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

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 in vivo 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.

• Authors: 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 Said, Ted 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
• Journal: Molecular oncology (Mol Oncol) Vol. 7 Issue 4 Pg. 776-90 (Aug 2013) ISSN: 1878-0261 [Electronic] United States
• PMID: 23607916 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Chemical References

• Antibodies, Monoclonal, Humanized
• Gonanes
• PX-866
• Phosphoinositide-3 Kinase Inhibitors
• Receptor, Notch1
• Receptor, Notch2
• EGFR protein, mouse
• ErbB Receptors
• Cetuximab

Topics

• Alphapapillomavirus (pathogenicity)
• Animals
• Antibodies, Monoclonal, Humanized (therapeutic use)
• Blotting, Western
• Carcinoma, Squamous Cell (drug therapy, virology)
• Cetuximab
• Computational Biology
• ErbB Receptors (genetics, metabolism)
• Gonanes (pharmacology)
• Head and Neck Neoplasms (drug therapy, virology)
• Humans
• Immunohistochemistry
• Mice
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Receptor, Notch1 (genetics, metabolism)
• Receptor, Notch2 (genetics, metabolism)
• Squamous Cell Carcinoma of Head and Neck
• Xenograft Model Antitumor Assays