title: 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.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine (UCSOM), Aurora, CO 80045, United States.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Keysar
authors.forename: David P
authors.initials: DP
authors.lastname: Astling
authors.forename: Ryan T
authors.initials: RT
authors.lastname: Anderson
authors.forename: Brian W
authors.initials: BW
authors.lastname: Vogler
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Bowles
authors.forename: J Jason
authors.initials: JJ
authors.lastname: Morton
authors.forename: Jeramiah J
authors.initials: JJ
authors.lastname: Paylor
authors.forename: Magdalena J
authors.initials: MJ
authors.lastname: Glogowska
authors.forename: Phuong N
authors.initials: PN
authors.lastname: Le
authors.forename: Justin R
authors.initials: JR
authors.lastname: Eagles-Soukup
authors.forename: Severine L
authors.initials: SL
authors.lastname: Kako
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Takimoto
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Sehrt
authors.forename: Adrian
authors.initials: A
authors.lastname: Umpierrez
authors.forename: Morgan A
authors.initials: MA
authors.lastname: Pittman
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Macfadden
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Helber
authors.forename: Scott
authors.initials: S
authors.lastname: Peterson
authors.forename: Diana F
authors.initials: DF
authors.lastname: Hausman
authors.forename: Sherif
authors.initials: S
authors.lastname: Said
authors.forename: Ted H
authors.initials: TH
authors.lastname: Leem
authors.forename: Julie A
authors.initials: JA
authors.lastname: Goddard
authors.forename: John J
authors.initials: JJ
authors.lastname: Arcaroli
authors.forename: Wells A
authors.initials: WA
authors.lastname: Messersmith
authors.forename: William A
authors.initials: WA
authors.lastname: Robinson
authors.forename: Fred R
authors.initials: FR
authors.lastname: Hirsch
authors.forename: Marileila
authors.initials: M
authors.lastname: Varella-Garcia
authors.forename: David
authors.initials: D
authors.lastname: Raben
authors.forename: Xiao-Jing
authors.initials: XJ
authors.lastname: Wang
authors.forename: John I
authors.initials: JI
authors.lastname: Song
authors.forename: Aik-Choon
authors.initials: AC
authors.lastname: Tan
authors.forename: Antonio
authors.initials: A
authors.lastname: Jimeno
mesh_terms: D052685:Alphapapillomavirus / Q000472:pathogenicity; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000821:virology; D000068818:Cetuximab; D019295:Computational Biology; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D006067:Gonanes / Q000494:pharmacology; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism; D051883:Receptor, Notch2 / Q000235:genetics / Q000378:metabolism; D000077195:Squamous Cell Carcinoma of Head and Neck; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000068818:Cetuximab; D066246:ErbB Receptors; D006067:Gonanes; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051881:Receptor, Notch1; D051883:Receptor, Notch2; C496788:PX-866; C541485:EGFR protein, mouse
keywords: EGFR; Head and neck cancer; Human papillomavirus; NOTCH1; PI3K; Xenografts