Abstract LB-314: Preclinical investigation of antitumor effects of dual PI3K/mTOR inhibitor PF-04691502 in human xenograft and murine Pten/Tgfbr1 deficient head and neck cancer models.

Abstract

Abstract Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and has a 5-year survival rate of ~50%. Therapy for HNSCC has only improved marginally over the past four decades, due in part to treatment resistance because of tumor heterogeneity. As such, effort is being directed toward personalizing treatment regimens for individual HNSCC patients using tumor genotyping and targeted small molecule inhibitors of the most activated and deleterious tumor pathways. The PI3K-Akt-mTOR axis is one of the most frequently altered signaling cascades in HNSCC, with amplifications or mutations in >90% of HNSCC tumors, and plays an important role in its pathogenesis. Recent evidence also implicates TP53 underexpression or mutation in over 80% of HNSCC tumor samples. As such, PI3K/mTOR and TP53 pathways are important in HNSCC development and could serve as useful therapeutic targets. In this study, we investigate the in vitro and in vivo effects of a novel dual molecular antagonist of PI3K/mTOR, PF-04691502 (PF-502), on PI3K/mTOR targets, TP53 activity, and HNSCC tumorigenesis. A panel of HNSCC (UM-SCC) cell lines was surveyed, the majority of which exhibited elevated expression of PI3K/mTOR pathway proteins when compared to normal human oral keratinocytes. These proteins include PI3K p110α, pAKT(S473), pAKT(T308), pmTOR, p4EBP1(S65, T37/46), and pS6(S240/244). PF-502 inhibits phosphorylation of these PI3K/mTOR targets and induces TP53 and p73 expression in UM-SCC cell lines. PI3K/mTOR target inhibition and TP53/p73 induction is associated with decreased cellular proliferation by MTT assay and increased apoptosis by flow cytometry. TP53 inhibition by pifithrin-α or siRNA knockdown partially attenuates the effects of PF-502, supporting a role of TP53 in growth inhibition. The effects of PF-502 on tumorigenicity were examined in human HNSCC xenografts in SCID mice and in conditional double Pten/Tgfbr1 knockout mice (2cKO), which develop HNSCC spontaneously. PF-502 inhibited or prevented tumor growth and prolonged host survival. PF-502 decreased pAKT(S473), p4EBP1(T37/46), pS6(S240/244) and proliferation marker, Ki67, as well as increased expression of TP53, p73, and TUNEL staining for apoptosis in tumor specimens by immunohistochemistry. Thus, PF-502 improves survival and inhibits the development and progression of HNSCC in preclinical models. Inhibition of pAkt, p4EBP1, pS6, and induction of TP53 and p73 are linked with the antitumor effects of PF-502 in HNSCC in vitro and in vivo, warranting further investigation of PI3K/mTOR inhibitors in a clinical subset of HNSCC patients with overactivation of PI3K/mTOR pathway and repression of TP53. Supported by NIH Medical Research Scholars Program (RVB), NIDCD intramural project ZIA-DC-000073, 74 (CVW) and NIDCR intramural project ZIA-DE-000698 (ABK). Citation Format: Robert Vander Broek, Yansong Bian, Amanda Herzog, Bradford Hall, Jamie Coupar, Zhong Chen, Ashok B. Kulkarni, Carter Van Waes. Preclinical investigation of antitumor effects of dual PI3K/mTOR inhibitor PF-04691502 in human xenograft and murine Pten/Tgfbr1 deficient head and neck cancer models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-314. doi:10.1158/1538-7445.AM2013-LB-314