A patient tumor transplant model of squamous cell cancer identifies PI3K inhibitors as candidate therapeutics in defined molecular bins

Stephen B. Keysar, David P. Astling, Ryan T. Anderson, Brian W. Vogler, Daniel W. Bowles, J. Jason Morton, Jeramiah J. Paylor, Magdalena J. Glogowska, Phuong N. Le, Justin R. Eagles-Soukup, Severine L. Kako, Sarah M. Takimoto, Daniel B. Sehrt, Adrian Umpierrez, Morgan A. Pittman, Sarah M. Macfadden, Ryan M. Helber, Scott Peterson, Diana F. Hausman, Sherif SaidTed H. Leem, Julie A. Goddard, John J. Arcaroli, Wells A. Messersmith, William A. Robinson, Fred R. Hirsch, Marileila Varella-Garcia, David Raben, Xiao Jing Wang, John I. Song, Aik Choon Tan, Antonio Jimeno

Research output: Contribution to journalArticle

94 Citations (Scopus)

Abstract

Targeted therapy development in head and neck squamous cell carcinoma (HNSCC) is challenging given the rarity of activating mutations. Additionally, HNSCC incidence is increasing related to human papillomavirus (HPV). We sought to develop an invivo model derived from patients reflecting the evolving HNSCC epidemiologic landscape, and use it to identify new therapies. Primary and relapsed tumors from HNSCC patients, both HPV+ and HPV-, were implanted on mice, giving rise to 25 strains. Resulting xenografts were characterized by detecting key mutations, measuring protein expression by IHC and gene expression/pathway analysis by mRNA-sequencing. Drug efficacy studies were run with representative xenografts using the approved drug cetuximab as well as the new PI3K inhibitor PX-866. Tumors maintained their original morphology, genetic profiles and drug susceptibilities through serial passaging. The genetic makeup of these tumors was consistent with known frequencies of TP53, PI3KCA, NOTCH1 and NOTCH2 mutations. Because the EGFR inhibitor cetuximab is a standard HNSCC therapy, we tested its efficacy and observed a wide spectrum of efficacy. Cetuximab-resistant strains had higher PI3K/Akt pathway gene expression and protein activation than cetuximab-sensitive strains. The PI3K inhibitor PX-866 had anti-tumor efficacy in HNSCC models with PIK3CA alterations. Finally, PI3K inhibition was effective in two cases with NOTCH1 inactivating mutations. In summary, we have developed an HNSCC model covering its clinical spectrum whose major genetic alterations and susceptibility to anticancer agents represent contemporary HNSCC. This model enables to prospectively test therapeutic-oriented hypotheses leading to personalized medicine.

Original languageEnglish
Pages (from-to)776-790
Number of pages15
JournalMolecular Oncology
Volume7
Issue number4
DOIs
Publication statusPublished - 2013 Aug

Keywords

  • EGFR
  • Head and neck cancer
  • Human papillomavirus
  • NOTCH1
  • PI3K
  • Xenografts

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Oncology
  • Cancer Research

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  • Cite this

    Keysar, S. B., Astling, D. P., Anderson, R. T., Vogler, B. W., Bowles, D. W., Morton, J. J., Paylor, J. J., Glogowska, M. J., Le, P. N., Eagles-Soukup, J. R., Kako, S. L., Takimoto, S. M., Sehrt, D. B., Umpierrez, A., Pittman, M. A., Macfadden, S. M., Helber, R. M., Peterson, S., Hausman, D. F., ... Jimeno, A. (2013). A patient tumor transplant model of squamous cell cancer identifies PI3K inhibitors as candidate therapeutics in defined molecular bins. Molecular Oncology, 7(4), 776-790. https://doi.org/10.1016/j.molonc.2013.03.004