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

缺乏有效的系统治疗是遗传复杂软组织疾病中尚未解决的主要临床问题。 组织肉瘤（STS）。虽然临床和生物学上存在差异，但总体而言，该STS子集的典型代表为 攻击性行为，高复发率和转移性扩散，以及对化疗的抵抗， 导致预后不佳。几十年来，总生存率一直停留在5年50%的水平， 不能手术的STS通常是致命的考虑到分子的异质性和调控的复杂性， 针对这些STS，针对共同的统一细胞去调节过程的治疗策略是合乎逻辑的， approach.临床前研究表明广谱组蛋白去乙酰化酶具有很好的治疗作用 针对多种STS组织学的HDACIs。重要的是，发现HDACis使STS敏感 细胞在体外和体内临床上使用的常规化疗（例如阿霉素）。当前 应用程序旨在通过第二阶段临床试验将这些发现转化为临床， HDACi联合化疗治疗晚期STS患者;分子相关性预测 将阐明对这种新的治疗方法的反应/抗性。特别是转移性的 平滑肌肉瘤（LMS）患者，一个相对同质的队列，代表遗传复杂的 STS将被纳入这项“原理证明”研究，该研究将由多机构SARC支持 赞助这项申请。此外，研究将集中在评估HDACi诱导的 治疗反应中的自噬。初步研究表明，这一过程证实 STS中的治疗耐受性;如果是这样，自噬阻断可能进一步增强HDACI效应。最后是 HDAC是一个蛋白质家族;目前在临床测试中的大多数HDAC阻断了多个 HDAC同种型。尽管这些药物前景看好，但仍需要提高其治疗指数 考虑到它们的潜在毒性。一种这样的增强可以源自靶向单个HDAC同种型。 在令人兴奋的初始数据的支持下，这里提出的研究针对一种特征不佳的HDAC亚型， HDACS;研究HDACS特异性抑制剂目前可用。总体而言， 本研究的长期目标是推进STS治疗，改善患者的预后。建筑 关于实质性的初步见解和独特的STS模型和生物资源的可用性， 结合“低”和“高”通量实验，设计了相应的实验方案。 提出了三个具体目的：1）评价HDACi/阿霉素组合在患者中的活性 2）检查自噬作为促进HDACi的新过程的作用 耐受性：3）确定HDACS阻断对体外和体内STS生长的影响。

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.