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.
|Choy, Edwin; Ballman, Karla; Chen, James et al. (2018) SARC018_SPORE02: Phase II Study of Mocetinostat Administered with Gemcitabine for Patients with Metastatic Leiomyosarcoma with Progression or Relapse following Prior Treatment with Gemcitabine-Containing Therapy. Sarcoma 2018:2068517|
|Yu, Peter Y; Lopez, Gonzalo; Braggio, Danielle et al. (2018) miR-133a function in the pathogenesis of dedifferentiated liposarcoma. Cancer Cell Int 18:89|
|Ignatius, Myron S; Hayes, Madeline N; Moore, Finola E et al. (2018) tp53 deficiency causes a wide tumor spectrum and increases embryonal rhabdomyosarcoma metastasis in zebrafish. Elife 7:|
|Hawkins, Allegra G; Basrur, Venkatesha; da Veiga Leprevost, Felipe et al. (2018) The Ewing Sarcoma Secretome and Its Response to Activation of Wnt/beta-catenin Signaling. Mol Cell Proteomics 17:901-912|
|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|
|Heinrich, Michael C; Rankin, Cathryn; Blanke, Charles D et al. (2017) Correlation of Long-term Results of Imatinib in Advanced Gastrointestinal Stromal Tumors With Next-Generation Sequencing Results: Analysis of Phase 3 SWOG Intergroup Trial S0033. JAMA Oncol 3:944-952|
|Berberoglu, Michael A; Gallagher, Thomas L; Morrow, Zachary T et al. (2017) Satellite-like cells contribute to pax7-dependent skeletal muscle repair in adult zebrafish. Dev Biol 424:162-180|
|Lopez, Gonzalo; Pollock, Raphael E (2017) Evaluating the Effect of HDAC8 Inhibition in Malignant Peripheral Nerve Sheath Tumors. Methods Mol Biol 1510:365-374|
|Tang, Fan; Choy, Edwin; Tu, Chongqi et al. (2017) Therapeutic applications of histone deacetylase inhibitors in sarcoma. Cancer Treat Rev 59:33-45|
|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|
Showing the most recent 10 out of 111 publications