Abstract A248: Therapeutic effects of the dual phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor PF-04691502 on in vitro and in vivo models of head and neck squamous cell carcinoma.

Abstract

Abstract Purpose: The therapeutic potential of a novel dual inhibitor of PI3K and mTOR kinases, PF-04691502 (PF-502), was investigated in human head and neck squamous cell carcinomas (HNSCC), and a novel TGF-Receptor 1 and PTEN conditional knockout (2cKO) mouse model in which mice develop HNSCC with activation of the PI3K-mTOR pathway. Experimental Design: Human oral keratinocytes (HOK) and a panel of 9 UM-SCC cell lines were examined for activation of PI3K-mTOR signaling by Western blot. Cell proliferation was assessed by MTT assay. Human HNSCC xenografts were established utilizing 5×106 wtTP53 UM-SCC 1 and mtTP53 UM-SCC 46 cells implanted subcutaneously into the flank of SCID mice. A novel 2cKO transgenic mouse model was created by generating Tgfbr1/Pten 2cKO mice (K14-CreERtam;Tgfbr1f/f;Ptenf/f). PF-502 10 mg/kg in 0.5% methylcellulose vehicle or vehicle alone was administered by oral gavage daily for 21 days. Tumor volume, weight, and body conditioning score were measured on a M/W/F schedule. Tumor immunostaining for inhibition of PI3K-mTOR activation (pAKT, pS6) and proliferation (Ki67) was performed. Results: UM-SCC cell lines showed increased activation of the PI3K/Akt/mTOR pathway as compared with HOKs. Treatment of UM-SCC 1 and 46 with PF-502 decreased pAkt and pS6 and caused a significant decrease in cell density (IC50 1.9 uM and 0.60uM respectively). UM-SCC 1 xenograft mice treated with PF-502 showed a decreased average tumor volume of 0.96 ± 0.40 cm3 versus control, 2.49 ± 0.94 cm3 on day 21. Median survival was improved with PF-502 from 23 days to 32 days. PF-502 treatment in UM-SCC 46 xenograft mice decreased the average tumor volume of 0.36 ± 0.40 cm3 versus control at 0.55 ± 0.14 cm3 on day 21, but no survival advantage was found. In 2cKO mice, PF-502 decreased average tumor volume to 0.0036 ± 0.0005 cm3 as compared to 0.916 ± 0.060 cm3 tumor volume in control mice. HNSCC tumors in 2cKO mice on day 21 were reduced from an average of 3.23 tumors in control to 0.26 tumors in PF-502 treated mice. Median survival was also improved to 64 days with PF-502 as compared to 39 days in controls. Tumors harvested from UM-SCC 1 and 46 xenograft and 2cKO mice treated with PF-502 showed inhibition of the PI3K/Akt/mTOR pathway as evidenced by decreased pAkt and pS6, and decreased proliferation via Ki67. PF-502 caused limited or no significant weight loss or cachexia during treatment, or long term adverse effects up to 6 months after treatment. Conclusions: PI3K/mTOR pathway activation was observed in most HNSCC lines as compared with HOK cells. PF-502 inhibited the PI3K/mTOR signaling and cell density of human HNSCC cell lines in vitro. PF-502 blocked development of HNSCC in a novel 2cKO mouse model, and significantly inhibited tumor growth and improved survival in human UM-SCC 1 with wtTP53 when compared UM-SCC 46 mtTP53 xenograft tumors. PF-502 was tolerated without symptomatic weight loss at the dosage tested. These results suggest PI3K/mTOR activation is an important target for therapy in HNSCC. Supported by NIDCD project ZIA-DC-000016, NIDCR project ZIA-DE-000698, and Howard Hughes Medical Institute-NIH Scholars program (AH). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A248.