(P 31) TARGETING CANCER STEM CELLS BY TYROSINE PEPTIDE ANALOGUE IN REFRACTORY SARCOMA

Objective: Disease recurrence in aggressive sarcomas following conventional therapies remains common among cancer patients and is often accompanied by tumor regrowth and metastatic spread. Cancer relapse is frequently linked to drug resistance, driven by small population of cancer stem cells (CSC). We have recently shown that a tyrosine peptide analogue (TPA), developed in our laboratory, specifically targets CSC’s.The purpose of this study was to explore TPA’s effect on tumor growth of human HT1080 fibrosarcoma, dedifferentiated chondrosarcoma with fibroblastic features cell line xenograft mouse model.

Methods: In our primary tumor growth model, luciferase-labeled human fibrosarcoma HT1080 cells were xenografted in the quadriceps of immunocompromised mice. Doxorubicin (DOX) was delivered intravenously while TPA systemically using osmotic minipumps transplanted subcutaneously. To generate a model for relapsed tumors, cells obtained from orthotopic tumors that had regrown after two rounds of DOX were isolated, expanded in vitro and reinjected in mice orthotopically.For the experimental metastasis model, luciferase-labeled HT1080 cells were injected intravenously .

Results: Our results show that TPA inhibits CSC growth by reducing drastically expression of the polycomb group protein enhancer of zester (EZH2) and its downstream cancer stem marker ALDH1A1, along with embryonic transcription factor NANOG. Moreover, TPA when dosed at 40µg/ml and higher prevented spheroid formation. The combination of TPA and DOX led to a seven-fold decrease in primary tumor burden with 2- fold, and in experimental metastatic model 3-fold improvement in overall survival.

Conclusion: In combination with DOX, TPA significantly decreased tumor growth and extended overall survival in both primary and metastatic models.Future studies will shed light on the ability of TPA to prevent metastatic formation Combining conventional chemotherapy drugs with CSC targeting agents is predicted to be more effective as it targets both CSC and non-CSC.