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.

缺乏有效的系统治疗是遗传性复杂软组织尚未解决的主要临床问题。 组织肉瘤(STSS)。虽然在临床和生物学上是不同的，但总的来说，这个STS亚群的典型特征是 攻击性行为，高复发率和转移性扩散，以及对化疗的耐药性， 导致了一个糟糕的预后。几十年来，总存活率一直停滞不前在5年50%的水平上 无法手术的STS普遍是致命的。考虑到分子的异质性和调控的复杂性 这些针对共同统一的细胞放松调控过程的STSS、治疗策略是合乎逻辑的 接近。临床前研究表明广谱组蛋白脱乙酰酶具有良好的治疗作用 抗多种STS组织学的抑制剂(HDACI)。重要的是，HDACi被发现能敏感性传播疾病 细胞在体外和体内临床应用常规化疗药物(如阿霉素)。海流 应用程序旨在通过二期临床试验将这些发现转化为临床试验 晚期STS患者的HDACI联合化疗：分子相关性预测 对这种新的治疗方法的反应/抗药性将被阐明。具体地说，转移的 平滑肌肉瘤(LMS)患者，基因复杂的相对同源队列的代表 STS将被包括在这项由多机构SARC支持的“原则证明”研究中 此应用程序的赞助商。此外，调查将集中于评估HDACI诱导的作用 治疗反应中的自噬。初步研究表明，这一过程证实了 STS的治疗耐受性；如果是这样的话，自噬阻断可能会进一步增强HDACi的效果。最后，它是 与此相关的是，HDAC是一个蛋白质家族；大多数HDAC目前正在进行临床测试，阻止了多个 HDAC亚型。尽管这些药物前景看好，但仍需改进其治疗指数。 考虑到它们的潜在毒性。一种这样的扩增可能源于靶向单一的HDAC亚型。 在令人兴奋的初始数据的支持下，这里提出的研究针对的是一种特征不佳的HDAC亚型， HDACs；研究中的HDACs特异性抑制剂目前可用。总而言之，最重要的是 拟议研究的长期目标是推进STS治疗并改善患者的预后。建房 关于实质性的初步见解以及独特的STS模式和生物资源的可用性，a 结合“低”和“高”吞吐量实验，设计了与翻译相关的计划。 提出了三个具体目标：1)评估HDACi/阿霉素联合疗法在患者中的活性 与转移性LMS；2)研究自噬作为促进HDACI的新过程的作用 耐受性：3)测定HDAC阻断对体内外STS生长的影响。