使用了包括蛋白酶体抑制剂（硼替佐米）和免疫调节药物（沙利度胺、来那度胺）在内的新型药物，但仍然无法治愈。因此，迫切需要基于生物学的新型治疗策略来改善MM患者的结局。脱乙酰酶（DAC）抑制剂是一类新型药物，在临床前研究中具有显著的抗MM作用;然而，由于DAC亚型广泛抑制引起的不可忽视的毒性（包括疲劳、腹泻和血小板减少症），其临床活性有限。我们在此假设，亚型选择性DAC抑制可以避免这些不良反应，同时保持有效的抗MM细胞毒性。我们之前已经证明，DAC 6选择性抑制剂（tubacin，ACY-1215）与硼替佐米联合使用时显示出显著的抗MM活性，并在临床前研究中证明了其机制。重要的是，我们已经迅速将ACY-1215转化为临床试验，单独使用或与硼替佐米一起使用，显示出良好的耐受性和有希望的临床活性。在我们的初步研究中，DAC 3选择性敲低和小分子抑制剂BG 45在体外和体内小鼠异种移植模型中显示出显著的MM细胞生长抑制。在Aim 1中，我们将进一步验证DAC 3选择性敲除及其对MM细胞生长，存活和耐药性的功能影响，并描述观察到的效应的转录和分子信号传导机制。在Aim 2中，我们将在骨髓微环境中使用我们建立的MM体外系统开发和验证新型DAC 3选择性抑制剂（单独和组合）。在目标3中，我们将在体内验证DAC 3选择性抑制剂单独或与蛋白酶体抑制剂特异性组合的抗MM活性。这些研究将为DAC 3抑制剂治疗MM的衍生临床试验提供基础。我们最近在短短两年内将DAC 6抑制剂ACY-1215从实验室转化为I/II期临床试验，并将以类似的方式迅速关注DAC 3生物学和作为MM新临床靶点的潜力。

DESCRIPTION (provided by applicant): 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.