Functional and biologic significance of deacetylase3 inhibition in myeloma

描述(申请人提供)：多发性骨髓瘤(MM)是第二种最常见的血液系统恶性肿瘤，尽管有新的药物包括蛋白酶体抑制剂(Bortezomib)和免疫调节药物(沙利度胺、来那度胺)，但仍无法治愈。因此，迫切需要基于生物学的新的治疗策略来改善多发性骨髓瘤患者的预后。脱乙酰酶(DAC)抑制剂是一类在临床前研究中具有显著抗MM效果的新型药物，但由于DAC亚型的广泛抑制而引起的疲劳、腹泻和血小板减少等不良毒性限制了它们的临床活性。我们在此假设，选择性异构体DAC抑制可以避免这些副作用，同时保持强大的抗MM细胞毒性。我们之前已经证明DAC6选择性抑制剂(Tubacin，Acy-1215)与Bortezomib联合使用显示出显著的抗MM活性，并在临床前研究中证实了其机制。重要的是，我们已经将Acy-1215迅速转化为临床试验，无论是单独使用还是与Bortezomib一起使用，都显示出良好的耐受性和良好的临床活性。在我们的初步研究中，DAC3选择性基因敲除和小分子抑制剂BG45在体外和体内小鼠异种移植模型中显示出显著的抑制MM细胞生长的作用。在AIM1中，我们将进一步验证DAC3选择性敲除及其对MM细胞生长、存活和耐药性的功能影响，并阐明所观察到的影响的转录和分子信号机制。在AIM2中，我们将在骨髓微环境的背景下，利用我们建立的MM体外系统，单独和联合开发和验证新型的DAC3选择性抑制剂。在目标3中，我们将在体内验证DAC3选择性抑制剂的抗多发性骨髓瘤活性，单独或与蛋白酶体抑制剂联合使用。这些研究将为DAC3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DAC6抑制剂Acy-1215从试验台转移到I/II期临床试验，并将以类似的方式迅速关注DAC3的生物学和作为MM的新临床靶点的潜力。

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.