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.