Targeting cancer stem cells by TPA leads to inhibition of refractory sarcoma and extended overall survival

Refractory cancer recurrence in patients is a serious challenge in modern medicine. Tumor regrowth in a more aggressive and invasive drug-resistant form is caused by a specific sub-population of tumor cells defined as cancer stem cells (CSCs). While the role of CSCs in cancer relapse is recognized, the signaling pathways of CSCs-driven chemoresistance are less well understood. Moreover, there are no effective therapeutic strategies that involve specific inhibition of CSCs responsible for cancer recurrence and drug resistance. There is a clinical need to develop new therapies for patients with refractory sarcomas, particularly fibrosarcoma. These aggressive tumors, with poor overall survival, do not respond to conventional therapies. Standard systemic chemotherapy for these tumors includes doxorubicin (DOX). A Tyr peptide analog (TPA), developed in our laboratory, specifically targets CSCs by drastically reducing expression of the polycomb group protein enhancer of zester (EZH2) and its downstream targets, specifically ALDH1A1 and Nanog. In vivo experiments demonstrated that TPA inhibited tumor growth in nu/nu mice with relapsed DOX-treated fibrosarcoma 7-fold and led to improved overall (2-fold) survival. In an experimental metastatic model, the combination of TPA with DOX treatment extended overall survival 3-fold, suggesting that targeting CSC can become an effective strategy in the treatment of refractory/relapse fibrosarcoma.