The Dual Pi3k/Mtor Inhibitor, Pi-103, Demonstrates Therapeutic Efficacy In Undifferentiated Pleomorphic Sarcoma

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL The lack of effective systemic therapy is the major unresolved clinical problem in undifferentiated pleomorphic sarcoma (UPS)/malignant fibrohistocytoma (MFH). Novel effective therapeutic approaches are crucially needed. Given the heterogeneity of UPS/MFH, identifying common molecular deregulations amenable to therapeutic targeting would be of major importance. PI3K/AKT/mTOR pathway has been implicated in cancer progression and metastasis, and is highly activated in soft tissue sarcoma (STS). However, not much is known about this pathway in UPS/MFH specifically. We sought to assess AKT/mTOR pathway expression and activation in human UPS/MFH specimens and to evaluate whether combined inhibition of this pathway affects the proliferation and survival of UPS/MFH cells. Materials and methods: A UPS/MFH tissue microarray (TMA) consisting of 180 primary UPS/MFH samples from patients who underwent complete surgical resection has been used to detect the expression of phospho-AKT. Human UPS/MFH primary cell strains/cell lines and murine undifferentiated pleomorphic sarcoma cell lines have been established to determine the pro-tumorigenic effects of PI3K/AKT/mTOR intracellular signaling and to evaluate the efficacy of dual PI3K/mTOR inhibitor PI-103 on cell growth and survival. Results: Phospho-AKT was found to be commonly expressed in UPS/MFH. Enhanced pAKT expression levels inversely correlated with shorter 5-yr disease specific survival (DSS). Phosphorylation of AKT, p70S6K and 4E-BP1 were observed in a panel of human UPS/MFH primary cell strains/cell lines and murine UPS cell lines. PI-103 inhibited PI3/AKT/mTOR pathway signaling in UPS/MFH as observed by WB analysis resulting in marked decrease in tumor cell proliferation, enhanced G1 phase cell cycle arrest, and abrogated migration and invasion. Interestingly, PI103 treatment resulted in decreased expression and activation of the tyrosine kinase receptors EGFR and c-MET. This novel finding suggests that a feedback loop may exist between AKT/mTOR and tyrosine kinase receptor expression. Conclusions: PI3K/AKT/mTOR pathway is a common molecular deregulation in the heterogeneous group of UPS/MFH. The Dual PI3K/mTOR inhibitor, PI-103, should be further be investigated for its anti-UPS/MFH effects. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4484. doi:10.1158/1538-7445.AM2011-4484