Functional and biologic significance of deacetylase3 inhibition in myeloma

脱乙酰酶 3 抑制在骨髓瘤中的功能和生物学意义

基本信息

批准号：
9320918
负责人：
KENNETH C. ANDERSON
金额：
$ 35.33万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9320918
关键词：
Acetylation Adverse effects Aftercare Amino Acids Binding Biological Biological Markers Biology Bone Marrow Bortezomib Cell Culture Techniques Cells Clinical Clinical Trials Complex Country Deacetylase Development Diarrhea Dose-Limiting Drug resistance Dynein ATPase Epigenetic Process FDA approved Fatigue Genetic Genetic Transcription Goals Hematologic Neoplasms Heterogeneity Histone H3 Human In Vitro Incidence Lysine Malignant Neoplasms Methylation Modeling Molecular Multiple Myeloma Mus Pathogenesis Patient-Focused Outcomes Pattern Persons Pharmaceutical Preparations Phase Plasma Cells Plasmacytoma Play Pre-Clinical Model Proteasome Inhibitor Protein Acetylation Protein Isoforms Proteins Proteomics Refractory Relapse Role Signal Transduction Stable Isotope Labeling System Thalidomide Therapeutic Agents Thrombocytopenia Toxic effect Transcriptional Activation Translating Translations Treatment Protocols Tubulin Ubiquitinated Protein Degradation Validation Vorinostat Xenograft Model Xenograft procedure base cell growth cell motility cytotoxicity design histone modification immunoregulation improved in vitro Model in vitro activity in vivo in vivo Model inhibitor/antagonist knock-down lenalidomide loss of function molecular targeted therapies neoplastic cell non-histone protein novel novel therapeutics potential biomarker pre-clinical preclinical study prototype public health relevance research clinical testing screening small hairpin RNA small molecule inhibitor treatment strategy tubacin

项目摘要

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.

描述（由申请人提供）：多发性骨髓瘤（MM）是第二常见的血液恶性肿瘤，尽管有蛋白酶体抑制剂（硼替佐米）和免疫调节药物（沙利度胺、来那度胺）等新药，但仍无法治愈。因此，迫切需要基于生物学的新型治疗策略来改善 MM 患者的预后。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着的抗MM效果；然而，由于广泛抑制 DAC 亚型所带来的不良毒性，包括疲劳、腹泻和血小板减少症，它们的临床活性受到限制。我们在此假设异构体选择性 DAC 抑制可以避免这些副作用，同时保持有效的抗 MM 细胞毒性。我们之前已经证明，DAC6 选择性抑制剂（tubacin、ACY-1215）与硼替佐米联合使用显示出显着的抗 MM 活性，并在临床前研究中证明了其机制。重要的是，我们已迅速将 ACY-1215 单独或与硼替佐米联合应用进行临床试验，显示出良好的耐受性和有前景的临床活性。在我们的初步研究中，DAC3 选择性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着的 MM 细胞生长抑制作用。在 Aim1 中，我们将进一步验证 DAC3 选择性敲低及其对 MM 细胞生长、存活和耐药性的功能影响，并描述观察到的效果的转录和分子信号传导机制。在 Aim2 中，我们将使用我们在骨髓微环境中建立的体外 MM 系统，单独或组合开发和验证新型 DAC3 选择性抑制剂。在目标 3 中，我们将验证 DAC3 选择性抑制剂单独或与蛋白酶体抑制剂联合使用的体内抗 MM 活性。这些研究将为DAC3抑制剂治疗MM的衍生临床试验提供基础。最近，我们仅用了两年时间就将 DAC6 抑制剂 ACY-1215 从实验室转化为 I/II 期临床试验，并且我们将以类似的方式快速关注 DAC3 生物学及其作为 MM 新型临床靶点的潜力。