Abstract 1929: Tyrosine kinase inhibition with sorafenib but not pazopanib enriches for sarcoma cancer stem cells in diverse models of soft tissue sarcoma

Abstract

Abstract Purpose: Cancer stem cells (CSCs) are a putative source of resistance and relapse following conventional anti-proliferative therapies. We hypothesized that anti-proliferative, but not anti-angiogenic, tyrosine kinase inhibitors would enrich for CSCs in models of soft tissue sarcoma. Experimental Design: We exposed multiple human sarcoma cell lines to sorafenib and pazopanib and assessed cell viability and expression of CSC markers. We exposed mice harboring lung/liver Ewing's sarcoma metastases to daily sorafenib and evaluated survival and CSC expression. We exposed dissociated primary sarcoma tumors to overnight sorafenib and pazopanib. We used tissue microarray (TMA) to evaluate the frequency and intensity of CSC markers in clinical sarcoma samples after neoadjuvant therapy with sorafenib. Results: Viability following sorafenib exposure in vitro ranged from 1 - 20% with a corresponding 2 - 8.2 fold increase in ALDHbright cells from baseline (P<0.05), while negligible effects from pazopanib were observed. In vivo, sorafenib treatment improved median survival by 10 days (P<0.05), but increased the population of ALDHbright cells 2.5 - 2.8 fold (P<0.05). Analysis of primary human sarcoma samples revealed direct cytotoxicity following exposure to sorafenib with a corresponding increase in ALDHbright cells (P<0.05). Again, negligible effects from pazopanib were observed. TMA analysis of clinical sarcoma specimens demonstrated significant enrichment for ALDHbright cells in the post-treatment resection specimen following neoadjuvant therapy including sorafenib (P<0.05). Conclusions: Sorafenib, but not pazopanib, exerts a direct anti-proliferative effect on sarcoma cells with a corresponding enrichment in sarcoma CSCs. Sustained anti-sarcoma therapeutic effects may require targeting of the CSC population in combination with cytotoxic treatments. Note: This abstract was not presented at the meeting. Citation Format: Robert J. Canter, Erik Ames, Stephanie Mac, Steve K. Grossenbacher, Mingyi Chen, Joe Tellez, Arta M. Monjazeb, William J. Murphy. Tyrosine kinase inhibition with sorafenib but not pazopanib enriches for sarcoma cancer stem cells in diverse models of soft tissue sarcoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1929. doi:10.1158/1538-7445.AM2014-1929