Histone deacetylase inhibitor (HDACi)-based therapeutic strategies for the treat

基于组蛋白脱乙酰酶抑制剂 (HDACi) 的治疗策略

• 批准号: 8395367
• 负责人: Dina Chelouche Lev
• 金额: $ 26.22万
• 依托单位: SARC
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-26 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8395367
• 关键词: Aggressive behavior; Aneuploidy; Apoptosis; Autophagocytosis; Cell Line; Cells; Chloroquine; Clinic; Clinical; Clinical Trials; Complex; Cytotoxic agent; Data; Doxorubicin; Family; Future; Gene Expression Profile; Goals; Growth; Heterogeneity; Histologic; Histology; Histone Deacetylase; Histone Deacetylase Inhibitor; Human; In Vitro; Individual; Investigation; Karyotype; Knowledge; Malignant Neoplasms; Medical; Metastatic Leiomyosarcoma; Modeling; Molecular; Outcome; Patients; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Process; Progression-Free Survivals; Protein Family; Protein Isoforms; Proteins; Reaction Time; Recurrence; Resistance; Role; Safety; Systemic Therapy; Testing; Therapeutic; Therapeutic Index; Toxic effect; Translating; Vorinostat; advanced disease; base; chemotherapy; cohort; effective therapy; fusion gene; improved; in vivo; inhibitor/antagonist; innovation; insight; leiomyosarcoma; molecular marker; novel; novel therapeutic intervention; oncology; outcome forecast; pre-clinical; preclinical study; research clinical testing; response; sarcoma; single molecule; small molecule; soft tissue; synergism; treatment strategy; tumor; tumor growth; tumorigenic

The lack of effective systemic therapies is the major unresolved clinical problem in genetically complex soft tissue sarcoma (STSs). While clinically and biologically diverse, collectively this STS subset is typified by aggressive behavior, a high rate of recurrence and metastatic spread, and resistance to chemotherapy, resulting in a dismal prognosis. Overall survival has stagnated at the 5 year 50% level for decades and inoperable STSs are universally fatal. Considering the molecular heterogeneity and regulatory intricacy of these STSs, treatment strategies that target common unifying cellular deregulatory processes are a logical approach. Preclinical studies suggest a promising therapeutic role for broad spectrum histone deacetylase inhibitors (HDACIs) against multiple STS histologies. Importantly, HDACis were found to sensitize STS cells to clinically utilized conventional chemotherapies (e.g. doxorubicin) in vitro and in vivo. The current application aims to translate these findings into the clinic through a phase-ll clinical trial testing a combination of HDACi and chemotherapy in patients with advanced STS; molecular correlates predicting response/resistance to this novel therapeutic approach will be elucidated. Specifically, metastatic leiomyosarcoma (LMS) patients, a relatively homogenous cohort representative of genetically complex STS will be included in this 'proof of principle' study which will be enabled by the multi-institutional SARC sponsorship of this application. In addition, investigations will focus on evaluating the role of HDACiinduced autophagy in therapeutic response. Preliminary studies suggest that this process confirms therapeutic tolerance in STS; if so, autophagy blockade might further enhance HDACI effects. Finally, it is pertinent that HDACs are a family of proteins; most of the HDACis currently in clinical testing block multiple HDAC isoforms. Despite their promise, improvement in the therapeutic index of these drugs is needed given their potential toxicities. One such augmentation may derive from targeting a single HDAC isoform. Buttressed by exciting initial data, studies proposed here target one poorly characterized HDAC isoform, HDACS; investigational HDACS-specific inhibitors are currently available. Taken together, the overarching long term goal of the proposed studies is to advance STS therapy and improve patients' outcome. Building on substantial preliminary insights and the availability of unique STS models and bioresources, a translationally relevant plan has been devised combining 'low' and 'high' throughput experimentation. Three Specific Aims are proposed: 1) Evaluate the activity of an HDACi/doxorubicin combination in patients with metastatic LMS; 2) Examine the role of autophagy as a novel process contributing to HDACi tolerance: 3) Determine the impact of HDACS blockade on STS growth in vitro and in vivo.

缺乏有效的全身疗法是遗传复杂软的主要未解决的临床问题 组织肉瘤（STSS）。虽然在临床和生物学上多样化，但该STS子集的含义是 侵略性行为，高复发率和转移性扩散率以及对化学疗法的抵抗力， 导致惨淡的预后。数十年来，总体生存一直停滞在5年的50％水平上， 无法使用的STS普遍致命。考虑分子异质性和调节性的复杂性 这些STS，靶向常见统一细胞放松管制过程的治疗策略是合乎逻辑的 方法。临床前研究表明，广谱组蛋白脱乙酰基酶的有希望的治疗作用 针对多个STS组织学的抑制剂（HDACIS）。重要的是，发现hdacis敏感 细胞在体外和体内进行临床利用的常规化学疗法（例如阿霉素）。电流 应用程序旨在通过一阶段LL临床试验将这些发现转化为诊所 晚期STS患者HDACI和化学疗法的组合；分子相关的预测 将阐明对这种新型治疗方法的反应/抗性。具体而言，转移性 平滑肌肉瘤（LMS）患者，一位相对同质的遗传复杂代表 STS将包括在此“原则证明”研究中，该研究将由多机构SARC启用 赞助此应用程序。此外，调查将重点侧重于评估HDACI诱导的作用 自噬在治疗反应中。初步研究表明，此过程证实了 STS的治疗耐受性；如果是这样，自噬封锁可能会进一步增强HDACI效应。最后，是 HDAC是一个蛋白质家族的相关；目前在临床测试块中的大多数HDACI多数 HDAC同工型。尽管他们承诺，但仍需要改善这些药物的治疗指数 考虑到它们的潜在毒性。一种这样的增强可能来自靶向单个HDAC同工型。 在令人兴奋的初始数据的支撑下，这里提出的研究目标是一种特征不佳的HDAC同工型， HDACS;目前可以使用研究性HDACS特异性抑制剂。两者一起，总体 拟议的研究的长期目标是提高STS治疗并改善患者的结果。建筑 关于实质的初步见解以及独特的STS模型和生物包的可用性 翻译相关的计划已被设计结合了“低”和“高”吞吐量实验。 提出了三个具体目的：1）评估患者HDACI/阿霉素组合的活性 与转移性LMS； 2）研究自噬作为有助于HDACI的新过程的作用 公差：3）确定HDAC阻断对体外和体内STS生长的影响。