Epithelioid Sarcomas (ESs) are characterized by a locally aggressive behavior and a propensity for lymphatic and metastatic spread. Current therapy follows general STS treatment guidelines with complete surgical resection being the desired (when possible) approach; the impact of chemotherapy and radiotherapy is not well defined, but seems minimal. Five-year survival rates of 60% to 75% have been reported. Survival continues to decrease with time and 10YDSS rates of ~40-50% have been observed, a critical factor when taking into account the commonly young age at ES presentation; proximal ES outcomes are even less favorable. Loss of INI1, the product of the hSNF5/SMARCB1/BAF47 gene first identified as a tumor suppressor in malignant rhabdoid tumors, has recently been demonstrated to occur in the majority of ES. This molecular alteration potentially drives a pro-tumorigenic intra-cellular epigenetic landscape. Our preliminary studies suggest that ES cells are markedly sensitive to histone deacetylase inhibition (HDACi) and we hypothesize that this occurs through the reversal of INI1-loss driven gene expression deregulations.
We propose the following molecularly-driven translational Aims:
Aim#1: To unravel INI1-loss dependent ES gene expression signatures and evaluate whether HDACis can reverse these pro-tumorigenic profiles and induce epigenetic reprogramming
Aim#2: To examine the effects of HDACis on ES cellular properties in vitro and on the growth, recurrence, and metastasis of ES in vivo
HDACi are currently being clinically tested as an anti-cancer therapeutic approach in a large and diverse array of malignancies. Insights derived from our proposed studies will enhance our understanding of ES biology and will hopefully lay the foundation for future HDACi-based clinical trials for ES.