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.
Knowledge gained will enhance the molecular understanding of genetically complex STS, generate insights into autophagy, identify HDACi mechanisms of function, response, and cytotoxic agent synergism, and will determine the impact of HDAC8-isoform specific inhibition. Most importantly, studies here will will form a novel platform for future human STS clinical trials and will hopefully significantly impact patient management.
|Schaefer, Inga-Marie; Mariño-Enríquez, Adrián; Fletcher, Jonathan A (2017) What is New in Gastrointestinal Stromal Tumor? Adv Anat Pathol 24:259-267|
|Ignatius, Myron S; Hayes, Madeline N; Lobbardi, Riadh et al. (2017) The NOTCH1/SNAIL1/MEF2C Pathway Regulates Growth and Self-Renewal in Embryonal Rhabdomyosarcoma. Cell Rep 19:2304-2318|
|Chen, James L; David, Jason; Cook-Spaeth, Douglas et al. (2017) Autophagy Induction Results in Enhanced Anoikis Resistance in Models of Peritoneal Disease. Mol Cancer Res 15:26-34|
|Alomari, Ahmed K; Brown, Noah; Andea, Aleodor A et al. (2017) Cutaneous syncytial myoepithelioma: A recently described neoplasm which may mimic nevoid melanoma and epithelioid sarcoma. J Cutan Pathol 44:892-897|
|Hayashi, Masanori; Baker, Alissa; Goldstein, Seth D et al. (2017) Inhibition of porcupine prolongs metastasis free survival in a mouse xenograft model of Ewing sarcoma. Oncotarget 8:78265-78276|
|Svoboda, Laurie K; Bailey, Natashay; Van Noord, Raelene A et al. (2017) Tumorigenicity of Ewing sarcoma is critically dependent on the trithorax proteins MLL1 and menin. Oncotarget 8:458-471|
|Schaefer, Inga-Marie; Wang, Yuexiang; Liang, Cher-Wei et al. (2017) MAX inactivation is an early event in GIST development that regulates p16 and cell proliferation. Nat Commun 8:14674|
|Davis, Lara E; Janeway, Katherine A; Weiss, Aaron R et al. (2017) Clinical trial enrollment of adolescents and young adults with sarcoma. Cancer 123:3434-3440|
|Haak, Andrew J; Appleton, Kathryn M; Lisabeth, Erika M et al. (2017) Pharmacological Inhibition of Myocardin-related Transcription Factor Pathway Blocks Lung Metastases of RhoC-Overexpressing Melanoma. Mol Cancer Ther 16:193-204|
|Lee, Jen-Chieh; Li, Chien-Feng; Huang, Hsuan-Ying et al. (2017) ALK oncoproteins in atypical inflammatory myofibroblastic tumours: novel RRBP1-ALK fusions in epithelioid inflammatory myofibroblastic sarcoma. J Pathol 241:316-323|
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