Abstract 652: PI3K inhibition combined with either cetuximab or docetaxel in a direct patient tumor model of HPV-positive and negative head and neck cancers
Authors: Bowles Daniel W. , Keysar Stephen , Anderson Ryan , Sehrt Daniel , Helber Ryan , Song John , Hausman Diana F. , Peterson Scott , Jimeno Antonio 
Published: June 2012

Purpose: Data suggest that human papilloma virus (HPV)-positive head and neck squamous cell carcinomas (HNSCC) are distinct from HPV negative tumors. We have generated a direct patient tumor xenograft model (DPTM) of HNSCC. DPTM maintain tumor histology better than cell lines and are optimally positioned to investigate in vivo tumor sensitivity and changes in tumor initiating cell (TIC) biology in response to therapy based upon HPV status. Phosphatidyl inositol 3 kinase (PI3K) is a downstream signal of epidermal growth factor receptor (EGFR) that may play a critical role in TIC biology and resistance to chemotherapy or anti-EGFR monoclonal antibodies in HNSCC. PX-866 is an irreversible pan-isoform inhibitor of class 1 PI3K currently in early clinical trials. We aimed to test the in vivo efficacy of PX-866, cetuximab, docetaxel, or a combination of PX-866 and cetuximab or docetaxel. Methods: DPTM were left untreated or exposed to PX-866, docexatel, cetuximab, or a combination of PX-866 plus cetuximab or docetaxel for 25-29 days. Tumor measurements were taken twice weekly during therapy and thereafter until study conclusion. TIC population were determined by flow cytometry. Results: We have treated three DPTM (CUHN015, CUHN022, CUHN027) with PX-866, cetuximab, or PX-866 plus cetuximab, and three DPTM (CUHN004, CUHN011, CUHN015) with PX-866, docetaxel, or the combination of PX-866 plus docetaxel. Neither combination had increased toxicity compared with the single agents. All six untreated DPTM had rapid tumor growth. In two DPTM (CUHN015 and CUHN022) cetuximab was similar to no treatment, whereas single agent PX-866 was slightly more effective than no treatment in CUHN022 and significantly more effective in CUHN015. In CUHN027 both PX-866 and cetuximab arrested growth but the combination caused greater than 50% tumor reduction. The combination of cetuximab and PX-866 was more effective than cetuximab alone in all DPTM. Two xenografts treated with PX-866, docetaxel, or the combination showed decreased tumor growth with PX-866 compared to either docetaxel or no treatment (CUHN004 and CUHN015). In all three DTPM the combination of PX-866 and docetaxel was more effective than either single agent. In the HPV-positive xenograft (CUHN022) cetuximab had no effect. Treatment with chemotherapeutic agents induced TIC accumulation that was partially reversed by combination therapy. Conclusions: PX-866 was equal or superior to cetuximab or docetaxel at slowing tumor growth in 5 of 6 DPTM of HNSCC. The combination of PX-866 plus another agent was superior to single agent therapy in 5 of 6 DPTM. Cetuximab was more effective in HPV-negative cases. Correlations with pathway gene mutations and pharmacodynamic events, including pathway inhibition and TIC subpopulation dynamics, will be presented.

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 652. doi:10.1158/1538-7445.AM2011-652